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As confidentially submitted as Revision No. 1 to the confidential submission to the Securities and Exchange Commission on February 2, 2015

Registration No. 333-            

 

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

 

FORM S-1

REGISTRATION STATEMENT

Under

The Securities Act of 1933

 

 

ATYR PHARMA, INC.

(Exact name of registrant as specified in its charter)

 

 

 

Delaware		2836		20-3435077
(State or other jurisdiction of incorporation or organization)		(Primary Standard Industrial Classification Code Number)		(I.R.S. Employer Identification Number)

3545 John Hopkins Court, Suite #250

San Diego, CA 92121

(858) 731-8389

(Address, including zip code, and telephone number, including area code, of registrant’s principal executive offices)

 

 

John D. Mendlein, Ph.D.

Chief Executive Officer and Executive Chairman

3545 John Hopkins Court, Suite #250

San Diego, CA 92121

(858) 731-8389

(Name, address, including zip code, and telephone number, including area code, of agent for service)

 

 

Copies to:

 

Kingsley L. Taft Maggie L. Wong Mitzi Chang Goodwin Procter LLP 3 Embarcadero Center, 24th Floor San Francisco, CA 94111 (415) 733-6000		Nancy D. Krueger Vice President, Legal Affairs aTyr Pharma, Inc. 3545 John Hopkins Court, Suite #250 San Diego, CA 92121 (858) 731-8389		Alan F. Denenberg Davis Polk & Wardwell LLP 1600 El Camino Real Menlo Park, CA 94025 (650) 752-2000

 

Approximate date of commencement of proposed sale to the public: As soon as practicable after the effective date of this registration statement.

If any of the securities being registered on this Form are to be offered on a delayed or continuous basis pursuant to Rule 415 under the Securities Act of 1933, as amended, check the following box.  ¨

If this Form is filed to register additional securities for an offering pursuant to Rule 462(b) under the Securities Act, please check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.  ¨

If this Form is a post-effective amendment filed pursuant to Rule 462(c) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.  ¨

If this form is a post-effective amendment filed pursuant to Rule 462(d) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.  ¨

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller reporting company. See the definitions of “large accelerated filer,” “accelerated filer” and “smaller reporting company” in Rule 12b-2 of the Exchange Act.

 

Large Accelerated Filer		¨		Accelerated Filer		¨
Non-Accelerated Filer		x  (Do not check if a smaller reporting company)		Smaller Reporting Company		¨

 

 

CALCULATION OF REGISTRATION FEE

 

Title of Each Class of Securities to be Registered		Proposed Maximum Aggregate Offering Price (1)(2)		Amount of Registration Fee
Common Stock, par value $0.001 per share		$		$

(1)	Estimated solely for the purpose of calculating the registration fee pursuant to Rule 457(o) under the Securities Act.

(2)	Includes the offering price of shares that the underwriters may purchase pursuant to an over-allotment option.

 

 

The registrant hereby amends this registration statement on such date or dates as may be necessary to delay its effective date until the registrant shall file a further amendment which specifically states that this registration statement shall thereafter become effective in accordance with Section 8(a) of the Securities Act of 1933 or until this registration statement shall become effective on such date as the Commission, acting pursuant to said Section 8(a), may determine.

 

 

 

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The information in this preliminary prospectus is not complete and may be changed. We may not sell these securities until the registration statement filed with the Securities and Exchange Commission is effective. This preliminary prospectus is not an offer to sell nor does it seek an offer to buy these securities in any jurisdiction where the offer or sale is not permitted.

 

Subject to completion, dated                     , 2015

Preliminary Prospectus

            Shares

 

Common Stock

 

 

This is the initial public offering of shares of common stock of aTyr Pharma, Inc. We are offering shares to be sold in this offering. Prior to this offering, there has been no public market for our common stock. The initial public offering price of our common stock is expected to be between $         and $         per share. We intend to apply to list our common stock on The NASDAQ Global Market under the symbol “LIFE.”

We are an “emerging growth company” under applicable Securities and Exchange Commission rules and will be subject to reduced public company reporting requirements.

 

		Per share				Total
Initial public offering price		$				$
Underwriting discounts and commissions (1)		$				$
Proceeds to aTyr, before expenses		$				$

 

(1)	See “Underwriting” for additional disclosure regarding underwriting discounts, commissions and estimated offering expenses.

The underwriters may also purchase up to an additional             shares from us at the public offering price, less the underwriting discount, within 30 days from the date of this prospectus to cover over-allotments.

 

 

Investing in our common stock involves a high degree of risk. See “Risk Factors” beginning on page 11.

Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or determined if this prospectus is truthful or complete. Any representation to the contrary is a criminal offense.

The underwriters expect to deliver the shares on or about                     , 2015.

 

 

 

J.P. Morgan		Deutsche Bank Securities
BMO Capital Markets
William Blair

                    , 2015

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TABLE OF CONTENTS

 

		Page
Prospectus Summary			1
Risk Factors			11
Special Note Regarding Forward-Looking Statements			51
Use of Proceeds			53
Dividend Policy			55
Capitalization			56
Dilution			58
Selected Consolidated Financial Data			60
Management’s Discussion and Analysis of Financial Condition and Results of Operations			62
Business			77
Management			117
Executive and Director Compensation			125
Certain Relationships and Related Party Transactions			133
Principal Stockholders			136
Description of Capital Stock			140
Shares Eligible for Future Sale			146
Certain Material United States Federal Income Tax Considerations for Non-U.S. Holders			148
Underwriting			151
Legal Matters			157
Experts			157
Where You Can Find More Information			157
Index to Consolidated Financial Statements			F-1

Through and including                     , 2015 (the 25th day after the date of this prospectus), all dealers effecting transactions in these securities, whether or not participating in this offering, may be required to deliver a prospectus. This delivery requirement is in addition to the obligation of dealers to deliver a prospectus when acting as underwriters and with respect to their unsold allotments or subscriptions.

 

 

You should rely only on the information contained in this prospectus or in any free writing prospectus we file with the Securities and Exchange Commission. Neither we nor the underwriters have authorized anyone to provide you with information different from that contained in this prospectus or any free writing prospectus. We take no responsibility for, and can provide no assurance as to the reliability of, any other information that others may give you. We and the underwriters are offering to sell, and seeking offers to buy, common stock only in jurisdictions where offers and sales are permitted. The information contained in this prospectus is accurate only as of the date on the front cover page of this prospectus, or other earlier date stated in this prospectus, regardless of the time of delivery of this prospectus or of any sale of our common stock.

 

 

The market data and certain other statistical information used throughout this prospectus are based on independent industry publications, governmental publications, reports by market research firms or other independent sources. Some data are also based on our good faith estimates.

We own various U.S. federal trademark applications and unregistered trademarks, including our company name and Resolaris™. All other trademarks or trade names referred to in this prospectus are the property of their respective owners. Solely for convenience, the trademarks and trade names in this prospectus are referred to without the symbols ^® and ™, but such references should not be construed as any indicator that their respective owners will not assert, to the fullest extent under applicable law, their rights thereto.

 

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RISK FACTORS

Investing in our common stock involves a high degree of risk. You should carefully consider the risks described below along with all of the other information contained in this prospectus, including our consolidated financial statements and the related notes and “Management’s Discussion and Analysis of Financial Condition and Results of Operations,” before deciding whether to purchase our common stock. If any of the adverse events described in the following risk factors actually occurs, our business, results of operations and financial condition may suffer significantly. As a result, the trading price of our common stock could decline, and you may lose all or part of your investment in our common stock. Additional risks or uncertainties not presently known to us or that we do not currently deem material may also impair our business operations.

Risks related to the discovery, development and regulation of our product candidates

Resolaris and any other product candidates that we may develop from our Physiocrine discovery engine represent novel therapeutic approaches, which may cause significant delays or may not result in any commercially viable drugs.

We have concentrated our research and development efforts on Physiocrine biology, and our future success is highly dependent on the successful development of Physiocrine-based product candidates, including Resolaris and additional product candidates arising from the Resokine pathway. Physiocrine-based biology represents a novel approach to drug discovery and to our knowledge, no drugs have been developed using, or based upon, this approach. Despite the successful development of other naturally-occurring proteins, such as erythropoietin and insulin, as therapeutics, Physiocrines represent a novel class of protein therapeutics, and our development of these therapeutics is based on our new understanding of human physiology. In particular, the mechanism of action of Physiocrines and their role in immuno-modulation and tissue regeneration have not been studied extensively, nor has the safety of this class of protein therapeutics been evaluated extensively in humans. The Physiocrines that we elect to develop may not have the physiological functions that we currently ascribe to them, may have limited or no therapeutic applications, or may present safety problems of which we are not yet aware. We cannot be sure that our Physiocrine discovery engine will yield product candidates with therapeutic applications that are safe, effective, approvable by regulatory authorities, scalable, or profitable.

Because our technology and product candidates represent a new therapeutic approach, developing and commercializing our product candidates subjects us to a number of challenges, including:

 

•

defining indications within our targeted rare diseases and clinical endpoints within each indication that are appropriate to support regulatory approval;

 

•

obtaining regulatory approval from the U.S. Food and Drug Administration, or the FDA, and other regulatory authorities that have little or no experience with the development of Physiocrine-based therapeutics;

 

•

educating medical personnel regarding the potential side effect profile of each of our product candidates, such as the potential for the development of antibodies against our purified protein therapeutics;

 

•

developing processes for the safe administration of these product candidates, including long-term follow-up for all patients who receive our product candidates;

 

•

sourcing clinical and, if approved, commercial supplies for the materials used to manufacture and process our product candidates;

 

•

developing a manufacturing process and distribution network that ensures consistent manufacture of our product candidates in compliance with current Good Manufacturing Practices, or cGMPs, and related requirements, with a cost of goods that allows for an attractive return on investment;

 

•

establishing sales and marketing capabilities after obtaining any regulatory approval to gain market acceptance; and

 

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developing therapeutics for rare and more common diseases or indications beyond those addressed by our current product candidates.

Moreover, public perception of safety issues, including adoption of new therapeutics or novel approaches to treatment, may adversely influence the willingness of subjects to participate in clinical trials, or if approved, of physicians to adopt and prescribe novel therapeutics. Physicians, hospitals and third-party payors often are slow to adopt new products, technologies and treatment practices. Physicians may decide the therapy is too complex or unproven to adopt and may choose not to administer the therapy. Based on these and other factors, healthcare providers and payors may decide that the benefits of any Physiocrine-based therapeutic for which we receive regulatory approval do not or will not outweigh its costs.

We are highly dependent on the success of Resolaris, our first clinical product candidate, which is still in early clinical development. If we are unable to successfully complete clinical development, obtain regulatory or marketing approval for, or successfully commercialize, Resolaris, or experience significant delays in doing so, our business will be materially harmed.

To date, we have expended significant time, resources and effort on the discovery and development of Resolaris, including conducting preclinical studies and our Phase 1 clinical trial, and initiating and preparing for additional clinical trials. We have not yet commenced or completed any evaluation of Resolaris in human clinical trials designed to demonstrate efficacy to the satisfaction of the FDA. We currently generate no revenue from the sale of any product, and our ability to generate product revenues and to achieve commercial success, which we do not expect will occur for many years, if ever, will initially depend on our ability to successfully develop, obtain regulatory approval for and commercialize Resolaris for the treatment of one or more of our target rare disease indications in the United States and any foreign jurisdictions. Before we can market or sell Resolaris in the United States or foreign jurisdictions, we will need to commence and complete additional clinical trials (including larger, pivotal trials, which we have not yet commenced), manage clinical and manufacturing activities, obtain necessary regulatory approvals from the FDA in the United States and from similar regulatory authorities in other jurisdictions, obtain adequate clinical and commercial manufacturing supplies, build commercial capabilities, which may include entering into a marketing collaboration with a third party, and in some jurisdictions, obtain reimbursement authorization, among other things. We cannot assure you that we will be able to successfully complete the necessary clinical trials, obtain regulatory approvals, secure an adequate commercial supply for, or otherwise successfully commercialize, Resolaris. If we do not receive regulatory approvals for Resolaris, and even if we do obtain regulatory approvals, we may never generate significant revenues, if any, from commercial sales. If we fail to successfully commercialize Resolaris, we may be unable to generate sufficient revenues to sustain and grow our company, and our business, prospects, financial condition and results of operations will be adversely affected.

Data generated in our preclinical studies and patient sample data relating to the Resokine pathway may not be predictive of the immuno-modulatory activity or therapeutic effects, if any, of Resolaris in patients.

Our scientists discovered the Resokine pathway using in vivo screening systems designed to test potential immuno-modulatory activity in animal models of severe inflammation, combined with data relating to the potential blockade of the Resokine pathway in a population of patients with a particular rare myopathy, anti-synthetase syndrome with anti-Jo-1 antibodies. Translational medicine, or the application of basic scientific findings to develop therapeutics that promote human health, is subject to a number of inherent risks. In particular, scientific hypotheses formed from non-clinical observations may prove to be incorrect, and the data generated in animal models or observed in limited patient populations may not be applicable in clinical trials conducted under the controlled conditions required by applicable regulatory requirements and our protocols. For example, we have not studied the activity of the Resokine pathway in patients with rare genetic myopathies with an immune component, which forms the basis for our first clinical trial of Resolaris in facioscapulohumeral dystrophy, or FSHD, nor have we evaluated the activity of the Resokine pathway in patients with interstitial lung disease, or ILD. Our knowledge of the activity of this pathway in Jo-1 antibody patients may not be applicable to our target patient populations in rare genetic myopathies or rare pulmonary diseases with an immune component.

 

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Accordingly, the conclusions that we have drawn from animal studies and patient sample data regarding the potential immuno-modulatory activity of molecules containing the immono-modulatory domain, or iMod domain, may not be substantiated in clinical trials. Any failure to demonstrate in controlled clinical trials the requisite safety and efficacy of Resolaris or other product candidates that we may develop will adversely affect our business, prospects, financial condition and results of operations.

We have not studied Resolaris or any of our other product candidates in any human clinical trials designed to show efficacy.

Preclinical and clinical data are often susceptible to varying interpretations and analyses, which may delay, limit or prevent regulatory approval. Many companies that have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their products. Accordingly, our earlier studies should not be relied upon as evidence that our current or future clinical trials will succeed. Study designs and results from previous studies are not necessarily predictive of our future clinical trial designs or results, and initial results may not be confirmed upon full analysis of the complete study data. In particular, Resolaris may not achieve positive results in our current and planned Phase 1b/2 clinical trials in rare myopathies with an immune component, or RMICs, and any results observed in our ongoing Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD may not be predictive of results for subsequent cohorts or of the overall results of the trial. Additionally, Resolaris may fail to show the desired safety and efficacy in later stages of clinical development, such as pivotal clinical trials, despite having successfully advanced through initial clinical trials. Any failure of Resolaris or any other product candidates that we may develop at any stage in the clinical development process would have a material adverse impact on our business, prospects, financial condition and results of operations.

Because we are developing novel product candidates for the treatment of diseases in which there is little clinical experience and, in some cases, using new endpoints or methodologies, the regulatory pathways for approval are not well defined, and there is greater risk that the outcome of our clinical trials will not be favorable.

Our initial clinical focus is on the development of Physiocrine-based therapeutics for the treatment of rare diseases, including FSHD, where patients may benefit from the activation of immuno-modulatory pathways. There are currently no approved treatments for FSHD or other rare disease indications that we intend to initially pursue, such as limb-girdle muscular dystrophy, or LGMD. As a result, the design and conduct of clinical trials for these indications are subject to increased risk, and we may experience setbacks with our ongoing or planned clinical trials for Resolaris or other product candidates that we may develop because of the limited clinical experience in our target indications. In particular, regulatory authorities in the United States and European Union have not issued definitive guidance as to how to measure and achieve efficacy. In addition, the protocol for our Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD contemplates the use of magnetic resonance imaging, or MRI, data as a measure of potential immuno-modulatory effects of Resolaris in diseased muscle tissue. Regulators have not yet determined that such data in FSHD patients signifies a clinical meaningful result or can support regulatory approvals. We may not achieve the pre-specified endpoint with statistical significance in our planned clinical trials of Resolaris in this indication or in other indications where there is limited or no regulatory guidance regarding appropriate clinical endpoints, which would decrease the chance of obtaining marketing approval for Resolaris. Additionally, it is difficult to establish clinically relevant endpoints for some of these indications because it may take a long time before any therapeutic effects of a drug can be observed.

We could also face challenges in designing clinical trials and obtaining regulatory approval for product candidates from our Physiocrine discovery engine due to the lack of historical clinical trial experience for this novel class of therapeutics. At the moment, because no Physiocrine-based products have received regulatory approval anywhere in the world, it is difficult to determine whether regulatory agencies will be receptive to the approval of our product candidates and to predict the time and cost associated with obtaining regulatory approval. The clinical trial requirements of the FDA and other regulatory agencies and the criteria these regulators use to determine the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended

 

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use and market of the potential products. The regulatory approval process for novel product candidates such as ours can be more expensive and take longer than for other, better known or more extensively studied classes of product candidates. Any inability to design clinical trials with protocols and endpoints acceptable to applicable regulatory authorities, and to obtain regulatory approvals for our product candidates, would have an adverse impact on our business, prospects, financial condition and results of operations.

We may encounter substantial delays and other challenges in our clinical trials or we may fail to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities.

Before obtaining marketing approval from regulatory authorities for the sale of our product candidates, we must conduct extensive clinical trials to demonstrate the safety and efficacy of the product candidates in humans. Clinical trials are expensive, time-consuming, often delayed and uncertain as to outcome. We cannot guarantee that our ongoing and planned clinical trials of Resolaris in RMICs, or any other clinical trials that we may plan to conduct, will be initiated or conducted as planned or completed on schedule, if at all. Following our submission of an investigational new drug application, or IND, to the Division of Neurology Products at the FDA to evaluate Resolaris in a Phase 1b/2 trial in adult patients with FSHD in the United States, our IND was placed on full clinical hold to address the non-clinical issue of the comparability of the drug substance used in our preclinical toxicology studies to that used in our Phase 1 clinical trial and proposed for use in the U.S. clinical trial in FSHD patients. We responded to the FDA’s comparability request, and, in January 2015, our IND was removed from full clinical hold, allowing us to initiate the Phase 1b/2 trial in the United States. Our IND remains on partial clinical hold, which prohibits the evaluation of Resolaris at doses higher than our proposed 3.0 mg/kg dose pending our submission of additional non-clinical data to the FDA and the FDA’s review of that data. We intend to submit a complete response to address this concern in the second half of 2015. We cannot assure you that the FDA will deem our response to be a complete response or that it will determine to lift the partial clinical hold. Although we do not expect the partial clinical hold to have a material impact on our clinical development timeline for Resolaris in FSHD because we do not intend to evaluate Resolaris at doses higher than 3.0 mg/kg in the current clinical trial, any inability to initiate or complete our clinical trial of Resolaris in adult patients with FSHD in the United States, as a result of the partial clinical hold or otherwise, would delay our clinical development plans, may require us to incur additional clinical development costs and could impair our ability to obtain U.S. regulatory approval for Resolaris.

A failure of one or more clinical trials can occur at any stage of testing, and our clinical trials may not be successful. Events that may prevent successful or timely completion of clinical development include, but are not limited to:

 

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inability to generate sufficient preclinical, toxicology, or other in vivo or in vitro data to support the initiation of human clinical trials;

 

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delays in reaching consensus with regulatory agencies on trial design;

 

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delays in reaching agreement on acceptable terms with prospective contract research organizations, or CROs, and clinical trial sites;

 

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delays in obtaining required Institutional Review Board, or IRB, or Ethics Committee approval at each clinical trial site;

 

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delays in recruiting suitable patients to participate in our clinical trials, or delays that may result if the number of patients required for a clinical trial is larger than we anticipate;

 

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imposition of a clinical hold by regulatory agencies, which may occur after our submission of data to these agencies or an inspection of our clinical trial operations or trial sites;

 

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failure by our CROs, other third parties or us to adhere to clinical trial requirements;

 

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failure to perform in accordance with the FDA’s good clinical practices, or GCPs, or applicable regulatory requirements in other countries;

 

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delays in the testing, validation, manufacturing and delivery of our product candidates to the clinical sites;

 

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delays in having patients complete participation in a trial or return for post-treatment follow-up;

 

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disagreements with regulators regarding our interpretation of data from preclinical studies or clinical trials;

 

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occurrence of adverse events associated with the product candidate that are viewed to outweigh its potential benefits; or

 

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changes in regulatory requirements and guidance that require amending or submitting new clinical protocols.

Any delay in or inability to successfully complete preclinical and clinical development could result in additional costs to us and impair our ability to generate revenue. In addition, if we make manufacturing or formulation changes to our product candidates, we may need to conduct additional studies to bridge our modified product candidates to earlier versions. Clinical trial delays could also shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do, which could impair our ability to obtain orphan exclusivity and successfully commercialize our product candidates and may harm our business and results of operations.

If the results of our clinical trials are perceived to be negative or inconclusive, or if there are safety concerns or adverse events associated with our product candidates, we may:

 

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be required to perform additional clinical trials to support approval or be subject to additional post-marketing testing requirements;

 

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be delayed in obtaining marketing approval for our product candidates, if at all;

 

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obtain approval for indications or patient populations that are not as broad as intended or desired;

 

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obtain approval with labeling that includes significant use or distribution restrictions or safety warnings;

 

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be subject to changes in the way the product is manufactured or administered;

 

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have regulatory authorities withdraw their approval of the product or impose restrictions on its distribution in the form of a modified risk evaluation and mitigation strategy, or REMS;

 

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be subject to litigation; or

 

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experience damage to our reputation.

To date, the safety and efficacy of Physiocrine-based therapeutics in humans has not been studied to any significant extent. Accordingly, our product candidates could potentially cause adverse events that have not yet been predicted. In addition, the inclusion of critically ill patients in our clinical trials may result in deaths or other adverse medical events due to the natural progression of the disease. As described above, any of these events could prevent us from successfully completing the clinical development of our product candidates and impair our ability to commercialize any products.

We may not be successful in our efforts to identify or discover additional product candidates.

A key element of our strategy is to leverage our Physiocrine discovery engine to identify tRNA synthetases that exhibit activity in physiological disease pathways of interest, and to develop purified forms of these proteins that are suitable for therapeutic application. A significant portion of the research that we are conducting involves new compounds and drug discovery methods, including our proprietary technology. Our drug discovery activities using our proprietary technology may not be successful in identifying proteins that are useful in treating rare or more common diseases. Our research programs may initially show promise in identifying potential product candidates, yet fail to yield product candidates for clinical development for a number of reasons, including:

 

•

the research methodology used may not be successful in identifying appropriate potential product candidates; or

 

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potential product candidates may, on further study, be shown to have harmful side effects or other characteristics that indicate that they are unlikely to be medicines that will receive marketing approval and achieve market acceptance.

 

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Research programs to identify new product candidates require substantial technical, financial and human resources. We may choose to focus our efforts and resources on a potential product candidate that ultimately proves to be unsuccessful. If we are unable to identify suitable product candidates for preclinical and clinical development and regulatory approval, we will not be able to generate product revenues, which would have an adverse impact on our business, prospects, financial condition and results of operations.

We may encounter difficulties enrolling patients in our clinical trials for a variety of reasons, including the limited number of patients who have the diseases for which our product candidates are being studied, which could delay or halt the clinical development of our product candidates.

Identifying and qualifying patients to participate in our ongoing and planned clinical trials of Resolaris and any other clinical trials that we may conduct for our product candidates is critical to our success. In particular, each of the conditions for which we currently plan to evaluate Resolaris is a rare disease with limited patient pools from which to draw for clinical trials. For example, while estimates of FSHD prevalence vary, recent studies exploring the topic have identified average prevalence rates of approximately one in 17,000. Applying this rate to the U.S. population as of November 1, 2014 yields a domestic FSHD population of approximately 19,000. The eligibility criteria for our clinical trials, such as the requirement of at least one skeletal muscle in the lower extremities displaying an inflammatory immune response by MRI for enrollment in the second cohort of our ongoing Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD, may further limit the pool of available participants in the trial. We may be unable to identify and enroll a sufficient number of patients with the disease in question and who meet the eligibility criteria for our clinical trials.

Our ability to identify, recruit and enroll a sufficient number of patients, or those with required or desired characteristics to achieve diversity in a study, to complete our clinical trials in a timely manner may also be affected by other factors, including:

 

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proximity and availability of clinical trial sites for prospective patients;

 

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severity of the disease under investigation;

 

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design of the study protocol;

 

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perceived risks and benefits of the product candidate under study;

 

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availability of competing therapies and clinical trials for the patient populations and indications under study;

 

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efforts to facilitate timely enrollment in clinical trials;

 

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patient referral practices of physicians; and

 

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ability to monitor patients adequately during and after treatment.

We are initially focused on the development of Physiocrine-based therapeutics to treat rare conditions. We plan to seek initial marketing approval in the United States. We may not be able to initiate or continue clinical trials if we cannot enroll a sufficient number of eligible patients to participate in the clinical trials required by the FDA or other regulatory agencies. Our ability to successfully initiate, enroll and complete a clinical trial in any foreign country is subject to numerous risks unique to conducting business in foreign countries, including:

 

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difficulty in establishing or managing relationships with CROs and physicians;

 

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different requirements and standards for the conduct of clinical trials;

 

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our inability to locate qualified local consultants, physicians and partners; and

 

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the potential burden of complying with a variety of foreign laws, medical standards and regulatory requirements, including the regulation of pharmaceutical and biotechnology products and treatment.

 

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Additionally, if patients are unwilling to participate in our clinical trials because of negative publicity from adverse events in the biotechnology or protein therapeutics industries or for other reasons, including competitive clinical trials for similar patient populations, the timeline for recruiting patients, conducting studies and obtaining regulatory approval of potential products may be delayed. These delays could result in increased costs, delays in advancing our product development or termination of our clinical trials altogether. If we have difficulty enrolling a sufficient number of patients to conduct our clinical trials as planned for any reason, we may need to delay, limit or terminate ongoing or planned clinical trials, any of which would have an adverse effect on our business, prospects, financial condition and results of operations.

Our product candidates may cause undesirable side effects or have other properties that could delay or prevent their regulatory approval, limit the commercial profile of an approved label, or result in significant negative consequences following marketing approval, if any.

Undesirable side effects caused by our product candidates, or safety or toxicity issues that we may experience in our preclinical studies, clinical trials or in the future, could cause us or regulatory authorities to interrupt, restrict, delay, or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or other comparable foreign authorities. For example, in its partial clinical hold letter, the FDA has requested that, to support clinical trials of Resolaris at doses higher than our proposed 3.0 mg/kg dose, we will need to provide additional non-clinical data demonstrating that certain rodent deaths in our GLP safety studies of Resolaris at the highest doses administered to rodents were not drug-related or to propose a human clinical monitoring strategy acceptable to the FDA to prevent serious toxicity in humans. We intend to submit a complete response to address this concern in the second half of 2015. Any failure to proceed with clinical testing of Resolaris at the doses required to demonstrate efficacy will impair our ability to obtain regulatory approval.

In our Phase 1 clinical trial, we observed low levels of antibodies to Resolaris in some subjects in response to the administration of Resolaris. The development of higher levels of such antibodies over a longer course of treatment may ultimately limit the efficacy of Resolaris and trigger a negative autoimmune response, including the development of anti-synthetase syndrome. Additionally, our product candidates are designed to be administered by intravenous injection, which may cause side effects, including acute immune responses and injection site reactions. The risk of adverse immune responses remains a significant concern for protein therapeutics, and we cannot assure that these or other risks will not occur in any of our clinical trials for Resolaris or other product candidates we may develop. There is also a risk of delayed adverse events as a result of long-term exposure to protein therapeutics that must be administered repeatedly for the management of chronic conditions, such as the development of antibodies, which may occur over time. If any such adverse events occur, which may include the development of anti-synthetase syndrome from antibodies, further advancement of our clinical trials could be halted or delayed, which would have a material adverse effect on our business, prospects, financial condition and results of operations.

If one or more of our product candidates receives marketing approval, and we or others later identify undesirable side effects or other safety concerns caused by such products, a number of potentially significant negative consequences could result, including but not limited to:

 

•

regulatory authorities may withdraw approvals of such products;

 

•

regulatory authorities may require additional warnings on the label;

 

•

we may be required to create a REMS plan, which could include a medication guide outlining the risks of such side effects for distribution to patients, a communication plan for healthcare providers, or other elements to assure safe use;

 

•

we could be sued and held liable for harm caused to patients; and

 

•

our reputation may suffer.

Any of these events could prevent us from achieving or maintaining market acceptance of the particular product candidate, if approved, and could significantly harm our business, prospects, financial condition and results of operations.

 

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We may face challenges associated with the clinical or commercial manufacture of our Physiocrine-based therapeutics.

All entities involved in the preparation of therapeutics for clinical trials or commercial sale, including our existing contract manufacturers for our product candidates, are subject to extensive regulation. Components of a finished therapeutic product approved for commercial sale or use in late-stage clinical trials must be manufactured in accordance with cGMP. These regulations govern manufacturing processes and procedures (including record keeping) and the implementation and operation of quality systems to control and assure the quality of investigational products and products approved for sale. Poor control of production processes can lead to the introduction of contaminants or to inadvertent changes in the properties or stability of our product candidates that may not be detectable in final product testing. We or our contract manufacturers must supply all necessary documentation in support of a biologics license application, or BLA, on a timely basis and must adhere to the FDA’s good laboratory practices, or GLP, and cGMP regulations enforced by the FDA through its facilities inspection program. Some of our contract manufacturers have not produced a commercially-approved product and therefore have not undergone the requisite FDA or other regulatory pre-approval inspection to do so. The facilities and quality systems of our contract manufacturers and other third-party contractors must pass a pre-approval inspection for compliance with applicable regulations as a condition of regulatory approval of our product candidates. In addition, the regulatory authorities may, at any time, audit or inspect a manufacturing facility involved with the preparation of our product candidates or the associated quality systems for compliance with the regulations applicable to the activities being conducted. If these facilities do not pass a pre-approval plant inspection, FDA approval of the products will not be granted.

The regulatory authorities also may, at any time following approval of a product for sale, audit the facilities in which the product is manufactured. If any such inspection or audit of our facilities or those of our third-party contractors identifies a failure to comply with applicable regulations or if a violation of our product specifications or applicable regulations occurs independently of such an inspection or audit, we or the relevant regulatory authority may require remedial measures that may be costly or time-consuming for us or a third party to implement and that may include the temporary or permanent suspension of a clinical trial or commercial sales or the temporary or permanent closure of a facility. Any such remedial measures imposed upon us or third parties with whom we contract could materially harm our business.

If we or any of our third-party manufacturers fail to maintain regulatory compliance, the FDA can impose regulatory sanctions including, among other things, refusal to approve a pending application for a new drug product or biologic product, or revocation of a pre-existing approval. Additionally, if supply from one approved manufacturer is interrupted, there could be a significant disruption in clinical or commercial supply. An alternative manufacturer would need to be qualified through a BLA supplement which could result in further delay. The regulatory agencies may also require additional studies if a new manufacturer is relied upon for commercial production. Switching manufacturers may involve substantial costs and is likely to result in a delay in our desired clinical and commercial timelines.

In addition, the manufacture of Resolaris and any other Physiocrine-based therapeutics that we may develop presents challenges associated with biologics production, including the inherent instability of larger, more complex molecules and the need to ensure uniformity of the drug substance produced in different facilities or across different batches. Furthermore, although Physiocrines represent a class of proteins that may share immuno-modulatory properties in various physiological pathways, each Physiocrine has a different structure and may have unique manufacturing requirements that are not applicable across the entire class. For example, Fc fusion proteins, such as iModFc, include an additional antibody domain to improve pharmacokinetic, or PK, characteristics, and may therefore require a more complex and time-consuming manufacturing process than other Physiocrines. As a result, the manufacturing processes for one of our product candidates may not be readily adaptable to other product candidates that we develop, and we may need to engage multiple third-party manufacturers to produce our product candidates. Any inability to consistently manufacture adequate supplies of our product candidates for clinical trials or on a commercial scale will harm our business, prospects, financial condition and results of operations.

 

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We have submitted an application for orphan medicinal product designation, but we may not receive orphan drug designation under this application or any other similar applications that we may submit, and any orphan drug designations that we may receive may not confer marketing exclusivity or other expected commercial benefits.

We submitted an application to the European Medicines Agency, or the EMA, for orphan medicinal product designation for Resolaris for the treatment of FSHD and received a positive opinion from the EMA’s Committee for Orphan Medicinal Products recommending the granting of this orphan designation. We are currently awaiting the final decision from the European Commission. We may also apply for orphan drug designation in other territories and for other indications and product candidates. Orphan drug status confers up to ten years of marketing exclusivity in Europe, and up to seven years of marketing exclusivity in the United States, for a particular product in a specified indication. To date, we have not been granted orphan drug designation for any product candidate in any jurisdiction. We cannot assure you that we will be able to obtain orphan drug designation, or rely on orphan drug or similar designations to exclude other companies from manufacturing or selling biological products using the same principal mechanisms of action for the same indications that we pursue beyond these timeframes. Furthermore, marketing exclusivity in Europe can be reduced from ten years to six years if the initial designation criteria have significantly changed since the market authorization of the orphan product. Even if we are the first to obtain marketing authorization for an orphan drug indication, there are circumstances under which a competing product may be approved for the same indication during the period of marketing exclusivity, such as if the later product is shown to be clinically superior to the orphan product, or if the later product is deemed a different product than ours. Further, the marketing exclusivity would not prevent competitors from obtaining approval of the same product candidate as ours for indications other than those in which we have been granted orphan drug designation, or for the use of other types of products in the same indications as our orphan product.

Even if we complete the necessary preclinical studies and clinical trials, we cannot predict when or if we will obtain regulatory approval to commercialize a product candidate, and the scope of any approval may be narrower than we expect.

We cannot commercialize a product until the appropriate regulatory authorities have reviewed and approved the product candidate. Even if our product candidates demonstrate safety and efficacy in clinical trials, the regulatory agencies may not complete their review processes in a timely manner, or we may not be able to obtain regulatory approval. Additional delays may result if an FDA Advisory Committee or regulatory authority recommends non-approval or restrictions on approval. In addition, we may experience delays or rejections based upon additional government regulation from future legislation or administrative action, or changes in regulatory agency policy during the period of product development, clinical trials and the review process. Regulatory agencies also may approve a product candidate for fewer or more limited indications than requested, may impose restrictions on dosing or may grant approval subject to the performance of post-marketing studies. In addition, regulatory agencies may not approve the labeling claims that are necessary or desirable for the successful commercialization of our product candidates.

Failure to obtain marketing approval in international jurisdictions would prevent our medicines from being marketed in such jurisdictions.

In order to market and sell our medicines in the European Union and many other jurisdictions, we must obtain separate marketing approvals and comply with numerous and varying regulatory requirements. The approval procedure varies among countries and can involve additional testing, and we have limited regulatory experience in many jurisdictions. The time required to obtain approval in one jurisdiction may differ substantially from that required to obtain approval in other jurisdictions. The regulatory approval process outside the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries outside the United States, it is required that the product be approved for reimbursement before the product can be approved for sale in that country. We may not obtain approvals from regulatory authorities outside the United States on a timely basis, if at all. Approval by one regulatory authority does not ensure approval by regulatory authorities in other countries or jurisdictions, and we may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our medicines in any market.

 

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We may not elect or be able to take advantage of any expedited development or regulatory review and approval processes available to product candidates granted breakthrough therapy or fast track designation by the FDA.

We are evaluating the possibility of seeking breakthrough therapy or fast track designation for Resolaris and any other product candidates that we may develop, although we may elect not to do so. A breakthrough therapy program is for a product candidate intended to treat a serious or life-threatening condition, and preliminary clinical evidence indicates that the product candidate may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies. A fast track program is for a product candidate that treats a serious or life-threatening condition, and nonclinical or clinical data demonstrate the potential to address an unmet medical need. Although we believe Resolaris and other product candidates that we may develop from our Physiocrine discovery engine may qualify under either or both of the breakthrough therapy and fast track programs, we may elect not to pursue either of these programs, and even if we do, the FDA has broad discretion whether or not to grant these designations. Accordingly, even if we believe a particular product candidate is eligible for breakthrough therapy or fast track designation, we cannot assure you that the FDA would decide to grant it. Even if we do receive breakthrough therapy or fast track designation, we may not experience a faster development process, review or approval compared to conventional FDA procedures. The FDA may withdraw breakthrough therapy or fast track designation if it believes that the product no longer meets the qualifying criteria. In addition, the breakthrough therapy program is a relatively new program. As a result, we cannot be certain whether any of our product candidates can or will qualify for breakthrough therapy designation. Our business may be harmed if we are unable to avail ourselves of these or any other expedited development and regulatory pathways.

Even if we obtain regulatory approval for a product candidate, our products will remain subject to regulatory scrutiny.

Even if our product candidates are approved, they will be subject to ongoing regulatory requirements for manufacturing, labeling, packaging, storage, advertising, promotion, sampling, record-keeping, conduct of post-marketing studies, and submission of safety, efficacy, and other post-market information, including both federal and state requirements in the United States and requirements of comparable foreign regulatory authorities.

Manufacturers and manufacturers’ facilities are required to comply with extensive FDA, and comparable foreign regulatory authority, requirements, including ensuring that quality control and manufacturing procedures conform to cGMP regulations. As such, we and our contract manufacturers will be subject to continual review and inspections to assess compliance with cGMP and adherence to commitments made in any BLA, new drug application, or NDA, or marketing authorization application, or MAA. Accordingly, we and others with whom we work will need to continue to expend time, money, and effort in all areas of regulatory compliance, including manufacturing, production, and quality control.

Any regulatory approvals that we receive for our product candidates may be subject to limitations on the approved indicated uses for which the product may be marketed or to the conditions of approval, or contain requirements for potentially costly post-marketing testing, including Phase 4 clinical trials, and surveillance to monitor the safety and efficacy of the product candidate. We will be required to report certain adverse reactions and production problems, if any, to the FDA and comparable foreign regulatory authorities. Any new legislation addressing drug safety issues could result in delays in product development or commercialization, or increased costs to assure compliance.

We will have to comply with requirements concerning advertising and promotion for our products. Promotional communications with respect to prescription drugs are heavily scrutinized by the FDA, the Department of Justice, state attorneys general and comparable foreign regulatory authorities. For example, we may face claims associated with the use or promotion of our products for uses outside the scope of their approved label indications. Violations, including actual or alleged promotion of our products for unapproved, or off-label, uses are subject to enforcement letters, inquiries and investigations, and civil and criminal sanctions. Any actual or alleged failure to comply with labeling and promotion requirements may have a negative impact on our

 

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business. In the United States, engaging in impermissible promotion of our products for off-label uses can also subject us to false claims litigation under federal and state statutes, which can lead to civil and criminal penalties and fines and agreements that would materially restrict the manner in which we promote or distribute our drug products. These false claims statutes include the federal False Claims Act, which allows any individual to bring a lawsuit against a pharmaceutical company on behalf of the federal government alleging submission of false or fraudulent claims, or causing to present such false or fraudulent claims, for payment by a federal program such as Medicare or Medicaid. If the government prevails in the lawsuit, the individual will share in any fines or settlement funds. Since 2004, these False Claims Act lawsuits against pharmaceutical companies have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements based on certain sales practices promoting off-label drug uses. This growth in litigation has increased the risk that a pharmaceutical company will have to defend a false claims action, pay settlement fines or restitution, agree to comply with burdensome reporting and compliance obligations, and be excluded from Medicare, Medicaid and other federal and state healthcare programs. If we do not lawfully promote our approved products, we may become subject to such litigation and, if we are not successful in defending against such actions, those actions could compromise our ability to become profitable.

The holder of an approved BLA, NDA or MAA must submit new or supplemental applications and obtain approval for certain changes to the approved product, product labeling, or manufacturing process. We could also be asked to conduct post-marketing clinical trials to verify the safety and efficacy of our products in general or in specific patient subsets. If original marketing approval were obtained through an accelerated approval pathway, we could be required to conduct a successful post-marketing clinical trial to confirm clinical benefit for our products. An unsuccessful post-marketing study or failure to complete such a trial could result in the withdrawal of marketing approval.

If a regulatory agency discovers previously unknown problems with a product, such as adverse events of unanticipated severity or frequency, or problems with the facility where the product is manufactured, or disagrees with the promotion, marketing or labeling of a product, such regulatory agency may impose restrictions on that product or us, including requiring withdrawal of the product from the market. If we fail to comply with applicable regulatory requirements, a regulatory agency or enforcement authority may, among other things:

 

•

issue untitled or warning letters;

 

•

impose civil or criminal penalties;

 

•

suspend or withdraw regulatory approval;

 

•

suspend any of our ongoing clinical trials;

 

•

refuse to approve pending applications or supplements to approved applications submitted by us;

 

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impose restrictions on our operations, including closing our contract manufacturers’ facilities; or

 

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seize or detain products, or require a product recall.

Any government investigation of alleged violations of law could require us to expend significant time and resources in response, and could generate negative publicity. Any failure to comply with ongoing regulatory requirements may significantly and adversely affect our ability to commercialize and generate revenue from our products. If regulatory sanctions are applied or if regulatory approval is withdrawn, the value of our company and our operating results will be adversely affected.

Because of our focus on treatments for severe, rare diseases, Resolaris and other product candidates that we develop may be subject to requests for treatment use under individual patient INDs, which would present a variety of risks.

FDA regulations permit an investigational drug or biologic to be used for the treatment of an individual patient by a licensed physician under certain circumstances if the patient has a serious disease or condition, generally defined as a disease or condition associated with morbidity that has a substantial impact on day-to-day

 

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functioning. We believe that Resolaris and other product candidates that we develop may be susceptible to physician requests for use in these settings given the severity of the disease indications that we are targeting and the limited availability of approved and other investigational therapeutics for these indications. The treatment use of our product candidates under individual patient INDs would present a number of risks, including the following:

 

•

The treatment use of our product candidates under individual patient INDs may be subject to less stringent or otherwise different protocols from our clinical trials, subjecting the patient to additional risk, which could negatively affecting the perception of our product candidates among physicians, patients and regulators;

 

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The actual or perceived availability of a product candidate for use under individual patient INDs may impair patient enrollment in our clinical trials; and

 

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Any decision to make quantities of our product candidates available for use under individual patient INDs may impair our or our third-party manufacturers’ ability to timely supply adequate quantities of our product candidates for our clinical trials.

Physicians may independently file individual patient INDs for Resolaris or one of our other product candidates. We may disagree with a physician’s or the FDA’s conclusion that our product candidate is suitable for evaluation under a particular individual patient IND, and any decision by us not to make our product candidate available for evaluation under this setting may subject us to negative publicity or market perception.

Risks related to our financial condition and capital requirements

We have incurred significant losses since our inception and anticipate that we will continue to incur significant losses for the foreseeable future.

We are a clinical stage biotherapeutics company, and we have not yet generated any revenues from product sales. We have incurred net losses in each year since our inception in 2005, including net losses of $12.9 million and $20.0 million for the years ended December 31, 2012 and 2013, respectively, and $18.3 million for the nine months ended September 30, 2014. As of September 30, 2014, we had an accumulated deficit of $104.1 million.

We have devoted most of our financial resources to research and development, including our clinical and preclinical development activities. To date, we have financed our operations primarily through the sale of equity securities and convertible debt and through commercial bank debt. The amount of our future net losses will depend, in part, on the rate of our future expenditures and our ability to obtain funding through equity or debt financings, grant funding or strategic collaborations. We have not commenced pivotal clinical trials for any product candidate and it will be several years, if ever, before we have a product candidate ready for commercialization. Even if we obtain regulatory approval to market a product candidate, our future revenues will depend upon the size of any markets in which our product candidates have received approval, and our ability to achieve sufficient market acceptance, reimbursement from third-party payors and adequate market share for our product candidates in those markets. However, even if we obtain adequate market share for our product candidates, because the potential markets in which our product candidates may ultimately receive regulatory approval are very small, we may never become profitable despite obtaining such market share and acceptance of our products.

We expect to continue to incur significant expenses and increasing operating losses for the foreseeable future. We anticipate that our expenses will increase substantially if and as we:

 

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continue our research and preclinical and clinical development of Resolaris, our lead product candidate, or any other product candidates that we may develop;

 

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continue our current clinical trial of Resolaris in adult patients with FSHD and initiate and conduct our planned additional clinical trials of Resolaris in FSHD, LGMD and other RMICs;

 

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•

initiate and conduct any additional preclinical studies, clinical trials or other studies for Resolaris and any other product candidates that we may develop;

 

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further develop the manufacturing process for our product candidates;

 

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change or add additional manufacturers, including manufacturers of quantities of drug substance suitable for pivotal clinical trials and commercialization;

 

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seek regulatory and marketing approvals for our product candidates that successfully complete clinical trials;

 

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establish a sales, marketing and distribution infrastructure to commercialize any products for which we may obtain marketing approval;

 

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seek to identify and validate additional product candidates;

 

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make milestone or other payments under our in-license agreements;

 

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maintain, protect and expand our portfolio of owned and in-licensed intellectual property;

 

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acquire or in-license other product candidates and technologies;

 

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attract and retain skilled personnel;

 

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create additional infrastructure to support our operations as a public company and our product development and planned future commercialization efforts; and

 

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experience any delays or encounter challenges with any of the above.

The net losses we incur may fluctuate significantly from quarter to quarter and year to year, such that a period-to-period comparison of our results of operations may not be a good indication of our future performance. In any particular quarter or quarters, our operating results could be below the expectations of securities analysts or investors, which could cause our stock price to decline.

We have never generated any revenue from product sales and may never be profitable.

Our ability to generate revenue and achieve profitability depends on our ability to successfully complete the development of, and obtain the regulatory approvals necessary to commercialize, Resolaris and any other product candidates that we may develop. We do not anticipate generating revenues from product sales for the foreseeable future, if ever. Our ability to generate future revenues from product sales depends heavily on our success in:

 

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completing research, preclinical development and clinical development of Resolaris and other product candidates;

 

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seeking and obtaining regulatory and marketing approvals for product candidates for which we complete clinical trials;

 

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developing a sustainable, scalable, reproducible, and transferable manufacturing process for Resolaris and any other product candidates that we may develop;

 

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establishing and maintaining supply and manufacturing relationships with third parties that can provide products and services that are adequate in both amount and quality to support clinical development and the market demand for our product candidates, if approved;

 

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launching and commercializing product candidates for which we obtain regulatory and marketing approval, by establishing a sales force, marketing and distribution infrastructure;

 

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maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trademarks, trade secrets and know-how;

 

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obtaining market acceptance of Physiocrine therapeutics and our product candidates as viable treatment options for our target indications;

 

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addressing any competing technological and market developments;

 

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•

implementing additional internal systems and infrastructure, as needed;

 

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identifying and validating new Physiocrine therapeutic product candidates;

 

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attracting, hiring and retaining qualified personnel; and

 

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negotiating favorable terms in any licensing, collaboration or other arrangements into which we may enter.

Even if Resolaris or any of the other product candidates that we may develop is approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved product candidate. Our expenses could increase beyond expectations if we are required by the FDA or other regulatory agencies, domestic or foreign, to perform clinical trials and other studies in addition to those that we currently anticipate. In cases where we are successful in obtaining regulatory approvals to market one or more of our product candidates, our revenue will be dependent, in part, upon the size of the markets in the territories for which we gain regulatory approval, the accepted price for the product, the ability to get reimbursement at any price, the competition we face, and whether we own the commercial rights for that territory. If the number of our addressable rare disease patients is not as significant as we estimate, the indication approved by regulatory authorities is narrower than we expect, or the reasonably accepted population for treatment is narrowed by competition, physician choice or treatment guidelines, we may not generate significant revenue from sales of such products, even if approved. Even if we are able to generate revenues from the sale of any approved products, we may not become profitable and may need to obtain additional funding to continue operations.

Even if this offering is successful, we will need to raise additional funding, which may not be available on acceptable terms, or at all. Failure to obtain this necessary capital when needed may force us to delay, limit or terminate our product development efforts or other operations.

We are currently advancing Resolaris through clinical development and conducting preclinical development activities directed at the identification and selection of additional Physiocrine-based therapeutic candidates. The development of protein therapeutics is expensive, and we expect our research and development expenses to increase substantially in connection with our ongoing activities, particularly as we advance Resolaris into further clinical trials in multiple indications.

As of September 30, 2014, our cash, cash equivalents and investments were approximately $23.5 million. We estimate that the net proceeds from this offering will be approximately $         million, based on an assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. We expect that the net proceeds from this offering and our existing cash, cash equivalents and investments will be sufficient to fund our current operations through at least the next 12 months. However, our operating plan may change as a result of many factors currently unknown to us, and we may need to seek additional funds sooner than planned, through public or private equity or debt financings, government or other third-party funding, marketing and distribution arrangements and other collaborations, strategic alliances and licensing arrangements or a combination of these approaches. Our future funding requirements will depend on many factors, including but not limited to:

 

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the scope, rate of progress, results and cost of our clinical trials, nonclinical testing, and other related activities;

 

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the cost of manufacturing clinical supplies, and establishing commercial supplies, of our product candidates and any products that we may develop;

 

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the number and characteristics of product candidates that we pursue;

 

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the cost, timing, and outcomes of regulatory review of our product candidates;

 

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the cost and timing of establishing sales, marketing, and distribution capabilities; and

 

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•

the terms and timing of any collaborative, licensing, and other arrangements that we may establish, including any required milestone and royalty payments thereunder.

In any event, we will require additional capital to complete additional clinical trials, including larger, pivotal clinical trials, to obtain regulatory approval for, and to commercialize, our product candidates. Raising funds in the current economic environment may present additional challenges. Even if we believe we have sufficient funds for our current or future operating plans, we may seek additional capital if market conditions are favorable or if we have specific strategic considerations. If we are unable to obtain funding on a timely basis, we may be required to significantly curtail, delay or discontinue one or more of our research or development programs or the commercialization of any product candidates, or we may be unable to expand our operations or otherwise capitalize on our business opportunities, as desired, which could materially affect our business, financial condition and results of operations.

Raising additional capital may cause dilution to our existing stockholders, restrict our operations, require us to relinquish rights to our technologies or product candidates on terms unfavorable to us and divert management’s attention from our product development activities.

The terms of any financing may adversely affect the holdings or the rights of our stockholders and the issuance of additional securities, whether equity or debt, by us, or the possibility of such issuance, may cause the market price of our shares to decline. The sale of additional equity or convertible securities would cause dilution to all of our stockholders. The incurrence of indebtedness would increase our fixed payment obligations and may require us to agree to certain restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire, sell or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business. We could also be required to seek funds through arrangements with collaborative partners or otherwise at an earlier stage than desirable and we may be required to relinquish rights to some of our technologies or product candidates or otherwise agree to terms unfavorable to us, any of which may have a material adverse effect on our business, operating results and prospects. In addition, any fundraising efforts may divert our management from their day-to-day activities, which may adversely affect our ability to develop and commercialize our product candidates.

We are party to a loan and security agreement that contains operating covenants that may restrict our business and financing activities.

In April 2012, we entered into a loan and security agreement with Silicon Valley Bank, which was subsequently amended in July 2013, pursuant to which we have been extended term loans in the aggregate principal amount of $10.0 million. Borrowings under this loan and security agreement are secured by substantially all of our assets, excluding certain intellectual property rights. The loan and security agreement restricts our ability, among other things, to:

 

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sell, transfer or otherwise dispose of any of our business or property, subject to limited exceptions;

 

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make material changes to our business or management;

 

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enter into transactions resulting in significant changes to the voting control of our stock;

 

•

make certain changes to our organizational structure;

 

•

consolidate or merge with other entities or acquire other entities;

 

•

move our principal office location or add new office locations;

 

•

incur additional indebtedness or create encumbrances on our assets, subject to limited exceptions;

 

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pay dividends, other than dividends paid solely in shares of our common stock, or make distributions on and, in certain cases, repurchase our stock;

 

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enter into transactions with our affiliates, subject to limited exceptions;

 

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•

repay subordinated indebtedness; or

 

•

make certain investments.

In addition, we are required under our loan agreement to comply with various affirmative operating covenants. The operating covenants and restrictions and obligations in our loan and security agreement, as well as any future financing agreements that we may enter into, may restrict our ability to finance our operations, engage in business activities or expand or fully pursue our business strategies. Our ability to comply with these covenants may be affected by events beyond our control, and we may not be able to meet those covenants. A breach of any of these covenants could result in a default under the loan and security agreement, which could cause all of the outstanding indebtedness under the facility to become immediately due and payable.

If we are unable to generate sufficient cash available to repay our debt obligations when they become due and payable, either as or when such obligations become due, when they mature, or in the event of a default, we may not be able to obtain additional debt or equity financing on favorable terms, if at all, which may negatively impact our business operations and financial condition.

Risks related to our reliance on third parties

We rely, and expect to continue to rely, on third parties to conduct some or all aspects of our product manufacturing, protocol development, research and preclinical and clinical testing, and these third parties may not perform satisfactorily.

We currently rely, and expect to continue to rely, on third parties to conduct some or all aspects of product manufacturing, protocol development, research and preclinical and clinical testing with respect to our product candidates. Any of these third parties may terminate their engagements with us at any time. If we need to enter into alternative arrangements, it could delay our product development activities. Our reliance on these third parties for research and development activities reduces our control over these activities but does not relieve us of our responsibility to ensure compliance with all required regulations and study protocols. For example, for Resolaris and any other product candidates that we develop and commercialize on our own, we will remain responsible for ensuring that each of our clinical trials is conducted in accordance with the applicable study plan and protocols.

If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct our research and development activities, including clinical trials, in accordance with regulatory requirements or our stated study plans and protocols, we will not be able to complete, or may be delayed in completing, the preclinical studies and clinical trials required to support future BLA submissions and approval of our product candidates.

We rely on a third party to manufacture our clinical supply of Resolaris, and we intend to rely on third parties to produce non-clinical, clinical and commercial supplies of any future product candidate.

We do not have, nor do we plan to acquire, the infrastructure or capability internally to manufacture our nonclinical and clinical quantities of our product candidates, and we lack the resources and the capability to manufacture any of our product candidates on a clinical or commercial scale. Reliance on third-party manufacturers entails risks to which we would not be subject if we manufactured the product candidates ourselves, including:

 

•

the inability to negotiate manufacturing agreements with third parties under commercially reasonable terms;

 

•

reduced control as a result of using third-party manufacturers for all aspects of manufacturing activities;

 

•

termination or nonrenewal of manufacturing agreements with third parties in a manner or at a time that is costly or damaging to us; and

 

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•

disruptions to the operations of our third-party manufacturers or suppliers caused by conditions unrelated to our business or operations, including the insolvency or bankruptcy of the manufacturer or supplier.

Any of these events could lead to clinical trial delays or failure to obtain regulatory approval, or impact our ability to successfully commercialize future products. Some of these events could be the basis for FDA action, including injunction, recall, seizure or total or partial suspension of production.

Additionally, each manufacturer may require licenses to manufacture our product candidates or components thereof if the applicable manufacturing processes are not owned by the manufacturer or in the public domain, and we may be unable to transfer or sublicense the intellectual property rights we may have with respect to such activities. These factors could cause the delay of clinical development, regulatory submissions, required approvals or commercialization of our product candidates, cause us to incur higher costs and prevent us from commercializing our products successfully.

We currently rely on a single manufacturer for Resolaris in our clinical trials. We do not have long-term contracts with our manufacturers, and our manufacturers may terminate their agreements with us for a variety of reasons. Furthermore, the manufacturing facilities in which our product candidates are made could be adversely affected by earthquakes and other natural disasters, labor shortages, power failures, and numerous other factors. If our manufacturers fail to meet contractual requirements, and we are unable to secure one or more replacement manufacturers capable of production at a substantially equivalent cost, our clinical development activities may be delayed, or we could lose potential revenue. Manufacturing biologic drugs is complicated and tightly regulated by the FDA and comparable regulatory authorities around the world, and although alternative third-party manufacturers with the necessary manufacturing and regulatory expertise and facilities exist, it could be expensive and take a significant amount of time to arrange for alternative manufacturers, transfer manufacturing procedures to these alternative manufacturers, and demonstrate comparability of material produced by such new manufacturers. New manufacturers of any product would be required to qualify under applicable regulatory requirements. These manufacturers may not be able to manufacture our product candidates at costs, or in quantities, or in a timely manner necessary to complete the clinical development of our product candidates or make commercially successful products.

We rely, and expect to continue to rely, on third parties to conduct, supervise and monitor our clinical trials, and if these third parties perform in an unsatisfactory manner, it may harm our business.

We have relied, and expect to continue to rely, on third-party CROs and clinical trial sites to ensure our clinical trials are conducted properly and on time. While we have and will continue to enter into agreements governing their activities, we will have limited influence over their actual performance. We will control only certain aspects of our CROs’ activities. Nevertheless, we will be responsible for ensuring that each of our clinical trials is conducted in accordance with the applicable protocol, legal and regulatory requirements, and scientific standards, and our reliance on the CROs does not relieve us of our regulatory responsibilities.

We and our CROs are required to comply with GCPs for conducting, recording and reporting the results of IND-enabling studies and clinical trials to assure that the data and reported results are credible and accurate and that the rights, integrity and confidentiality of clinical trial participants are protected. The FDA enforces GCPs through periodic inspections of study sponsors, principal investigators and clinical trial sites. If we or our CROs fail to comply with applicable GCPs, the clinical data generated in our future clinical trials may be deemed unreliable and the FDA may require us to perform additional unanticipated clinical trials before approving any marketing applications. Upon inspection, the FDA may determine that our clinical trials did not comply with GCPs. In addition, our future clinical trials will require a sufficient number of test subjects to evaluate the safety and effectiveness of our product candidates. Accordingly, if our CROs fail to comply with these regulations or fail to recruit a sufficient number of patients, we may be required to repeat such clinical trials, which would delay the regulatory approval process.

 

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Our CROs are not our employees, and we are therefore unable to directly monitor whether or not they devote sufficient time and resources to our clinical and nonclinical programs. These CROs may also have relationships with other commercial entities, including our competitors, for whom they may also be conducting clinical trials or other drug development activities that could harm our competitive position. If our CROs do not successfully carry out their contractual duties or obligations, fail to meet expected deadlines, or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols or regulatory requirements, or for any other reasons, our clinical trials may be extended, delayed or terminated, and we may not be able to obtain regulatory approval for, or successfully commercialize our product candidates. As a result, our financial results would be harmed, our costs could increase, our ability to generate revenues could be delayed and the commercial prospects for our product candidates will be adversely affected.

Our reliance on third parties requires us to share our trade secrets, which increases the possibility that a competitor will discover them or that our trade secrets will be misappropriated or disclosed.

We rely on third parties to manufacture our product candidates, and we collaborate with various academic institutions in the development of our Physiocrine therapeutic discovery engine. In connection with these activities, we are required, at times, to share trade secrets with them. We seek to protect our proprietary technology in part by entering into confidentiality agreements and, if applicable, material transfer agreements, collaborative research agreements, consulting agreements or other similar agreements with our collaborators, advisors, employees and consultants prior to beginning research or disclosing proprietary information. These agreements typically limit the rights of the third parties to use or disclose our confidential information, such as trade secrets. Despite the contractual provisions employed when working with third parties, the need to share trade secrets and other confidential information increases the risk that such trade secrets become known by our competitors, are inadvertently incorporated into the technology of others, or are disclosed or used in violation of these agreements. Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of our trade secrets or other unauthorized use or disclosure would impair our competitive position and may have a material adverse effect on our business, prospects, financial condition and results of operations.

In addition, these agreements typically restrict the ability of our collaborators, advisors, employees and consultants to publish data potentially relating to our trade secrets. Our academic collaborators typically have rights to publish data, provided that we are notified in advance and may delay publication for a specified time in order to secure intellectual property rights to which we are entitled arising from the collaboration. In other cases, publication rights are controlled exclusively by us, although in some cases we may share these rights with other parties. We also conduct joint research and development programs that may require us to share trade secrets under the terms of our research and development partnerships or similar agreements. Despite our efforts to protect our trade secrets, our competitors may discover our trade secrets, either through breach of these agreements, independent development or publication of information including our trade secrets in cases where we do not have proprietary or otherwise protected rights at the time of publication. A competitor’s discovery of our trade secrets would impair our competitive position and have an adverse impact on our business, prospects, financial condition and results of operations.

Risks related to the commercialization of our product candidates

If we are unable to establish sales and marketing capabilities or enter into agreements with third parties to market and sell our product candidates, we may be unable to generate any revenues.

We do not currently have any infrastructure for the sales, marketing and distribution of pharmaceutical products. In order to market our product candidates, if approved by the FDA or any other regulatory body, we must build our sales, marketing, managerial and other non-technical capabilities or make arrangements with third parties to perform these services. There are risks involved with both establishing our own sales and marketing capabilities and entering into arrangements with third parties to perform these services. For example, recruiting

 

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and training a sales force is expensive and time consuming and could delay any product launch. If the commercial launch of a product candidate for which we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses. This may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing personnel.

Factors that may inhibit our efforts to commercialize our medicines on our own include:

 

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our inability to recruit and retain adequate numbers of effective sales and marketing personnel;

 

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the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe any future medicines;

 

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the lack of complementary medicines to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and

 

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unforeseen costs and expenses associated with creating an independent sales and marketing organization.

If we enter into arrangements with third parties to perform sales, marketing and distribution services, our product revenues or the profitability of these product revenues to us are likely to be lower than if we were to market and sell any medicines that we develop ourselves. In addition, we may not be successful in entering into arrangements with third parties to sell and market our product candidates or may be unable to do so on terms that are favorable to us. We likely will have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our medicines effectively. If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing our product candidates.

We rely on third-party manufacturers to produce Resolaris and any other product candidates that we may develop, but we have not entered into agreements with any such manufacturers to support commercialization.

We have not yet secured manufacturing capabilities for commercial quantities of Resolaris or other product candidates. Although we intend to rely on third-party manufacturers for commercialization, we have only entered into agreements with such manufacturers to support our human proof-of-concept clinical trials. We have not yet entered into a long-term commercial supply agreement to support full scale commercial production, and we may be unable to negotiate agreements with the manufacturers to support our commercialization activities at commercially reasonable terms.

No manufacturer currently has the experience or ability to produce our product candidates at commercial levels. We or our contract manufacturers will need to develop a scalable manufacturing process for Resolaris or any other product candidates that we may develop and commercialize. We may run into technical or scientific issues related to manufacturing or development that we may be unable to resolve in a timely manner or with available funds. If we or our manufacturing partners are unable to scale the manufacturing process to produce commercial quantities of our product candidates, or our manufacturing partners do not pass required regulatory pre-approval inspections, our commercialization efforts will be harmed.

In addition, any significant disruption in our relationships with our manufacturers could harm our business. There are a relatively small number of potential manufacturers for Resolaris and other product candidates that we may develop, and such manufacturers may not be able to supply our drug products at the times we need them or on commercially reasonable terms. Any disruption to our relationship with our current manufacturer and any manufacturers that we contract with in the future will result in delays in our ability to complete the clinical development of, or to commercialize, Resolaris and any other product candidates we may develop, and may require us to incur additional costs.

 

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We face intense competition and rapid technological change and the possibility that our competitors may develop therapies that are more advanced or effective than ours, which may adversely affect our financial condition and our ability to successfully commercialize our product candidates.

We are engaged in the development of medicines for severe, rare diseases, which is a competitive and rapidly changing field. We have competitors both in the United States and internationally, including major multi-national pharmaceutical companies, biotechnology companies and universities and other research institutions. We expect to compete with various companies, academic institutions and other organizations that have products in development for some of our target RMIC indications. For example, although there are currently no approved products for the treatment of FSHD, Acceleron Pharma Inc. is developing a clinical candidate, ACE-083, a locally acting protein therapeutic designed to increase muscle mass and strength in patients with neuromuscular disorders and other diseases characterized by a loss of muscle function, including FSHD. In addition, Facio Therapies recently announced its plans to screen chemical libraries to identify chemical compounds that will boost the expression of proteins known to repress one of the causal genes responsible for FSHD. Many larger companies, universities and private and public research institutions are also actively engaged in the development of therapeutics to address muscle loss and muscle weakness in a variety of indications.

Many of our competitors have substantially greater financial, technical and other resources, such as larger research and development staff and experienced marketing and manufacturing organizations. Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Our competitors may succeed in developing, acquiring or licensing on an exclusive basis products that are more effective, safer, more convenient or less costly than any product candidate that we may develop, or achieve earlier patent protection, regulatory approval, product commercialization and market penetration than us. Additionally, technologies developed by our competitors may render our potential product candidates uneconomical or obsolete, and we may not be successful in marketing our product candidates against competitors.

Even if we are successful in achieving regulatory approval to commercialize a product candidate faster than our competitors, we may face competition from biosimilars due to the changing regulatory environment. In the United States, the Biologics Price Competition and Innovation Act of 2009 created an abbreviated approval pathway for biological products that are demonstrated to be “highly similar,” or biosimilar, to or “interchangeable” with an FDA-approved biological product. This new pathway could allow competitors to reference data from biological products already approved after 12 years from the time of approval. In Europe, the European Commission has granted marketing authorizations for several biosimilars pursuant to a set of general and product class-specific guidelines for biosimilar approvals issued over the past few years. In Europe, a competitor may reference data from biological products already approved, but will not be able to get on the market until ten years after the time of approval. This ten year period will be extended to 11 years if, during the first eight of those ten years, the marketing authorization holder obtains an approval for one or more new therapeutic indications that bring significant clinical benefits compared with existing therapies. In addition, companies may be developing biosimilars in other countries that could compete with our products. If competitors are able to obtain marketing approval for biosimilars referencing our products, our products may become subject to competition from such biosimilars, with the attendant competitive pressure and consequences. Expiration or successful challenge of our applicable patent rights could also trigger competition from other products, assuming any relevant exclusivity period has expired.

Finally, as a result of the expiration or successful challenge of our patent rights, we could face more litigation with respect to the validity or scope of patents relating to our competitors’ products. The availability of our competitors’ products could limit the demand, and the price we are able to charge, for any products that we may develop and commercialize.

 

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The commercial success of any current or future product candidate will depend upon the degree of market acceptance by physicians, patients, third-party payors and others in the medical community.

Even with the requisite approval from the FDA and comparable foreign regulatory authorities, the commercial success of our product candidates will depend in part on the medical community, patients, and third-party payors accepting our product candidates as medically useful, cost-effective, and safe. Any product that we bring to the market may not gain market acceptance by physicians, patients, third-party payors and others in the medical community. If these products do not achieve an adequate level of acceptance, we may not generate significant product revenue and may not become profitable. The degree of market acceptance of these product candidates, if approved for commercial sale, will depend on a number of factors, including:

 

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the potential efficacy and potential advantages over alternative treatments;

 

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the prevalence and severity of any side effects, including any limitations or warnings contained in a product’s approved labeling;

 

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the prevalence and severity of any side effects resulting from the administration of our product candidates by injection;

 

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the clinical indications for which approval is granted;

 

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relative convenience and ease of administration;

 

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the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies;

 

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the strength of marketing and distribution support and timing of market introduction of competitive products;

 

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publicity concerning our products or competing products and treatments; and

 

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the availability of sufficient third-party insurance coverage or reimbursement.

Even if a potential product displays a favorable efficacy and safety profile in preclinical studies and clinical trials, market acceptance of the product will not be known until after it is launched. Our efforts to educate the medical community and third-party payors on the benefits of the product candidates may require significant resources and may never be successful. Such efforts to educate the marketplace may require more resources than are required by the conventional technologies marketed by our competitors, and our competitors may have substantially greater resources or brand recognition to effectively market their products. If our product candidates are approved but fail to achieve an adequate level of acceptance by physicians, patients, third-party payors, and others in the medical community, we will not be able to generate sufficient revenue to become or remain profitable.

The insurance coverage and reimbursement status of newly-approved products is uncertain. Failure to obtain or maintain adequate coverage and reimbursement for new or current products could limit our ability to market those products and decrease our ability to generate revenue.

There is significant uncertainty related to the insurance coverage and reimbursement of newly approved products. In the United States, the principal decisions about reimbursement for new medicines are typically made by the Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S. Department of Health and Human Services, as CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare. Private payors often follow CMS with respect to coverage policy and payment limitations in setting their own reimbursement policies. It is difficult to predict what CMS will decide with respect to reimbursement for fundamentally novel products such as ours, as there is no body of established practices and precedents for these new products. Reimbursement agencies in Europe may be more conservative than CMS. For example, a number of cancer drugs have been approved for reimbursement in the United States, but have not been approved for reimbursement in certain European countries. There may be significant delays in obtaining

 

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reimbursement for newly approved medicines, and our inability to promptly obtain coverage and profitable payment rates from third-party payors for any approved medicines could have a material adverse effect on our business, prospects, financial condition and results of operations.

Outside the United States, international sales are generally subject to extensive governmental price controls and other market regulations, and we believe the increasing emphasis on cost-containment initiatives in Europe, Canada, and other countries has and will continue to put pressure on the pricing and usage of our product candidates. In many countries, the prices of medical products are subject to varying price control mechanisms as part of national health systems. In general, the prices of medicines under such systems are substantially lower than in the United States. Other countries allow companies to fix their own prices for medicines, but monitor and control company profits. Additional foreign price controls or other changes in pricing regulation could restrict the amount that we are able to charge for our product candidates. Accordingly, in markets outside the United States, the reimbursement for our products may be reduced compared with the United States and may be insufficient to generate commercially reasonable revenues and profits. Net prices for medicines may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that currently restrict imports of medicines from countries where they may be sold at lower prices than in the United States.

Moreover, increasing efforts by governmental and third-party payors, in the United States and abroad, to cap or reduce healthcare costs may cause such organizations to limit both coverage and level of reimbursement for new products and, as a result, they may not cover or provide adequate payment for our product candidates. We expect to experience pricing pressures in connection with the sale of any of our product candidates, due to the trend toward managed healthcare, the increasing influence of health maintenance organizations and additional legislative changes. The downward pressure on healthcare costs in general, particularly prescription drugs and surgical procedures and other treatments, has become very intense. As a result, increasingly high barriers are being erected to the entry of new products.

If the market opportunities for our product candidates are smaller than we believe they are, our revenues may be adversely affected and our business may suffer. Because the target patient populations of our product candidates are small, we must be able to successfully identify patients and capture a significant market share to achieve and maintain profitability.

We focus our research and product development on treatments for rare diseases. Given the small number of patients who have the diseases that we are targeting, it is critical to our ability to grow and become profitable that we continue to successfully identify patients with these rare diseases. Our projections of both the number of people who have these diseases, as well as the subset of people with these diseases who have the potential to benefit from treatment with our product candidates, are based on our beliefs and estimates. These estimates have been derived from a variety of sources, including the scientific literature, surveys of clinics, patient foundations, or market research, and may prove to be incorrect. New studies may change the estimated incidence or prevalence of these diseases. The number of patients may turn out to be lower than expected. The effort to identify patients with diseases we seek to treat is in early stages, and we cannot accurately predict the number of patients for whom treatment might be possible. Additionally, the potentially addressable patient population for each of our product candidates may be limited or may not be amenable to treatment with our product candidates, and new patients may become increasingly difficult to identify or gain access to, which would adversely affect our results of operations and our business. Further, even if we obtain significant market share for our product candidates, because the potential target populations are very small, we may never achieve profitability despite obtaining such significant market share.

Our target patient populations are relatively small, and there is currently no standard of care treatment directed at some of our target indications, such as FSHD. As a result, the pricing and reimbursement of our product candidates, if approved, is uncertain, but must be adequate to support commercial infrastructure. If we are unable to obtain adequate levels of reimbursement, our ability to successfully market and sell our product candidates will be adversely affected. The manner and level at which reimbursement is provided for services

 

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related to our product candidates (e.g., for administration of our product to patients) is also important. Inadequate reimbursement for such services may lead to physician resistance and adversely affect our ability to market or sell our products.

Risks related to our intellectual property

If we are unable to obtain, maintain or protect intellectual property rights related to our product candidates, or if the scope of such intellectual property protection is not sufficiently broad, we may not be able to compete effectively in our markets.

We rely upon a combination of patents, trade secret protection and confidentiality agreements to protect the intellectual property related to our technologies and product candidates. Our success depends in large part on our and our licensors’ abilities to obtain and maintain patent and other intellectual property protection in the United States and in other countries for our proprietary technology and product candidates.

We have sought to protect our proprietary position by filing patent applications in the United States and abroad related to our novel technologies and product candidates that are important to our business. This process is expensive and time consuming, and we may not be able to file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection.

The patentability of inventions, and the validity, enforceability and scope of patents in the biotechnology and pharmaceutical fields involves complex legal and scientific questions and can be uncertain. As a result, patent applications that we own or in-license may not issue as patents with claims that cover our product candidates, or at all, in the United States or in foreign countries for many reasons. For example, there is no assurance that we were the first to invent or the first to file patent applications in respect of the inventions claimed in our patent applications or that our patent applications claim patentable subject matter. We may also be unaware of potentially relevant prior art relating to our patents and patent applications, and this prior art, if any, may be used by third parties as grounds to seek to invalidate a patent or to prevent a patent from issuing from a pending patent application. Even if patents do successfully issue and even if such patents disclose aspects of our product candidates, third parties may challenge their validity, enforceability or scope, which may result in such patents being narrowed or invalidated. Furthermore, even if they are unchallenged, our patents and patent applications may not adequately protect our intellectual property, provide exclusivity for our product candidates or prevent others from designing around our claims. If the breadth or strength of protection provided by the patents and patent applications we hold, license or pursue with respect to our product candidates is threatened, it could threaten our ability to commercialize our product candidates. Further, if we encounter delays in our clinical trials, the period of time during which we could market any of our product candidates under patent protection, if approved, would be reduced. Since patent applications in the United States and most other countries are confidential for a period of time after filing, we cannot be certain that we were the first to file any patent application related to our product candidates. Changes to the patent laws in the United States and other jurisdictions could also diminish the value of our patents and patent applications or narrow the scope of our patent protection. Any of these outcomes could impair our ability to prevent competition from third parties, which may have an adverse impact on our business.

If the patent applications we own or have in-licensed that relate to our programs or product candidates do not issue as patents, if their breadth or strength of protection is threatened, or if they fail to provide exclusivity for our product candidates, it could dissuade companies from collaborating with us to develop product candidates, and threaten our ability to commercialize future products. We cannot offer any assurances about which, if any, patents will issue, the breadth of any such patents or whether any issued patents will be found invalid and unenforceable or will be threatened by third parties. Any successful opposition to these patents or any other patents owned by or licensed to us could deprive us of rights necessary for the successful commercialization of any product candidates that we may develop. In addition, patents have a limited term. In the United States, the natural expiration of a patent is generally 20 years after it is filed. Although various

 

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extensions may be available, the life of a patent, and the protection it affords, is limited. Even if a patent does issue for any of our pending patent applications, possible delays in regulatory approvals could mean that the period of time during which we could market a product candidate under patent protection could be reduced from what we generally would expect. Since patent applications in the United States and most other countries are confidential for a period of time after filing, and some remain so until issued, we cannot be certain that we were the first to file any patent application related to a product candidate. Furthermore, if third parties have filed such patent applications, an interference proceeding in the United States can be initiated by a third party to determine who was the first to invent any of the subject matter covered by the patent claims of our applications. Even if patents covering aspects of our product candidates are obtained, once the patent life has expired for a product, we may be open to competition from generic medications.

In addition to the protection afforded by patents, we rely on trade secret protection and confidentiality agreements to protect proprietary know-how that is not patentable or that we elect not to patent, processes for which patents are difficult to enforce and any other elements of our product candidate discovery and development processes that involve proprietary know-how, information or technology that is not covered by patents. However, trade secrets can be difficult to protect. We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our employees, consultants, scientific advisors and contractors. We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems, but it is possible that these security measures could be breached. Although we expect all of our employees and consultants to assign their inventions to us, and all of our employees, consultants, advisors and any third parties who have access to our proprietary know-how, information or technology to enter into confidentiality agreements, we cannot provide any assurances that all such agreements have been duly executed or that our trade secrets and other confidential proprietary information will not be disclosed or that competitors will not otherwise gain access to our trade secrets or independently develop substantially equivalent information and techniques. For example, any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches. Misappropriation or unauthorized disclosure of our trade secrets could impair our competitive position and may have a material adverse effect on our business. Additionally, if the steps we take to maintain the confidentiality of our trade secrets are inadequate, we may have insufficient recourse against third parties for misappropriating our proprietary information and processes. In addition, others may independently discover our trade secrets and proprietary information. For example, the FDA, as part of its Transparency Initiative, is currently considering whether to make additional information publicly available on a routine basis, including information that we may consider to be trade secrets or other proprietary information, and it is not clear at the present time how the FDA’s disclosure policies may change in the future, if at all.

If we are unable to prevent material disclosure of the non-patented intellectual property related to our technologies to third parties, and there is no guarantee that we will have any such enforceable trade secret protection, we may not be able to establish or maintain a competitive advantage in our market, which could materially adversely affect our business, results of operations and financial condition.

Further, the laws of some foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the United States. As a result, we may encounter significant problems in preventing third parties from practicing our inventions in countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions.

Claims that our product candidates or the sale or use of our future products infringe the patent or other intellectual property rights of third parties could result in costly litigation or could require substantial time and money to resolve, even if litigation is avoided.

Our commercial success depends in part on our avoiding infringement of the patents and proprietary rights of third parties. There is a substantial amount of litigation, both within and outside the United States, involving patent and other intellectual property rights in the biotechnology and pharmaceutical industries, including patent

 

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infringement lawsuits, interferences, oppositions and inter partes reexamination proceedings before the United States Patent and Trademark Office, or USPTO, and corresponding foreign patent offices. Numerous U.S. and foreign issued patents and pending patent applications, which are owned by third parties, exist in the fields in which we are pursuing development candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our product candidates may be subject to claims of infringement of the patent rights of third parties.

Third parties may assert that we are employing their proprietary technology without authorization. There may be third-party patents or patent applications with claims to materials, formulations, methods of manufacture or methods for treatment related to the use or manufacture of our product candidates. Because patent applications can take many years to issue, there may be currently pending patent applications which may later result in issued patents that our product candidates may infringe. In addition, third parties may obtain patents in the future and claim that use of our technologies infringes upon these patents. If any third-party patents were held by a court of competent jurisdiction to cover the manufacturing process of any of our product candidates, any molecules formed during the manufacturing process or any final product itself, the holders of any such patents may be able to block our ability to commercialize such product candidate unless we obtained a license under the applicable patents, or until such patents expire.

Similarly, if any third-party patents are held by a court of competent jurisdiction to cover aspects of our formulations, processes for manufacture or methods of use, the holders of any such patents may be able to block our ability to develop and commercialize the applicable product candidate unless we obtain a license or until such patent expires. In either case, such a license may not be available on commercially reasonable terms or at all.

Parties making claims against us may obtain injunctive or other equitable relief, which could effectively block our ability to further develop and commercialize one or more of our product candidates. Defense of these claims, regardless of their merit, would involve substantial litigation expense and would be a substantial diversion of employee resources from our business. In the event of a successful claim of infringement against us, we may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, pay royalties, redesign our infringing products or obtain one or more licenses from third parties, which may not be able to be obtained on reasonable commercial terms or at all, or require substantial time and monetary expenditure.

We may not be successful in obtaining or maintaining necessary rights to our Physiocrine therapeutic product candidates and processes for our development pipeline through acquisitions and in-licenses.

We believe that we have rights to intellectual property, through licenses from third parties and under patents that we own, that is necessary or useful to develop our product candidates. Because our programs may involve additional product candidates that may require the use of proprietary rights held by third parties, the growth of our business will likely depend in part on our ability to acquire, in-license or use these proprietary rights. In addition, our product candidates may require specific formulations to work effectively and efficiently and these rights may be held by others. We may be unable to acquire or in-license any compositions, methods of use, processes or other third-party intellectual property rights from third parties that we identify on reasonable commercial terms or at all. The licensing and acquisition of third-party intellectual property rights is a competitive area, and a number of more established companies are also pursuing strategies to license or acquire third-party intellectual property rights that we may consider attractive. These established companies may have a competitive advantage over us due to their size, cash resources and greater clinical development and commercialization capabilities.

We sometimes collaborate with U.S. and foreign academic institutions to accelerate our preclinical research or development under written agreements with these institutions. These institutions may provide us with an option to negotiate a license to the institution’s rights in technology resulting from the collaboration. Regardless

 

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of any such right of first negotiation for intellectual property, we may be unable to negotiate a license within the specified time frame or under terms that are acceptable to us. If we are unable to do so, the institution may offer the intellectual property rights to other parties, potentially blocking our ability to pursue our program.

In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us. We also may be unable to license or acquire third-party intellectual property rights on terms that would allow us to make an appropriate return on our investment. If we are unable to successfully obtain rights to required third-party intellectual property rights, our business, financial condition and prospects for growth could suffer.

If we fail to comply with our obligations in the agreements under which we license intellectual property rights from third parties or otherwise experience disruptions to our business relationships with our licensors, we could lose license rights that are important to our business.

We are a party to a number of intellectual property license agreements that are important to our business and expect to enter into additional license agreements in the future. Our existing license agreements impose, and we expect that future license agreements will impose, various diligence, milestone payment, royalty and other obligations on us. If we fail to comply with our obligations under these agreements, or we are subject to a bankruptcy, the licensor may have the right to terminate the license, in which event we would not be able to market products covered by the license. For example, under the terms of the license agreements that we may enter into pursuant to our amended and restated research funding and option agreement with The Scripps Research Institute, or TSRI, TSRI has the right to terminate the license under various circumstances, including our failure to make payments to TSRI when due, our default in our indemnification and insurance obligations under the agreement, our failure to meet diligence obligations, as determined by TSRI, our underreporting or underpayment of amounts due to TSRI, our conviction of a felony related to the manufacture, use or sale of licensed products, services or processes and our institution of any challenges to the validity or enforceability of any of the licensed patents.

We may need to obtain licenses from third parties to advance our research or allow commercialization of our product candidates, and we have done so from time to time. We may fail to obtain any of these licenses at a reasonable cost or on reasonable commercial terms, if at all. In that event, we may be required to expend significant time and resources to develop or license replacement technology. If we are unable to do so, we may be unable to develop or commercialize the affected product candidates, which could harm our business significantly. We cannot provide any assurances that third-party patents do not exist which might be enforced against our current product candidates or future products, resulting in either an injunction prohibiting our sales, or, with respect to our sales, an obligation on our part to pay royalties or other forms of compensation to third parties.

In some cases, patent prosecution of our licensed technology is controlled by the licensor. Under the license agreements that we may enter into pursuant to our amended and restated research funding and option agreement with TSRI, TSRI is responsible for the prosecution and maintenance of the licensed patent rights, subject to our right to be consulted and to be informed of the progress of patent applications, patents and related submissions. If our licensors fail to obtain and maintain patent or other protection for the proprietary intellectual property we license from them, we could lose our rights to the intellectual property or our exclusivity with respect to those rights, and our competitors could market competing products using such intellectual property. In certain cases, we may control the prosecution of patents resulting from licensed technology. In the event we breach any of our obligations related to such prosecution, we may incur significant liability to our licensors. Licensing of intellectual property is of critical importance to our business and involves complex legal, business and scientific issues and is complicated by the rapid pace of scientific discovery in our industry. Disputes may arise regarding intellectual property subject to a license agreement, including:

 

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the scope of rights granted under the license agreement and other interpretation-related issues;

 

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the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the license agreement;

 

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the sublicensing of patent and other rights under our collaborative development relationships;

 

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our diligence obligations under the license agreement and what activities satisfy those diligence obligations;

 

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the ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our licensors and us and our sublicensees or partners, if any; and

 

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the priority of invention of patented technology.

If disputes over intellectual property that we have licensed prevent or impair our ability to maintain our current licensing arrangements on acceptable terms, we may be unable to successfully develop and commercialize the affected product candidates.

We may become involved in lawsuits to protect or enforce our patents or the patents of our licensors, which could be expensive, time-consuming and unsuccessful.

Competitors may infringe or otherwise violate our patents, the patents of our licensors or our other intellectual property rights. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive and time-consuming. Any claims that we assert against perceived infringers could also provoke these parties to assert counterclaims against us alleging that we infringe their intellectual property rights. In addition, in an infringement proceeding, a court may decide that a patent of ours or our licensors is not valid, is unenforceable or is not infringed, or may refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question. An adverse result in any litigation or defense proceedings could put one or more of our patents at risk of being invalidated or interpreted narrowly and could put our patent applications at risk of not issuing.

Interference or derivation proceedings provoked by third parties or brought by us may be necessary to determine the priority of inventions or other matters of inventorship with respect to our patents or patent applications or those of our licensors. We may also become involved in other proceedings, such as re-examination or opposition proceedings, before the USPTO or its foreign counterparts relating to our intellectual property or the intellectual property rights of others. An unfavorable outcome in any such proceedings could require us to cease using the related technology or to attempt to license rights to it from the prevailing party, or could cause us to lose valuable intellectual property rights. Our business could be harmed if the prevailing party does not offer us a license on commercially reasonable terms, if any license is offered at all. Our defense of litigation or interference proceedings may fail and, even if successful, may result in substantial costs and distract our management and other employees. We may not be able to prevent, alone or with our licensors, misappropriation of our intellectual property rights, particularly in countries where the laws may not protect those rights as fully as in the United States. In addition, the uncertainties associated with litigation could have a material adverse effect on our ability to raise the funds necessary to continue our clinical trials, continue our research programs, license necessary technology from third parties, or enter into development partnerships that would help us bring our product candidates to market. We may also become involved in disputes with others regarding the ownership of intellectual property rights. For example, we jointly develop intellectual property with certain parties, and disagreements may therefore arise as to the ownership of the intellectual property developed pursuant to these relationships. If we are unable to resolve these disputes, we could lose valuable intellectual property rights.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation. There could also be public announcements of the results of hearings, motions or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a material adverse effect on the price of our common stock.

 

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We may be subject to claims that our employees, consultants or independent contractors have wrongfully used or disclosed confidential information of third parties or that our employees have wrongfully used or disclosed alleged trade secrets of their former employers.

We employ individuals who were previously employed at universities or other biotechnology or pharmaceutical companies, including our competitors or potential competitors. Although we try to ensure that our employees, consultants and independent contractors do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or our employees, consultants or independent contractors have inadvertently or otherwise used or disclosed intellectual property, including trade secrets or other proprietary information, of any of our employee’s former employer or other third parties. Litigation may be necessary to defend against these claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel, which could adversely impact our business. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

We may be subject to claims challenging the inventorship or ownership of our patents and other intellectual property.

Although we are not currently experiencing any claims challenging the inventorship of our patents or ownership of our intellectual property, we may in the future be subject to claims that former employees, collaborators or other third parties have an ownership interest in our patents or other intellectual property. For example, we may have inventorship disputes arise from conflicting obligations of consultants or others who are involved in developing our product candidates. Litigation may be necessary to defend against these and other claims challenging inventorship or ownership. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, valuable intellectual property. Such an outcome could have a material adverse effect on our business. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.

Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on patents or applications will be due to be paid to the USPTO and various governmental patent agencies outside of the United States in several stages over the lifetime of the patents or applications. We have systems in place to remind us to pay these fees, and we employ an outside firm and rely on our outside counsel to pay these fees due to non-U.S. patent agencies. The USPTO and various non-U.S. governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application process. We employ law firms and other professionals to help us comply, and in many cases, an inadvertent lapse can be cured by payment of a late fee or by other means in accordance with the applicable rules. However, there are situations in which non-compliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. In such an event, our competitors might be able to enter the market and this circumstance would have a material adverse effect on our business.

Issued patents covering our product candidates could be found invalid or unenforceable if challenged in court.

If we or one of our licensors initiated legal proceedings against a third party to enforce a patent covering one of our product candidates, the defendant could counterclaim that the patent covering our product candidate is invalid or unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity or unenforceability are commonplace. Grounds for a validity challenge could be an alleged failure to meet any of several statutory requirements, including lack of novelty, obviousness or non-enablement. Grounds for an

 

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unenforceability assertion could be an allegation that someone connected with prosecution of the patent withheld relevant information from the USPTO, or made a misleading statement, during prosecution. Third parties may also raise similar claims before administrative bodies in the United States or abroad, even outside the context of litigation. Such mechanisms include re-examination, post grant review, and equivalent proceedings in foreign jurisdictions (e.g., opposition proceedings). Such proceedings could result in revocation or amendment to our patents in such a way that they no longer cover our product candidates. The outcome following legal assertions of invalidity and unenforceability is unpredictable. With respect to the validity question, for example, we cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during prosecution. If a defendant were to prevail on a legal assertion of invalidity or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our product candidates. Such a loss of patent protection would have a material adverse impact on our business.

Changes in patent law could diminish the value of patents in general, thereby impairing our ability to protect our products.

As is the case with many other biotechnology companies, our success is heavily dependent on intellectual property, particularly patents. Obtaining and enforcing patents in the biotechnology industry involve both technological and legal complexity, and is therefore obtaining, maintaining and enforcing biotechnology patents is costly, time-consuming and inherently uncertain. In addition, recent legislative and judicial developments in the United States and elsewhere have in some cases removed the protection afforded to patent owners, made patents more difficult to obtain, or increased the uncertainty regarding the ability to obtain, maintain and enforce patents. For example, Congress has recently passed, and the United States is currently implementing, wide-ranging patent reform legislation, and may pass further patent reform legislation in the future. Recent U.S. Supreme Court rulings have narrowed the scope of patent protection available in certain circumstances and weakened the rights of patent owners in certain situations. For example, in a recent case, Association for Molecular Pathology v. Myriad Genetics, Inc., the U.S. Supreme Court held that certain claims to naturally-occurring substances are not patentable. Although we do not believe that any of the patents owned or licensed by us will be found invalid based on this decision, we cannot predict how future decisions by the courts, the U.S. Congress, or the USPTO may impact the value of our patents. In addition to increasing uncertainty with regard to our ability to obtain patents in the future, this combination of events has created uncertainty with respect to the value of patents generally, once obtained. Depending on decisions and actions by the U.S. Congress, the federal courts, the USPTO and their respective foreign counterparts, the laws and regulations governing patents could change in unpredictable ways that would weaken our ability to obtain new patents or to maintain and enforce our existing patents and patents that we might obtain in the future.

Recent patent reform legislation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the validity or defense of our issued patents.

On September 16, 2011, the Leahy-Smith America Invents Act, or the Leahy-Smith Act, was signed into law. The Leahy-Smith Act includes a number of significant changes to U.S. patent law, including provisions that affect the way patent applications will be prosecuted and may also affect patent litigation. The USPTO is currently developing regulations and procedures to govern administration of the Leahy-Smith Act, and many of the substantive changes to patent law associated with the Leahy-Smith Act, and in particular, the first to file provisions, were enacted March 16, 2013. Although it is not clear what, if any, impact the Leahy-Smith Act will have on the operation of our business, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business and financial condition.

We have not yet registered trademarks for a commercial trade name for Resolaris and failure to secure such registrations could adversely affect our business.

We have not yet registered any trademarks for a commercial trade name for Resolaris. During trademark registration proceedings, we may receive rejections. Although we would be given an opportunity to respond to

 

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those rejections, we may be unable to overcome such rejections. In addition, in the USPTO and in comparable agencies in many foreign jurisdictions, third parties are given an opportunity to oppose pending trademark applications and to seek to cancel registered trademarks. Opposition or cancellation proceedings have been filed and may in the future be filed against certain of our trademarks, and our trademarks may not survive such proceedings. Moreover, any name we propose to use with our product candidates in the United States must be approved by the FDA, regardless of whether we have registered it, or applied to register it, as a trademark. The FDA typically conducts a review of proposed product names, including an evaluation of potential for confusion with other product names. If the FDA objects to any of our proposed proprietary product names, we may be required to expend significant additional resources in an effort to identify a suitable substitute name that would qualify under applicable trademark laws, not infringe the existing rights of third parties and be acceptable to the FDA.

We may not be able to protect our intellectual property rights throughout the world.

Filing, prosecuting and defending patents on product candidates in all countries throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the United States can be less extensive than those in the United States. In addition, the laws of some foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the United States. Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions. Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own products and further, may export otherwise infringing products to territories where we have patent protection, but enforcement is not as strong as that in the United States. These products may compete with our products and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets and other intellectual property protection, particularly those relating to biotechnology products, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of our proprietary rights generally. Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us. We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.

Risks related to our business operations

Our future success depends on our ability to retain key employees, consultants and advisors and to attract, retain and motivate qualified personnel.

We are highly dependent on principal members of our executive team listed under “Management” located elsewhere in this prospectus, the loss of whose services may adversely impact the achievement of our objectives. Additionally, our principal financial and accounting officer is a consultant and we may face conflicts of interest as he allocates his time across various interests. While we have entered into employment agreements with each of our other executive officers, any of them could leave our employment at any time, as all of our employees are “at will” employees. Recruiting and retaining other qualified employees, consultants and advisors for our business, including scientific and technical personnel, will also be critical to our success. There is currently a shortage of skilled executives in our industry, which is likely to continue. As a result, competition for skilled personnel is intense and the turnover rate can be high. We may not be able to attract and retain personnel on acceptable terms

 

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given the competition among numerous pharmaceutical and biotechnology companies for individuals with similar skill sets. In addition, failure to succeed in preclinical studies or clinical trials may make it more challenging to recruit and retain qualified personnel. The inability to recruit or loss of the services of any executive, key employee, consultant or advisor may impede the progress of our research, development and commercialization objectives. Furthermore, many of our employees have become or will soon become vested in a substantial amount of stock or number of stock options. Our employees may be more likely to leave us if the shares they own or the shares underlying their vested options have significantly appreciated in value relative to the original purchase prices of the shares or the exercise prices of the options, or if the exercise prices of the options that they hold are significantly below the market price of our common stock. Further, our employees’ ability to exercise those options and sell their stock in a public market after the closing of this offering may result in a higher than normal turnover rate.

We are subject to a variety of risks associated with international operations that could materially adversely affect our business.

We currently conduct research activities through our majority-owned Hong Kong subsidiary, Pangu BioPharma Limited, in collaboration with the Hong Kong University of Science and Technology and maintain a representative office for this subsidiary in China. Additionally, we are currently conducting our Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD in the European Union, and the supply of Resolaris for our clinical trials is currently produced in India by a third-party manufacturer. If any of our product candidates are approved for commercialization outside of the United States, we expect to either use our own sales organization or selectively enter into agreements with third parties to market our products on a worldwide basis or in more limited geographical regions. We are, and we expect that we will continue to be, subject to a variety of risks related to international operations, including:

 

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different regulatory requirements for approval of drugs and biologics in foreign countries;

 

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reduced or uncertain protection for intellectual property;

 

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unexpected changes in tariffs, trade barriers and regulatory requirements;

 

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economic weakness, including inflation, or political instability in particular foreign economies and markets;

 

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compliance with tax, employment, immigration and labor laws for employees living or traveling abroad; and

 

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foreign currency fluctuations, which could result in reduced revenues, and other obligations incident to doing business in another country.

Any failure to continue our international operations or to commercialize our product candidates outside of the United States may impair our ability to generate revenues and harm our business, prospects and results of operations.

We will need to expand our organization and we may experience difficulties in managing this growth, which could disrupt our operations.

We have recently increased the size of our management team and as of January 1, 2015, we had 46 full-time employees. As we continue our Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD, prepare for additional clinical trials of Resolaris and expand our other clinical development activities, as well as begin our operations as a public company, we expect to increase our full-time employee base and to hire more consultants and contractors. In addition to certain members of our management team being relatively new to our company, our management may need to divert a disproportionate amount of its attention away from our day-to-day activities and devote a substantial amount of time to managing these growth activities. We may not be able to effectively manage the expansion of our operations, which may result in weaknesses in our infrastructure, operational mistakes, loss of business opportunities, loss of employees and reduced productivity among

 

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remaining employees. Our expected growth could require significant capital expenditures and may divert financial resources from other projects, such as the conduct of additional clinical activities for Resolaris and the development of additional product candidates. If our management is unable to effectively manage our growth, our expenses may increase more than expected, our ability to generate or grow revenues could be reduced, and we may not be able to implement our business strategy. Our future financial performance and our ability to develop and commercialize product candidates and compete effectively will depend, in part, on our ability to effectively manage any future growth.

We may use our financial and human resources to pursue a particular business strategy, research program or product candidate and fail to capitalize on strategies, programs or product candidates that may be more profitable or for which there is a greater likelihood of success.

Because we have limited resources, we may forego or delay pursuit of certain strategic opportunities or opportunities with certain programs or product candidates or for indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. In addition, we may elect to pursue a research, clinical or commercial strategy that ultimately does not yield the results that we desire. Our spending on current and future research and development programs for product candidates may not result in any commercially viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through strategic collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate, or we may allocate internal resources to a product candidate in a therapeutic area or market in which it would have been more advantageous to enter into a partnering arrangement. Any failure to allocate resources or capitalize on strategies in a successful manner will have an adverse impact on our business.

Our employees, principal investigators, consultants and commercial partners may engage in misconduct or other improper activities, including non-compliance with regulatory standards and requirements and insider trading.

We are exposed to the risk of fraud or other misconduct by our employees, principal investigators, consultants and commercial partners. Misconduct by these parties could include intentional failures to comply with the regulations of the FDA and non-U.S. regulators, provide accurate information to the FDA and non-U.S. regulators, comply with healthcare fraud and abuse laws and regulations in the United States and abroad, report financial information or data accurately or disclose unauthorized activities to us. In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other business arrangements. Such misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and cause serious harm to our reputation. We intend to adopt, prior to the completion of this offering, a code of conduct applicable to all of our employees, but it is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to comply with these laws or regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other sanctions.

 

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We face potential product liability, and, if successful claims are brought against us, we may incur substantial liability and costs. If the use of our product candidates harms patients, or is perceived to harm patients even when such harm is unrelated to our product candidates, our regulatory approvals could be revoked or otherwise negatively impacted and we could be subject to costly and damaging product liability claims.

The use of our product candidates in clinical trials and the sale of any products for which we obtain marketing approval exposes us to the risk of product liability claims. Product liability claims might be brought against us by patients, healthcare providers, pharmaceutical companies or others selling or otherwise coming into contact with our products. There is a risk that our product candidates may induce adverse events. If we cannot successfully defend against product liability claims, we could incur substantial liability and costs. In addition, regardless of merit or eventual outcome, product liability claims may result in:

 

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impairment of our business reputation;

 

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withdrawal of clinical trial participants;

 

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costs due to related litigation;

 

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distraction of management’s attention from our primary business;

 

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substantial monetary awards to patients or other claimants;

 

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the inability to commercialize our product candidates; and

 

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decreased demand for our product candidates, if approved for commercial sale.

We carry product liability insurance for our clinical trials covering $5.0 million per occurrence and up to $5.0 million in the aggregate, subject to certain deductibles and exclusions. Although we believe the amount of our insurance coverage is typical for companies similar to us in our industry, we may not have adequate insurance coverage or be able to maintain insurance coverage at a reasonable cost or in sufficient amounts to protect us against losses due to liability. If and when we obtain marketing approval for product candidates, we intend to expand our insurance coverage to include the sale of commercial products; however, we may be unable to obtain product liability insurance on commercially reasonable terms or in adequate amounts. On occasion, large judgments have been awarded in class action lawsuits based on drugs or medical treatments that had unanticipated adverse effects. A successful product liability claim or series of claims brought against us could cause our stock price to decline and adversely affect our reputation and, if judgments exceed our insurance coverage, could adversely affect our results of operations and business.

Patients with the diseases targeted by our product candidates are often already in severe and advanced stages of disease and may have both known and unknown significant pre-existing and potentially life-threatening health risks. During the course of treatment, patients may suffer adverse events, including death, for reasons that may be related to our product candidates. Such events could subject us to costly litigation, require us to pay substantial amounts of money to injured patients, delay, negatively impact or end our opportunity to receive or maintain regulatory approval to market our products, or require us to suspend or abandon our commercialization efforts. Even in a circumstance in which we do not believe that an adverse event is related to our products, the investigation into the circumstance may be time-consuming or inconclusive. These investigations may interrupt our sales efforts, delay our regulatory approval process in other countries, or impact and limit the type of regulatory approvals our product candidates receive or maintain. As a result of these factors, a product liability claim, even if successfully defended, could have a material adverse effect on our business, financial condition or results of operations.

If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on the success of our business.

We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials

 

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and wastes. Our operations involve the use of hazardous and flammable materials, including chemicals and biological materials. Our operations also produce hazardous waste products. We generally contract with third parties for the disposal of these materials and wastes. We cannot eliminate the risk of contamination or injury from these materials. In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties.

Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials or other work-related injuries, this insurance may not provide adequate coverage against potential liabilities. In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may impair our research, development or production efforts. Failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions.

We are subject to anti-corruption laws in the jurisdictions in which we operate.

We are subject to a number of anti-corruption laws, including the U.S. Foreign Corrupt Practices Act, or the FCPA, and various other anti-corruption laws. The FCPA generally prohibits companies and their intermediaries from making improper payments to foreign officials for the purpose of obtaining or keeping business and/or other benefits. Our business relies on approvals and licenses from government and regulatory entities, and as a result, we are subject to certain elevated risks associated with interactions with these entities. Although our employee handbook strictly forbids gifts to government employees, to date we have not developed formal policies and procedures governing the interactions of employees with government entities to mitigate these risks. If we are not in compliance with anti-corruption laws and other laws governing the conduct of business with government entities (including local laws), we may be subject to criminal and civil penalties and other remedial measures, which could harm our reputation and have a material adverse impact on our business, financial condition, results of operations and prospects. Any investigation of any actual or alleged violations of such laws could also harm our reputation or have an adverse impact on our business, prospects, financial condition and results of operations.

We will incur significant increased costs as a result of operating as a public company, and our management will be required to devote substantial time to new compliance initiatives.

As a public company, we will incur significant legal, accounting and other expenses that we did not incur as a private company. In addition, the Sarbanes-Oxley Act of 2002, or Sarbanes-Oxley Act, as well as rules subsequently implemented by the Securities and Exchange Commission, or SEC, and The Nasdaq Global Market have imposed various requirements on public companies. In July 2010, the Dodd-Frank Wall Street Reform and Consumer Protection Act, or the Dodd-Frank Act, was enacted. There are significant corporate governance and executive compensation related provisions in the Dodd-Frank Act that require the SEC to adopt additional rules and regulations in these areas such as “say on pay” and proxy access. Recent legislation permits smaller “emerging growth companies” to implement many of these requirements over a longer period and up to five years from the pricing of this offering. We intend to take advantage of this legislation but cannot guarantee that we will not be required to implement these requirements sooner than budgeted or planned and thereby incur unexpected expenses. Stockholder activism, the current political environment and the current high level of government intervention and regulatory reform may lead to substantial new regulations and disclosure obligations, which may lead to additional compliance costs and impact the manner in which we operate our business in ways we cannot currently anticipate. Our management and other personnel will need to devote a substantial amount of time to these compliance initiatives. Moreover, these rules and regulations will increase our legal and financial compliance costs and will make some activities more time-consuming and costly. For example, we expect these rules and regulations to make it more difficult and more expensive for us to obtain director and officer liability insurance and we may be required to incur substantial costs to maintain our current levels of such coverage.

 

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Unfavorable global economic conditions could adversely affect our business, financial condition or results of operations.

Our results of operations could be adversely affected by general conditions in the global economy and in the global financial markets. The recent global financial crisis caused extreme volatility and disruptions in the capital and credit markets. A severe or prolonged economic downturn, such as the recent global financial crisis, could result in a variety of risks to our business, including inability to raise additional capital when needed on acceptable terms, if at all. A weak or declining economy could also strain our manufacturers, possibly resulting in supply disruption. Any of the foregoing could harm our business and we cannot anticipate all of the ways in which the current economic climate and financial market conditions could adversely impact our business.

We or the third parties upon whom we depend may be adversely affected by earthquakes, droughts, floods, fires or other natural disasters and our business continuity and disaster recovery plans may not adequately protect us from a serious disaster.

We are located in San Diego, California, and our clinical supply of Resolaris is produced in India. We currently anticipate that if Resolaris receives marketing approval, commercial production may take place in the United Kingdom. Some of these geographic locations have in the past experienced natural disasters, including severe earthquakes. Earthquakes, droughts, floods, fires, disease epidemics or other natural disasters could severely disrupt our operations, and have a material adverse effect on our business, results of operations, financial condition and prospects. If a natural disaster, power outage or other event occurred that prevented us from using all or a significant portion of our facilities, that damaged critical infrastructure, such as the manufacturing facilities of our third-party contract manufacturers, or that otherwise disrupted operations, it may be difficult or, in certain cases, impossible for us to continue our business for a substantial period of time. The disaster recovery and business continuity plans we have in place currently are limited and are unlikely to prove adequate in the event of a serious disaster or similar event. We may incur substantial expenses as a result of the limited nature of our disaster recovery and business continuity plans, as well as limits on our insurance coverage, which could have a material adverse effect on our business, prospects, financial condition and results of operations.

Risks related to this offering and ownership of our common stock

An active trading market for our common stock may not develop.

Prior to this offering, there has not been a public market for our common stock. An active trading market for our common stock may not develop or be sustained following this offering. You may not be able to sell your shares quickly or at the market price if trading in our common stock is not active. The initial public offering price for the shares will be determined by negotiations between us and the representative of the underwriters and may not be indicative of prices that will prevail in the trading market.

The market price of our common stock may be highly volatile, and you may not be able to resell your shares at or above the initial public offering price.

The market price of our common stock is likely to be volatile. Our stock price could be subject to wide fluctuations in response to a variety of factors, including the following:

 

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adverse results or delays in preclinical studies or clinical trials;

 

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the imposition of a clinical hold on our product candidates or our inability to cause the clinical hold to be lifted;

 

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any delay in filing an IND or BLA for any of our product candidates and any adverse development or perceived adverse development with respect to the FDA’s review of that IND or BLA;

 

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•

failure to develop successfully and commercialize our product candidates;

 

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the perception of limited market sizes or pricing for our product candidates;

 

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failure by us or our licensors to prosecute, maintain or enforce intellectual property rights covering our product candidates and processes;

 

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changes in laws or regulations applicable to future products;

 

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inability to obtain adequate product supply for our product candidates or the inability to do so at acceptable prices;

 

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adverse regulatory decisions;

 

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introduction of new products, services or technologies by our competitors;

 

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inability to obtain additional funding;

 

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failure to meet or exceed financial or operational projections we may provide to the public;

 

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failure to meet or exceed the financial or operational projections of the investment community;

 

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the perception of the pharmaceutical industry by the public, legislatures, regulators and the investment community;

 

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significant acquisitions, strategic partnerships, joint ventures or capital commitments by us or our competitors;

 

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disputes or other developments relating to proprietary rights, including patents, litigation matters and our ability to obtain patent protection for our technologies;

 

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additions or departures of key scientific or management personnel;

 

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significant lawsuits, including patent or stockholder litigation;

 

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if securities or industry analysts do not publish research or reports about our business, or they issue an adverse or misleading opinion regarding our stock;

 

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changes in the market valuations of similar companies;

 

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general market or macroeconomic conditions;

 

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sales of our common stock by us or our stockholders in the future; and

 

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trading volume of our common stock.

In addition, companies trading in the stock market in general, and The Nasdaq Global Market in particular, have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of these companies. Broad market and industry factors may negatively affect the market price of our common stock, regardless of our actual operating performance.

Our executive officers, directors, principal stockholders and their affiliates own a significant percentage of our stock and will be able to exert significant control over matters submitted to stockholders for approval.

Our executive officers, directors, five percent stockholders and their affiliates beneficially own approximately 92% of our voting stock and, upon closing of this offering, that same group will beneficially own approximately     % of our outstanding voting stock (assuming no exercise of the underwriters’ option to purchase additional shares). Therefore, even after this offering, these stockholders will have the ability to influence us through their ownership positions and may be able to determine all matters requiring stockholder approval. For example, these stockholders, acting together, may be able to control elections of directors, amendments of our organizational documents, or approval of any merger, sale of assets, or other major corporate transaction. This may prevent or discourage unsolicited acquisition proposals or offers for our common stock that you may believe are in your best interest as one of our stockholders.

 

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We are an “emerging growth company,” and we cannot be certain if the reduced reporting requirements applicable to emerging growth companies will make our common stock less attractive to investors.

We are an “emerging growth company,” as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act. For as long as we continue to be an emerging growth company, we may take advantage of exemptions from various reporting requirements that are applicable to other public companies that are not emerging growth companies, including not being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act reduced disclosure obligations regarding executive compensation in this prospectus and our periodic reports and proxy statements and exemptions from the requirements of holding a nonbinding advisory vote on executive compensation and stockholder approval of any golden parachute payments not previously approved. We could be an emerging growth company for up to five years, although circumstances could cause us to lose that status earlier, including if the market value of our common stock held by non-affiliates exceeds $700.0 million as of any June 30 before that time or if we have total annual gross revenue of $1.0 billion or more during any fiscal year before that time, in which cases we would no longer be an emerging growth company as of the following December 31 or, if we issue more than $1.0 billion in non-convertible debt during any three-year period before that time, we would cease to be an emerging growth company immediately. Even after we no longer qualify as an emerging growth company, we may still qualify as a “smaller reporting company” which would allow us to take advantage of many of the same exemptions from disclosure requirements, including not being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act and reduced disclosure obligations regarding executive compensation in this prospectus and our periodic reports and proxy statements. We cannot predict if investors will find our common stock less attractive because we may rely on these exemptions. If some investors find our common stock less attractive as a result, there may be a less active trading market for our common stock and our stock price may be more volatile.

Under the JOBS Act, emerging growth companies can also delay adopting new or revised accounting standards until such time as those standards apply to private companies. We have irrevocably elected not to avail ourselves of this exemption from new or revised accounting standards and, therefore, will be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies.

You will incur immediate and substantial dilution in the book value of your shares.

Investors purchasing shares of common stock in this offering will pay a price per share that substantially exceeds the pro forma book value per share of our tangible assets after subtracting our liabilities. As a result, investors purchasing shares of common stock in this offering will incur immediate dilution of $         per share, based on the assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, and our pro forma net tangible book value as of September 30, 2014. For information on how the foregoing amounts were calculated, see “Dilution.” To the extent shares are issued under outstanding options or warrants, or pursuant to the conversion of convertible debt, investors will incur further dilution. As a result of the dilution to investors purchasing shares in this offering, investors may receive significantly less than the purchase price paid in this offering, if anything, in the event of our liquidation.

Sales of a substantial number of shares of our common stock in the public market could cause our stock price to fall.

If our existing stockholders sell, or indicate an intention to sell, substantial amounts of our common stock in the public market after the lock-up and other legal restrictions on resale discussed in this prospectus lapse, the market price of our common stock could decline. Based upon the number of shares of common stock outstanding on an as-converted basis as of September 30, 2014, upon the closing of this offering, we will have outstanding a total of              shares of common stock, assuming no exercise of the underwriters’ option to purchase additional shares and no exercise of outstanding warrants and options. Of these shares, as of the date of this prospectus, approximately              shares of our common stock, plus any shares sold upon exercise of the underwriters’

 

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option to purchase additional shares, will be freely tradable, without restriction, in the public market immediately following this offering, except for any shares purchased in this offering by certain of our stockholders or held by our “affiliates” as that term is defined under Rule 144 of the Securities Act of 1933, as amended, or the Securities Act. The underwriters, however, may, in their sole discretion and under the terms of the lock-up agreements, permit our officers, directors and other stockholders who are subject to the lock-up agreements to sell shares prior to the expiration of the lock-up agreements.

The lock-up agreements pertaining to this offering will expire 180 days from the date of this prospectus. After the lock-up agreements expire, based upon the number of shares of common stock outstanding on an as-converted basis as of September 30, 2014, up to an additional             shares of common stock will be eligible for sale in the public market,                 of which are held by directors, executive officers and other affiliates and will be subject to Rule 144 under the Securities Act.

In addition, as of September 30, 2014,             shares of common stock that are either subject to outstanding options, reserved for future issuance under our equity incentive plans or subject to outstanding warrants will become eligible for sale in the public market to the extent permitted by the provisions of various vesting schedules, the lock-up agreements and Rule 144 and Rule 701 under the Securities Act. If these additional shares of common stock are sold, or if it is perceived that they will be sold, in the public market, the market price of our common stock could decline.

After this offering, the holders of approximately             shares of our common stock will be entitled to rights with respect to the registration of their shares under the Securities Act, subject to the lock-up agreements described above. Registration of these shares under the Securities Act would result in the shares becoming freely tradable without restriction under the Securities Act, except for shares purchased by affiliates. Any sales of securities by these stockholders could have a material adverse effect on the market price of our common stock.

Future sales and issuances of our common stock or rights to purchase common stock, including pursuant to our equity incentive plans, could result in additional dilution of the percentage ownership of our stockholders and could cause our stock price to fall.

We will need additional capital in the future to continue our planned operations. To the extent we raise additional capital by issuing equity securities, our stockholders may experience substantial dilution. We may sell common stock, convertible securities or other equity securities in one or more transactions at prices and in a manner we determine from time to time. If we sell common stock, convertible securities or other equity securities in more than one transaction, investors may be materially diluted by subsequent sales. These sales may also result in material dilution to our existing stockholders, and new investors could gain rights superior to our existing stockholders.

Pursuant to our 2015 Stock Option and Incentive Plan, or the 2015 Plan, we are authorized to grant stock options and other equity-based awards to our employees, directors and consultants. The number of shares available for future grant under the 2015 Plan will automatically increase each year by up to     % of all shares of our capital stock outstanding as of December 31 of the prior calendar year, subject to the ability of our board of directors to take action to reduce the size of the increase in any given year. Currently, we plan to register the increased number of shares available for issuance under the 2015 Plan each year. If our board of directors elects to increase the number of shares available for future grant by the maximum amount each year, our stockholders may experience additional dilution, which could cause our stock price to decline.

If securities analysts do not publish research or reports about our business or if they publish negative evaluations of our stock, the price of our stock could decline.

The trading market for our common stock will rely in part on the research and reports that industry or financial analysts publish about us or our business. We may never obtain research coverage by industry or financial analysts. If no or few analysts commence coverage of us, the trading price of our stock would likely decrease. Even if we do

 

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obtain analyst coverage, if one or more of the analysts covering our business downgrade their evaluations of our stock, the price of our stock could decline. If one or more of these analysts cease to cover our stock, we could lose visibility in the market for our stock, which in turn could cause our stock price to decline.

We could be subject to securities class action litigation.

In the past, securities class action litigation has often been brought against a company following a decline in the market price of its securities. This risk is especially relevant for us because pharmaceutical companies have experienced significant stock price volatility in recent years. If we face such litigation, it could result in substantial costs and a diversion of management’s attention and resources, which could harm our business.

We have broad discretion in the use of the net proceeds from this offering and may not use them effectively.

Our management will have broad discretion in the application of the net proceeds from this offering, including for any of the purposes described in the section entitled “Use of Proceeds,” and you will not have the opportunity as part of your investment decision to assess whether the net proceeds are being used appropriately. Because of the number and variability of factors that will determine our use of the net proceeds from this offering, their ultimate use may vary substantially from their currently intended use. The failure by our management to apply these funds effectively could harm our business. Pending their use, we may invest the net proceeds from this offering in short-term, investment-grade, interest-bearing securities. These investments may not yield a favorable return to our stockholders.

Our ability to use our net operating loss carryforwards and certain other tax attributes may be limited.

We have incurred substantial losses during our history, we do not expect to become profitable in the near future and we may never achieve profitability. Unused losses generally are available to be carried forward to offset future taxable income, if any, until such unused losses expire. Under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, if a corporation undergoes an “ownership change,” generally defined as a greater than 50% change (by value) in its equity ownership over a three-year period, the corporation’s ability to use its pre-change net operating loss carryforwards, or NOLs, and other pre-change tax attributes (such as research tax credits) to offset its post-change taxable income or taxes may be limited. We completed an analysis through September 7, 2011, and determined that on November 30, 2006 an ownership change occurred, for which we have adjusted our NOL and research and development tax credit carryforwards. We may have experienced an ownership change subsequent to September 7, 2011, and we may also experience ownership changes in the future as a result of this offering or subsequent shifts in our stock ownership, some of which may be outside of our control. As a result, our ability to use our pre-change NOLs to offset U.S. federal taxable income may be subject to limitations, which could potentially result in increased future tax liability to us. In addition, at the state level, there may be periods during which the use of NOLs is suspended or otherwise limited, which could accelerate or permanently increase state taxes owed.

We do not intend to pay dividends on our common stock, and therefore any returns will be limited to the value of our stock.

We have never declared or paid any cash dividends on our common stock. We anticipate that we will retain future earnings for the development, operation and expansion of our business and do not anticipate declaring or paying any cash dividends for the foreseeable future. Any return to stockholders will therefore be limited to the appreciation of their stock.

 

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Provisions in our amended and restated certificate of incorporation and bylaws, as well as provisions of Delaware law, could make it more difficult for a third party to acquire us or increase the cost of acquiring us, even if doing so would benefit our stockholders or remove our current management.

Our amended and restated certificate of incorporation, amended and restated bylaws and Delaware law contain or will contain provisions that may have the effect of delaying or preventing a change in control of us or changes in our management. Our amended and restated certificate of incorporation and bylaws, which will become effective upon the closing of this offering, include provisions that:

 

•

authorize “blank check” preferred stock, which could be issued by our board of directors without stockholder approval and may contain voting, liquidation, dividend and other rights superior to our common stock;

 

•

create a classified board of directors whose members serve staggered three-year terms;

 

•

specify that special meetings of our stockholders can be called only by our board of directors, the chairperson of our board of directors, our chief executive officer or our president;

 

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prohibit stockholder action by written consent;

 

•

establish an advance notice procedure for stockholder approvals to be brought before an annual meeting of our stockholders, including proposed nominations of persons for election to our board of directors;

 

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provide that our directors may be removed only for cause;

 

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provide that vacancies on our board of directors may be filled only by a majority of directors then in office, even though less than a quorum;

 

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specify that no stockholder is permitted to cumulate votes at any election of directors;

 

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expressly authorize our board of directors to modify, alter or repeal our amended and restated bylaws; and

 

•

require supermajority votes of the holders of our common stock to amend specified provisions of our amended and restated certificate of incorporation and amended and restated bylaws.

These provisions, alone or together, could delay or prevent hostile takeovers and changes in control or changes in our management.

In addition, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the Delaware General Corporation Law, which limits the ability of stockholders owning in excess of 15% of our outstanding voting stock to merge or combine with us.

Any provision of our amended and restated certificate of incorporation or amended and restated bylaws or Delaware law that has the effect of delaying or deterring a change in control could limit the opportunity for our stockholders to receive a premium for their shares of our common stock, and could also affect the price that some investors are willing to pay for our common stock.

 

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SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This prospectus, including the sections entitled “Prospectus Summary,” “Risk Factors,” “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and “Business,” contains forward-looking statements that are based on our management’s belief and assumptions and on information currently available to our management. Although we believe that the expectations reflected in these forward-looking statements are reasonable, these statements relate to future events or our future operational or financial performance, and involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by these forward-looking statements. Forward-looking statements in this prospectus include, but are not limited to, statements about:

 

•

the success, cost and timing of our clinical trials, including our ongoing and planned Phase 1b/2 trials of Resolaris, and whether the results of our trials will be sufficient to support domestic or foreign regulatory approvals;

 

•

the likelihood and timing of regulatory approvals for Resolaris and any of our other product candidates;

 

•

our ability to identify and discover additional product candidates;

 

•

whether our existing capital resources and the net proceeds from this offering will be sufficient to enable us to complete any particular portion of our planned clinical development of Resolaris;

 

•

our ability to obtain, maintain, defend and enforce intellectual property rights protecting our product candidates;

 

•

our estimates of our expenses, ongoing losses, future revenue, capital requirements and our needs for or ability to obtain additional financing;

 

•

performance of third-party service providers and independent contractors upon whom we rely to conduct our clinical trials and to manufacture our product candidates or certain components of our product candidates;

 

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our ability to develop sales and marketing capabilities or to enter into strategic partnerships to develop and commercialize Resolaris or any of our other product candidates;

 

•

the timing and success of the commercialization of Resolaris or any of our other product candidates;

 

•

the rate and degree of market acceptance of our product candidates;

 

•

the size and growth of the potential markets for our product candidates and our ability to serve those markets;

 

•

regulatory developments in the United States and foreign countries;

 

•

the success of competing therapies that are or may become available;

 

•

our ability to attract and retain key scientific or management personnel;

 

•

our expectations regarding the period during which we qualify as an emerging growth company under the Jumpstart Our Business Startups Act of 2012; and

 

•

our use of the proceeds from this offering.

In some cases, you can identify forward-looking statements by terminology such as “may,” “will,” “should,” “expects,” “intends,” “plans,” “anticipates,” “believes,” “estimates,” “predicts,” “potential,” “continue” or the negative of these terms or other comparable terminology. These statements are only predictions. You should not place undue reliance on forward-looking statements because they involve known and unknown risks, uncertainties and other factors, which are, in some cases, beyond our control and which could materially affect results. Factors that may cause actual results to differ materially from current expectations include, among other

 

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things, those listed under “Risk Factors” and elsewhere in this prospectus. If one or more of these risks or uncertainties occur, or if our underlying assumptions prove to be incorrect, actual events or results may vary significantly from those implied or projected by the forward-looking statements. No forward-looking statement is a guarantee of future performance. You should read this prospectus and the documents that we reference in this prospectus and have filed with the Securities and Exchange Commission as exhibits to the registration statement, of which this prospectus is a part, completely and with the understanding that our actual future results may be materially different from any future results expressed or implied by these forward-looking statements.

The forward-looking statements in this prospectus represent our views as of the date of this prospectus. We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we have no current intention of doing so except to the extent required by applicable law. You should therefore not rely on these forward-looking statements as representing our views as of any date subsequent to the date of this prospectus.

 

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USE OF PROCEEDS

We estimate that the net proceeds to us from the sale of             shares of common stock in this offering will be approximately $         million based upon an assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. If the underwriters’ option to purchase additional shares in this offering is exercised in full, we estimate that our net proceeds will be approximately $         million, after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

A $1.00 increase (decrease) in the assumed initial public offering price of $         per share would increase (decrease) the net proceeds to us from this offering by approximately $         million, assuming the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. Similarly, each increase (decrease) of one million in the number of shares offered by us would increase (decrease) the net proceeds to us from this offering by approximately $         million, assuming the assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, remains the same and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

The principal purposes of this offering are to obtain additional capital to support our operations, to establish a public market for our common stock and to facilitate our future access to the public markets. We intend to use the net proceeds from this offering as follows:

 

•

approximately $         million to fund our ongoing Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD through completion of the third cohort;

 

•

approximately $         million to fund portions of additional Phase 1b/2 clinical trials of Resolaris in early onset FSHD, LGMD and an additional indication, such as ILD;

 

•

approximately $         million to fund the initiation of potential Phase 3 or pivotal clinical trials of Resolaris in adult patients with FSHD;

 

•

approximately $         million to advance other research, discovery and development activities; and

 

•

the remainder for working capital and other general corporate purposes, including funding the costs of operating as a public company.

In December 2011, in connection with our facility lease, we issued a $2.0 million subordinated convertible unsecured promissory note to the venture arm of our landlord, BioMed Realty, L.P. which was subsequently transferred to its affiliate, BMV Direct RE LP. The note bears interest at an annual rate of 8.0% and matures at the earlier of (i) May 2015, (ii) a liquidation event, and (iii) the closing of an initial firm commitment underwritten public offering of our common stock pursuant to a registration statement under the Securities Act, unless previously converted. At any time prior to maturity, the holder may elect to convert the principal outstanding under the promissory note into shares of our Series D redeemable convertible preferred stock at the price of $2.662 per share, and upon conversion, all accrued interest would be forgiven. We may use a portion of the proceeds from this offering to repay the principal and accrued interest under the note, equal to approximately $2.4 million as of September 30, 2014, assuming the note holder does not elect, on or prior to the date of completion of this offering, to forgive all accrued interest under the note and convert the $2.0 million in principal under the note into 751,314 shares of our Series D redeemable convertible preferred stock in accordance with the terms described above.

We may also use a portion of the net proceeds to in-license, acquire, or invest in additional businesses, technologies, products, or assets. Although we have no specific agreements, commitments, or understandings with respect to any in-license or acquisition, we evaluate such opportunities and engage in related discussions

 

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with other companies from time to time. As of the date of this prospectus, we cannot predict with certainty all of the particular uses for the net proceeds from this offering. The amounts and timing of our actual expenditures may vary significantly from our expectations depending upon numerous factors, including the progress of our research and development efforts, the progress of our clinical trials, our operating costs and capital expenditures and the other factors described under “Risk Factors” in this prospectus. Accordingly, we will retain the discretion to allocate the net proceeds of this offering among the identified uses described above, and we reserve the right to change the allocation of the net proceeds among the uses described above.

Pending these uses, we intend to invest the net proceeds in high quality, investment grade instruments, certificates of deposit or direct or guaranteed obligations of the U.S. government, or hold the net proceeds as cash.

 

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DIVIDEND POLICY

We have never declared or paid cash dividends on our capital stock. We currently intend to retain all available funds and any future earnings, if any, to fund the development and expansion of our business and we do not anticipate paying any cash dividends in the foreseeable future. Any future determination to pay dividends will be made at the discretion of our board of directors.

 

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CAPITALIZATION

The following table sets forth our cash, cash equivalents and investment securities and capitalization as of September 30, 2014:

 

•

on an actual basis;

 

•

on a pro forma basis to give effect to (i) the filing and effectiveness of our amended and restated certificate of incorporation, (ii) the conversion of all outstanding shares of our redeemable convertible preferred stock into an aggregate of 73,487,415 shares of common stock immediately prior to the completion of this offering, and the resultant reclassification of our redeemable convertible preferred stock to stockholders’ equity (deficit), (iii) the adjustment of our outstanding warrants to purchase redeemable convertible preferred stock into warrants to purchase 206,581 shares of our common stock, and the resultant reclassification of our preferred stock warrant liabilities to additional paid-in capital, a component of stockholders’ equity (deficit); and (iv) our repayment in cash, upon the completion of this offering, of approximately $2.4 million in principal and accrued interest as of September 30, 2014 under a convertible promissory note issued to an affiliate of our landlord, assuming the note holder does not elect, on or prior to the date of completion of this offering, to forgive all accrued interest under the note and convert the $2.0 million in principal under the note into 751,314 shares of our Series D redeemable convertible preferred stock, which would convert into 751,314 shares of common stock upon the completion of this offering; and

 

•

on a pro forma as adjusted basis to give further effect to our sale in this offering of             shares of common stock at an assumed initial public offering price of $         per share (the midpoint of the range set forth on the cover page of this prospectus), after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us.

You should read the following table together with “Management’s Discussion and Analysis of Financial Condition and Results of Operations,” “Description of Capital Stock,” and the consolidated financial statements and related notes appearing elsewhere in this prospectus.

 

		As of September 30, 2014
		Actual				Pro Forma				Pro Forma As Adjusted (1)
		(unaudited)
		(in thousands, except share and per share data)
Cash, cash equivalents and investment securities		$	23,453			$				$
Capitalization:
Commercial bank debt (including current portion)		$	9,027			$				$
Convertible promissory notes			2,000
Warrant liabilities			568
Redeemable convertible preferred stock, $0.001 par value; 75,772,871 shares authorized; 73,487,415 shares issued and outstanding, actual; no shares issued and outstanding, pro forma and pro forma as adjusted			93,581
Stockholders’ equity (deficit):
Preferred stock, $0.001 par value; no shares authorized, issued and outstanding, actual;             shares authorized and no shares issued and outstanding, pro forma and pro forma as adjusted			—
Common stock, $0.001 par value; 94,000,000 shares authorized; 7,237,571 shares issued and outstanding, actual;             shares authorized and             shares issued and outstanding, pro forma;              shares authorized and             shares issued and outstanding, pro forma as adjusted			7

 

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		As of September 30, 2014
		Actual				Pro Forma				Pro Forma As Adjusted (1)
		(unaudited)
		(in thousands, except share and per share data)
Additional paid-in capital			17,782
Stockholder note receivable			(69	)
Accumulated deficit			(104,113	)
Total stockholders’ equity (deficit) of aTyr Pharma, Inc.			(86,393	)
Noncontrolling interest.			2,443
Total stockholders’ equity (deficit)			(83,950	)
Total capitalization		$	21,226			$				$

 

(1)

A $1.00 increase (decrease) in the assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, would increase (decrease) the amount of cash, cash equivalents and investment securities, additional paid-in capital, total stockholders’ equity (deficit) and total capitalization by approximately $         million, assuming the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. Similarly, each increase (decrease) of one million shares in the number of shares offered by us would increase (decrease) cash, cash equivalents and investment securities, additional paid-in capital, total stockholders’ equity (deficit) and total capitalization by approximately $         million, assuming the assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, remains the same, and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. The pro forma as adjusted information discussed above is illustrative only and will be adjusted based on the actual public offering price and other terms of this offering determined at pricing.

The actual, pro forma and pro forma as adjusted information set forth in the table excludes:

 

•

10,679,777 shares of common stock issuable upon the exercise of stock options outstanding as of September 30, 2014 at a weighted average exercise price of $0.36 per share;

 

•

206,581 shares of common stock issuable upon the exercise of warrants outstanding as of September 30, 2014 at a weighted average exercise price of $1.82 per share, which warrants prior to the completion of this offering are exercisable to purchase redeemable convertible preferred stock; and

 

•

shares of common stock reserved for future issuance under the 2015 Plan, which will become effective immediately prior to the completion of this offering.

 

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DILUTION

If you invest in our common stock in this offering, your interest will be diluted to the extent of the difference between the public offering price per share of our common stock and the pro forma net tangible book value per share of our common stock immediately after this offering.

As of September 30, 2014, we had a historical net tangible book deficit of $(84.0) million, or $(11.60) per share of common stock, based on 7,237,571 shares of common stock outstanding at September 30, 2014. Our historical net tangible book value per share represents the amount of our total tangible assets less total liabilities and redeemable convertible preferred stock, divided by the total number of shares of common stock outstanding as of September 30, 2014.

On a pro forma basis, after giving effect to (i) the conversion of all outstanding shares of our redeemable convertible preferred stock into an aggregate of 73,487,415 shares of common stock immediately prior to the completion of this offering, and the resultant reclassification of our redeemable convertible preferred stock to stockholders’ equity (deficit) and (ii) the adjustment of our outstanding warrants to purchase redeemable convertible preferred stock into warrants to purchase 206,581 shares of our common stock, and the resultant reclassification of our preferred stock warrant liabilities to additional paid-in capital, a component of stockholders’ equity (deficit), our pro forma net tangible book value as of September 30, 2014 would have been approximately $         million, or approximately $         per share of our common stock.

After giving further effect to our sale of             shares of common stock in this offering at an assumed initial public offering price of $         per share (the midpoint of the price range set forth on the cover page of this prospectus), and after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us, our pro forma as adjusted net tangible book value as of September 30, 2014 would have been approximately $         million, or approximately $         per share. This amount represents an immediate increase in pro forma net tangible book value of $         per share to our existing stockholders and an immediate dilution in pro forma net tangible book value of approximately $         per share to new investors participating in this offering. The following table illustrates this dilution:

 

Assumed initial public offering price per share						$
Historical net tangible book deficit per share		$	(11.60	)
Pro forma increase in historical net tangible book deficit per share
Pro forma net tangible book value per share
Increase in pro forma net tangible book value per share attributable to investors participating in this offering
Pro forma as adjusted net tangible book value per share after this offering
Dilution per share to new investors participating in this offering						$

A $1.00 increase (decrease) in the assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, would increase (decrease) the pro forma as adjusted net tangible book value by $         per share and the dilution to new investors by $         per share, assuming the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same, and after deducting estimated underwriting discounts and commissions and estimated expenses payable by us. Similarly, each increase (decrease) of one million shares in the number of shares offered by us would increase (decrease) the pro forma as adjusted net tangible book value by $         per share and the dilution to new investors by $         per share, assuming the assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, remains the same and after deducting estimated underwriting discounts and commissions and estimated expenses payable by us. If the underwriters exercise their option to purchase additional shares of common stock in this offering in full, the pro forma as adjusted net tangible book value would be $         per share, and the dilution in pro forma net tangible book value per share to investors in this offering would be $         per share.

 

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The following table summarizes, on a pro forma basis, as of September 30, 2014, the difference between the number of shares of common stock purchased from us, the total consideration paid to us and the average price per share paid by existing stockholders and by new investors in this offering at an assumed initial public offering price of $     per share, the midpoint of the price range set forth on the cover page of this prospectus, before deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

 

		Shares Purchased						Total Consideration								Average Price Per Share
		Number		Percent				Amount				Percent
		(in thousands, except share and per share amounts)
Existing stockholders						%		$						%		$
New investors
Total					100	%		$					100	%

The above discussion and tables are based on 80,724,986 shares of common stock issued and outstanding as of September 30, 2014 and also reflects the conversion of all outstanding shares of redeemable convertible preferred stock into an aggregate of 73,487,415 shares of common stock immediately prior to the completion of this offering and excludes:

 

•

10,679,777 shares of common stock issuable upon the exercise of stock options outstanding as of September 30, 2014 at a weighted average exercise price of $0.36 per share;

 

•

206,581 shares of common stock issuable upon the exercise of warrants outstanding as of September 30, 2014 at a weighted average exercise price of $1.82 per share, which warrants prior to the completion of this offering are exercisable to purchase redeemable convertible preferred stock;

 

•

shares of common stock reserved for future issuance under the 2015 Plan, which will become effective immediately prior to the completion of this offering; and

 

•

751,314 shares of common stock issuable upon the conversion of 751,314 shares of Series D redeemable convertible preferred stock that may be issued under a convertible promissory note issued to an affiliate of our landlord, if the noteholder elects to convert the note in accordance with its terms.

A $1.00 increase (decrease) in the assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, would increase (decrease) the total consideration paid by new investors by approximately $         million, assuming the number of shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us. Similarly, each increase (decrease) of one million shares in the number of shares offered by us would increase (decrease) the total consideration paid by new investors by approximately $         million, assuming the assumed initial public offering price of $         per share, the midpoint of the price range set forth on the cover page of this prospectus, remains the same, and after deducting estimated underwriting discounts and commissions and estimated offering expenses payable by us.

To the extent that outstanding options and warrants are exercised, or the holder of our convertible promissory note elects to convert the note into shares of our Series D redeemable convertible preferred stock, you will experience further dilution. In addition, we may choose to raise additional capital due to market conditions or strategic considerations even if we believe we have sufficient funds for our current or future operating plans. To the extent that additional capital is raised through the sale of equity or convertible debt securities, the issuance of these securities may result in further dilution to our stockholders.

 

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SELECTED CONSOLIDATED FINANCIAL DATA

You should read the following selected historical consolidated financial data below together with “Management’s Discussion and Analysis of Financial Condition and Results of Operations” and the financial statements, related notes and other financial information included elsewhere in this prospectus. The selected consolidated financial data in this section are not intended to replace the financial statements and are qualified in their entirety by the consolidated financial statements and related notes included elsewhere in this prospectus.

The selected consolidated statement of operations data for the years ended December 31, 2012 and 2013 and the selected consolidated balance sheet data as of December 31, 2013 are derived from our audited consolidated financial statements appearing elsewhere in this prospectus. The selected consolidated statement of operations data for the nine months ended September 30, 2013 and 2014 and balance sheet data as of September 30, 2014 are derived from our unaudited consolidated financial statements and related notes appearing elsewhere in this prospectus. The unaudited consolidated financial statements have been prepared on a basis consistent with our audited consolidated financial statements included in this prospectus and, in the opinion of management, reflect all adjustments, consisting only of normal recurring adjustments, necessary to fairly state our financial position as of September 30, 2014 and results of operations for the nine months ended September 30, 2013 and 2014. Our historical results are not necessarily indicative of results that may be expected in the future and results of interim periods are not necessarily indicative of the results for the entire year.

 

		Years Ended December 31,								Nine Months Ended September 30,
		2012				2013				2013				2014
										(unaudited)
		(in thousands, except share and per share data)
Statements of Operations Data:
Operating expenses:
Research and development		$	7,745			$	13,832			$	9,723			$	12,436
General and administrative			4,854				5,710				4,512				5,088
Total operating expenses			12,599				19,542				14,235				17,524
Loss from operations			(12,599	)			(19,542	)			(14,235	)			(17,524	)
Other income (expense)			(261	)			(472	)			(344	)			(788	)
Net loss			(12,860	)			(20,014	)			(14,579	)			(18,312	)
Accretion to redemption value of redeemable convertible preferred stock			(4,748	)			(1,637	)			(1,499	)			(416	)
Net loss attributable to common stockholders		$	(17,608	)		$	(21,651	)		$	(16,078	)		$	(18,728	)
Net loss per share attributable to common stockholders, basic and diluted (1)		$	(3.19	)		$	(3.57	)		$	(2.68	)		$	(2.86	)
Weighted average shares outstanding, basic and diluted (1)			5,518,629				6,067,342				6,004,837				6,554,969
Pro forma net loss per share attributable to common stockholders, basic and diluted (unaudited) (1)						$	(0.27	)						$	(0.23	)
Pro forma weighted average shares outstanding, basic and diluted (unaudited) (1)							74,382,326								80,042,384

 

(1)	See Note 2 to our consolidated financial statements included elsewhere in this prospectus for an explanation of the method used to calculate the historical and pro forma net loss per share, basic and diluted, and the number of shares used in the computation of the per share amounts.

 

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		As of December 31,								As of September 30, 2014
		2012				2013
										(unaudited)
		(in thousands)
Consolidated Balance Sheet Data:
Cash, cash equivalents and investment securities		$	3,675			$	36,457			$	23,453
Total assets			7,397				39,786				26,755
Preferred stock warrant liabilities			42				207				568
Convertible promissory note			2,000				2,000				2,000
Working capital			960				31,814				13,674
Commercial bank debt, net of current portion			1,667				4,158				5,947
Redeemable convertible preferred stock			63,225				93,165				93,581
Accumulated deficit			(64,516	)			(85,801	)			(104,113	)
Noncontrolling interest			25				2,414				2,443
Total stockholders’ deficit			(64,554	)			(66,082	)			(83,950	)

 

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MANAGEMENT’S DISCUSSION AND ANALYSIS OF

FINANCIAL CONDITION AND RESULTS OF OPERATIONS

You should read the following discussion and analysis of our financial condition and results of operations together with our consolidated financial statements and related notes and other financial information appearing elsewhere in this prospectus. Some of the information contained in this discussion and analysis or set forth elsewhere in this prospectus, including information with respect to our plans and strategy for our business and related financing, includes forward-looking statements that involve risks and uncertainties. As a result of many factors, including those factors set forth in the “Risk Factors” section of this prospectus, our actual results could differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.

Overview

We engage in the discovery and clinical development of innovative medicines for patients suffering from severe rare diseases using our knowledge of Physiocrine biology, a newly discovered set of physiological modulators. We have discovered approximately 300 Physiocrines, a class of naturally-occurring human proteins that we believe promote homeostasis, a fundamental process of restoring stressed or diseased tissue to a healthier state. By leveraging our Physiocrine discovery engine and our knowledge of rare diseases, we aim to build a proprietary pipeline of novel product candidates with the potential to treat severe, rare diseases characterized by immune dysregulation and independently commercialize our Physiocrine-based therapeutics.

In the first quarter of 2014, we completed a double-blind, placebo-controlled Phase 1 clinical trial of Resolaris, our lead development candidate from our Physiocrine discovery engine, in which we assessed its safety and tolerability in 32 healthy subjects. Resolaris was shown to be well tolerated at all doses tested, and no serious adverse events were reported. Based on the favorable clinical safety, tolerability, pharmacokinetic and immunogenicity profile of Resolaris in this trial, we decided to advance Resolaris into clinical trials of patients affected by rare myopathies with an immune component. We recently initiated a multi-national exploratory Phase 1b/2 clinical trial of Resolaris in the European Union in adult patients with facioscapulohumeral muscular dystrophy, or FSHD, a severe, rare genetic myopathy with an immune component, for which there are currently no approved treatments. Subject to our interactions with regulatory authorities and patient enrollment in accordance with our clinical development plans, we expect to report initial results from this clinical trial in the second half of 2015.

Since our inception in 2005, we have devoted substantially all of our resources to the therapeutic application of Physiocrines, including the preclinical development of and clinical trials for Resolaris, the creation, licensing and protection of related intellectual property and the provision of general and administrative support for these operations. We have not generated any revenue from product sales and, to date, have funded our operations primarily with the aggregate net proceeds of $94.9 million from the private placement of redeemable convertible preferred stock and convertible promissory notes, $10.0 million of commercial bank debt and a $2.0 million convertible promissory note issued to our landlord.

We have never been profitable and have incurred net losses in each annual and quarterly period since our inception. Our net losses were $20.0 million, $14.6 million, and $18.3 million for the year ended December 31, 2013 and the nine months ended September 30, 2013 and 2014, respectively. As of September 30, 2014, we had an accumulated deficit of $104.1 million.

Substantially all of our net losses resulted from costs incurred in connection with our development of and clinical trials for Resolaris, our other research and development programs and from general and administrative costs associated with our operations. We expect to continue to incur significant expenses and increasing operating losses for the foreseeable future, at least until we apply for and receive regulatory approval for

 

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Resolaris or another product candidate and generate substantial revenues from its commercialization, if ever. Our net losses may fluctuate significantly from quarter to quarter and year to year, depending on the nature and extent of our research and development expenses and clinical trials. We expect our expenses will increase substantially in connection with our ongoing activities as we:

 

•

conduct clinical trials of Resolaris and any additional product candidates we may develop;

 

•

continue our research and product development efforts;

 

•

manufacture preclinical study and clinical trial materials;

 

•

expand, protect and maintain our intellectual property portfolio;

 

•

seek regulatory approvals for our product candidates that successfully complete clinical trials;

 

•

hire additional staff, including clinical, operational, financial and technical personnel to execute on our business plan and create additional infrastructure to support our operations as a public company; and

 

•

implement operational, financial and management systems.

We do not expect to generate any revenues from product sales unless and until we successfully complete development and obtain regulatory approval for one or more of our product candidates, which we expect will take at least a number of years. If we obtain regulatory approval for any of our product candidates, we expect to incur significant commercialization expenses related to product sales, marketing, manufacturing and distribution. Accordingly, we will need to raise substantial additional capital beyond the expected net proceeds from this offering. The amount and timing of our future funding requirement will depend on many factors, including the pace and results of our preclinical and clinical development efforts and the timing and nature of the regulatory approval process for our product candidates. We anticipate that we will seek to fund our operations through public or private equity or debt financings or other sources. However, we may be unable to raise additional funds or enter into such other arrangements when needed on favorable terms or at all. Our failure to raise capital or enter into such other arrangements when needed would have a negative impact on our financial condition and ability to develop our product candidates.

Financial Operations Overview

Organization and Business; Principles of Consolidation and Affiliates

We conduct substantially all of our activities through aTyr Pharma, Inc., a Delaware corporation, at our facility in San Diego, California. aTyr Pharma, Inc. was incorporated in the state of Delaware in September 2005. The consolidated financial statements include the accounts of aTyr Pharma, Inc., its 98% majority-owned subsidiary in Hong Kong, Pangu BioPharma Limited, and six variable interest entities, which we refer to as the Affiliates.

In October and November 2011, we established the Affiliates to perform research and development for specified programs. In April 2012, we purchased preferred and common stock of each Affiliate and subsequently issued those shares to each of our stockholders in the form of dividends, in proportion to their relative holdings of aTyr Pharma, Inc. in order to effectuate the spin-out of the Affiliates into stand-alone entities. We entered into nonexclusive license agreements allowing each Affiliate to utilize certain intellectual property owned by us. We also entered into research and development services agreements in our therapeutic program area of interest covered by the respective nonexclusive license agreement with each Affiliate. The working capital of the Affiliates was primarily provided by amounts borrowed from us under convertible promissory note agreements. The Affiliates were not capitalized with sufficient equity to finance their operations and were each therefore considered a variable interest entity, or VIE. In May 2012, the Affiliates commenced operations. The Affiliates had no employees and substantially all of their expenses related to the services provided to them by us, and the expenses related to services provided by us have been eliminated in consolidation. The liquidation preferences

 

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underlying the preferred stock issued by the Affiliates and the convertible promissory notes issued by the Affiliates to us effectively protected stockholders of the Affiliates from absorbing the losses of the Affiliates and, as a result, no losses were allocated to these noncontrolling interests and such losses are included in our consolidated net loss. None of the related parties to the Affiliates individually had the power and benefits to control the Affiliates. Because we were the related party that was most closely associated with each VIE, we have consolidated the six Affiliates for financial reporting purposes.

In the fourth quarter of 2014, the board of directors and stockholders of each of the Affiliates approved the dissolution of each applicable Affiliate in accordance with the laws of its respective jurisdiction of organization. In connection with the dissolution of the Affiliates, the license and operating agreements by and between aTyr Pharma, Inc. and each Affiliate were terminated. Our consolidated financial statements for periods after the effectiveness of the dissolution of the Affiliates will no longer include a noncontrolling interest, and the operating activities that the Affiliates performed prior to dissolution will be continued by aTyr Pharma, Inc.

Research and Development Expenses

To date, our research and development expenses have related primarily to the development of and clinical trials for Resolaris and to research efforts targeting the potential therapeutic application of other Physiocrine- based immuno-modulators in rare disease indications. These expenses consist primarily of:

 

•

salaries and employee-related expenses, including stock-based compensation and benefits for personnel in research and product development functions;

 

•

costs associated with conducting our preclinical, development and regulatory activities, including fees paid to third-party professional consultants, service providers and our scientific, therapeutic and clinical advisory board;

 

•

costs to acquire, develop and manufacture preclinical study and clinical trial materials;

 

•

costs incurred under clinical trial agreements with clinical research organizations, or CROs, and investigative sites;

 

•

costs for laboratory supplies;

 

•

payments related to licensed products and technologies; and

 

•

allocated facilities, depreciation and other allocable expenses.

Research and development costs are expensed as incurred. Clinical trial and other development costs incurred by third parties are expensed as the contracted work is performed. We accrue for costs incurred as the services are being provided by monitoring the status of the trial or project and the invoices received from our external service providers. We adjust our accrual as actual costs become known.

Product candidates in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. We expect that the levels of our research and development expenses will increase during the foreseeable future as we: (i) continue to advance Resolaris in clinical development; (ii) advance our iModFc discovery program; and (iii) engage in additional research, discovery and development activities relating to our Physiocrine discovery engine.

We cannot determine with certainty the timing of initiation, the duration or the completion costs of current or future preclinical studies and clinical trials of our product candidates. At this time, due to the inherently unpredictable nature of preclinical and clinical development and given the early stage of our program, we are unable to estimate with any certainty the costs we will incur or the timelines we will require in the continued development of Resolaris and any other product candidates that we may develop. Clinical and preclinical

 

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development timelines, the probability of success and development costs can differ materially from expectations. We anticipate that we will make determinations as to which product candidates to pursue and how much funding to direct to each product candidate on an ongoing basis in response to the results of ongoing and future preclinical studies and clinical trials, regulatory developments and our ongoing assessments as to each product candidate’s commercial potential. In addition, we cannot forecast which product candidates may be subject to future collaborations, when such arrangements will be secured, if at all, and to what degree such arrangements would affect our development plans and capital requirements.

General and Administrative Expenses

General and administrative expenses consist primarily of salaries and related costs for employees in executive, finance and administration, corporate development and administrative support functions, including stock-based compensation expenses and benefits. Other significant general and administrative expenses include accounting and legal services, expenses associated with applying for and maintaining patents, the cost of various consultants, occupancy costs, information systems costs and depreciation.

We anticipate that our general and administrative expenses will substantially increase for the foreseeable future as we increase our headcount to support the continued development of our product candidates and the increased costs of operating as a public company, including expenses related to services associated with maintaining compliance with NASDAQ listing rules and the Securities and Exchange Commission, or SEC, requirements, insurance and investor relations costs. These increases will likely include increased costs related to the hiring of additional personnel and fees to outside consultants, lawyers and accountants, among other expenses.

Other Income (Expense)

Other income (expense) primarily consists of interest income and expense and changes in the fair value of preferred stock warrant liabilities related to warrants we issued in connection with commercial bank debt. We do not expect any further fair value adjustments for these warrants subsequent to our initial public offering, when these liabilities will be reclassified to additional paid-in capital.

Critical Accounting Policies and Significant Judgments and Estimates

Our management’s discussion and analysis of financial condition and results of operations is based on our consolidated financial statements, which have been prepared in accordance with accounting principles generally accepted in the United States, or GAAP. The preparation of these consolidated financial statements requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities and the disclosure of contingent assets and liabilities as of the date of the consolidated financial statements, as well as the reported expenses during the reporting periods. We monitor and analyze these items for changes in facts and circumstances, and material changes in these estimates could occur in the future. We base our estimates on our historical experience and on various other factors we believe to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying value of assets and liabilities that are not readily apparent from other sources. Changes in estimates are reflected in reported results for the period in which they become known. Actual results may differ materially from these estimates under different assumptions or conditions.

While our significant accounting policies are more fully described in the notes to our consolidated financial statements appearing elsewhere in this prospectus, we believe the following accounting policies related to research and development expense accruals and stock-based compensation are most critical to understanding and evaluating our reported consolidated financial results.

 

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Research and Development Expense Accruals

As part of the process of preparing our consolidated financial statements, we are required to estimate our accrued expenses. This process involves reviewing open contracts and purchase orders, communicating with our personnel to identify services that have been performed on our behalf and estimating the level of service performed and the associated cost incurred for the service when we have not yet been invoiced or otherwise notified of the actual cost. The majority of our service providers invoice us monthly in arrears for services performed or when contractual milestones are met. We make estimates of our accrued expenses as of each balance sheet date in our consolidated financial statements based on facts and circumstances known to us at that time. We periodically confirm the accuracy of our estimates with the service providers and make adjustments if necessary. Examples of estimated accrued research and development expenses include fees paid to investigative sites and CROs in connection with clinical trials; service providers in connection with preclinical development activities; and service providers related to product manufacturing, development and distribution of clinical supplies.

We currently rely on third parties for the clinical development of Resolaris and the manufacture of Resolaris to support our ongoing Phase 1b/2 clinical trial in adult patients with FSHD. We pay these third parties, including consultants, CROs, manufacturers and other service providers, pursuant to contractual arrangements, which may include provisions for time and materials-based payments, project-based fees and milestone payments. We base our accrual for these expenses on our estimates of the services received and efforts expended pursuant to our contractual arrangements. The financial terms of these agreements are subject to negotiation, vary from contract to contract and may result in uneven payment flows. There may be instances in which payments made to our service providers will exceed the level of services provided and result in a prepayment of the clinical expense. Payments under some of these contracts depend on factors such as the successful enrollment of patients and the completion of clinical milestones. In accruing service fees, we estimate the time period over which services will be performed and the level of effort to be expended in each period. If the actual timing of the performance of services or the level of effort varies from our estimate, we adjust the accrual or prepaid accordingly.

Although we do not expect our estimates to be materially different from amounts actually incurred, if our estimates of the status and timing of services performed differs from the actual status and timing of services performed, we may report amounts that are too high or too low in any particular period. To date, there have been no material differences between our estimates and the amounts actually incurred.

Stock-Based Compensation

Stock-based compensation expense represents the grant date fair value of employee stock option grants recognized as expense over the requisite service period of the awards (usually the vesting period) on a straight-line basis, net of estimated forfeitures. For stock option grants with performance-based milestones, the expense is recorded over the service period after the achievement of the milestone is probable or the performance condition is achieved. We estimate the fair value of stock option grants using the Black-Scholes option pricing model. The Black-Scholes option pricing model requires the input of subjective assumptions, including the risk-free interest rate, the expected dividend yield of our common stock, the expected volatility of the price of our common stock, the expected term of the option and the fair value of our common stock. These estimates involve inherent uncertainties and the application of management’s judgment. If factors change and different assumptions are used, our stock-based compensation expense could be materially different in the future. See Note 7 to our consolidated financial statements included elsewhere in this prospectus for information concerning certain of the specific assumptions we used in applying the Black-Scholes option pricing model to determine the estimated fair value of our stock options granted in 2012, 2013 and the nine months ended September 30, 2014.

 

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The following table summarizes information related to stock options we granted from October 1, 2013 through October 24, 2014:

 

Grant Date		Number of Common Shares Underlying Options Granted				Exercise Price per Common Share				Estimated Fair Value per Common Share				Reassessed Fair Value per Common Share
December 6, 2013			57,000			$	0.51			$	0.51			$	0.51
March 5, 2014			2,549,861				0.51				0.51				0.85
July 10, 2014			2,061,736				0.51				0.51				1.65
October 10, 2014			611,232				2.23				2.23				N/A
October 24, 2014			770,285				2.23				2.23				N/A

The following table summarizes the stock-based compensation expense recognized in our consolidated financial statements:

 

		Years Ended December 31,								Nine Months Ended September 30,
		2012				2013				2013				2014
										(unaudited)
		(in thousands)
Research and development		$	28			$	96			$	64			$	324
General and administrative			138				59				21				461
Total stock-based compensation expense		$	166			$	155			$	85			$	785

As of September 30, 2014, the unrecognized stock-based compensation expense related to outstanding employee stock options was $5.9 million and is expected to be recognized as expense over a weighted average period of approximately 4.7 years. The intrinsic value of all outstanding stock options as of September 30, 2014 was approximately $         million, based on the assumed public offering price of $         per share, which is the midpoint of the estimated offering price range set forth on the cover page of this prospectus, of which approximately $         million related to vested options and approximately $         million related to unvested options.

Determination of the Fair Value of Common Stock

We are required to estimate the fair value of the common stock underlying our stock-based awards when performing fair value calculations, which is the most subjective input into the Black-Scholes option pricing model. The fair value of the common stock underlying our stock-based awards was determined on each grant date by our board of directors, taking into account input from management and our most recent independent third-party valuations. All options to purchase shares of our common stock are intended to be granted with an exercise price per share no less than the fair value per share of our common stock underlying those options on the date of grant, based on the information known to us on the date of grant. In the absence of a public trading market for our common stock, on each grant date we develop an estimate of the fair value of our common stock in order to determine an exercise price for the option grants. Our determinations of the fair value of our common stock were made using methodologies, approaches and assumptions consistent with the American Institute of Certified Public Accountants Audit and Accounting Practice Aid Series: Valuation of Privately Held Company Equity Securities Issued as Compensation, or the Practice Aid.

Our board of directors considered various objective and subjective factors, along with input from management, to determine the fair value of our common stock, including:

 

•

contemporaneous valuations of our common stock performed by independent third-party valuation specialists;

 

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•

our stage of development and business strategy, including the status of research and development efforts of our product candidates, and the material risks related to our business and industry;

 

•

our results of operations and financial position, including our levels of available capital resources;

 

•

the valuation of publicly traded companies in the life sciences and biotechnology sectors, as well as recently completed mergers and acquisitions of peer companies;

 

•

the lack of marketability of our common stock as a private company;

 

•

the prices of our redeemable convertible preferred stock sold to investors in arm’s length transactions and the rights, preferences, and privileges of our redeemable convertible preferred stock relative to those of our common stock;

 

•

the likelihood of achieving a liquidity event for the holders of our common stock, such as an initial public offering or a sale of our company, given prevailing market conditions;

 

•

trends and developments in our industry;

 

•

external market conditions affecting the life sciences and biotechnology industry sectors; and

 

•

the composition of, and changes to, our management team and board of directors.

Common Stock Valuation Methodologies and Methods Used to Allocate our Enterprise Value to Classes of Securities

Our valuations were prepared in accordance with the guidelines in the Practice Aid, which prescribes several valuation approaches for setting the value of an enterprise, such as the cost, income and market approaches, and various methodologies for allocating the value of an enterprise to its common stock. The cost approach establishes the value of an enterprise based on the cost of reproducing or replacing the property less depreciation and functional or economic obsolescence, if present. The income approach establishes the value of an enterprise based on the present value of future cash flows that are reasonably reflective of our company’s future operations, discounting to the present value with an appropriate risk adjusted discount rate or capitalization rate. The market approach is based on the assumption that the value of an asset is equal to the value of a substitute asset with the same characteristics. Each valuation methodology was considered in our valuations.

The various methods for allocating the enterprise value across our classes and series of capital stock to determine the fair value of our common stock in accordance with the Practice Aid include the following:

 

•

Current Value Method. Under the current value method, once the fair value of the enterprise is established, the value is allocated to the various series of preferred and common stock based on their respective seniority, liquidation preferences or conversion values, whichever is greatest.

 

•

Option Pricing Method, or OPM. Under the OPM, shares are valued by creating a series of call options with exercise prices based on the liquidation preferences and conversion terms of each equity class. The values of the preferred and common stock are inferred by analyzing these options.

 

•

Probability-Weighted Expected Return Method, or PWERM. The PWERM is a scenario-based analysis that estimates the value per share based on the probability-weighted present value of expected future investment returns, considering each of the possible outcomes available to us, as well as the economic and control rights of each share class.

There are significant judgments and estimates inherent in the determination of the fair value of our common stock. These judgments and estimates include assumptions regarding our future operating performance, the time to completing an initial public offering or other liquidity event and the determination of the appropriate valuation methods. If we had made different assumptions, our stock-based compensation expense, net loss and net loss per common share could have been significantly different.

 

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In accordance with the Practice Aid, we considered the various methods described above to determine our enterprise value and for allocating the enterprise value across our classes and series of capital stock to determine the fair value of our common stock at each valuation date.

Our valuations used to determine the exercise price of our December 2013 and March 2014 stock option grants utilized each of the cost and market approaches to determine our enterprise value and the enterprise value was allocated based on both the current value method and the OPM. Our valuations used to determine the exercise price of our July 2014 option grants utilized the cost and market approaches to determine our enterprise value and the enterprise value was allocated based on both the current value method and the OPM. We believed that the OPM and current value method were the most appropriate given the expectation of various potential liquidity outcomes and the difficulty of selecting and supporting appropriate enterprise values given our early stage of development. Our valuation effective September 30, 2014 was used to determine the exercise price of our stock option grants in October 2014 and utilized both the income and market approaches to determine our enterprise value, and the enterprise value was allocated based on the PWERM. We transitioned to the PWERM once we initiated our initial public offering process because we then had greater clarity as to our potential future liquidity events.

Retrospective Reassessment of Fair Value

As part of the preparation of the financial statements necessary for inclusion in the registration statement related to this offering, we reassessed for financial reporting purposes, on a retrospective basis, the fair value of our common stock for each stock option noted in the table above granted between October 1, 2013 and September 30, 2014. For purposes of this reassessment, we evaluated our original inputs and the methodologies used to determine our enterprise value and the methods we used to allocate enterprise value. In consideration of our decision to pursue an initial public offering in the third quarter of 2014, we determined to exclude the impact of the current value method from our determination of the fair value of our common stock for option grants made in 2014. We reassessed the fair value of our common stock for stock options granted on March 5, 2014 from $0.51 per share to $0.85 per share, using a straight-line method between the fair value of our common stock of $0.51 per share on December 31, 2013 and the fair value of our common stock of $1.07 per share on May 31, 2014, because we did not identify any significant internal or external value-generating events between the December 31, 2013 and May 31, 2014 valuation dates. The May 31, 2014 contemporaneous valuation, which was performed by an independent third-party valuation specialist, used the OPM and did not use the current value method.

We reassessed the fair value of our common stock for stock options granted on July 10, 2014 from $0.51 per share to $1.65 per share, using a straight-line method between the fair value of our common stock of $1.07 per share on May 31, 2014 and the fair value of our common stock of $2.23 per share on September 30, 2014, because we did not identify any significant internal or external value-generating events between the May 31, 2014 and September 30, 2014 valuation dates.

Following the completion of this offering, our board of directors will determine the fair value of our common stock based on its closing price as reported on the date of grant on the primary stock exchange on which our common stock is traded.

Other Company Information

Net Operating Loss and Research and Development Tax Credit Carryforwards

As of December 31, 2013, we had approximately $30.7 million, $31.9 million, and $5.0 million of net operating loss, or NOL, carryforwards for federal, state, and foreign purposes, respectively, available to offset future taxable income. The federal and state net operating loss carryforwards begin to expire in 2025 and 2016, respectively. The foreign net operating losses carry over indefinitely. As of December 31, 2013, we had federal and state research and development credit carryforwards of approximately $1.2 million, which begin to expire in 2026 for federal purposes and carry over indefinitely for state purposes.

 

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Utilization of the domestic NOL and research and development credit carryforwards may be subject to a substantial annual limitation due to ownership change limitations that may have occurred or that could occur in the future, as required by Section 382 and 383 of the Internal Revenue Code of 1986, as amended, or the Code, as well as similar state and foreign provisions. These ownership changes may limit the amount of NOL and research and development credit carryforwards that can be utilized annually to offset future taxable income and tax, respectively. In general, an “ownership change” as defined by Section 382 of the Code results from a transaction or series of transactions over a three-year period resulting in an ownership change of more than 50% of the outstanding stock of a company by certain stockholders. Since our formation, we have raised capital through the issuance of capital stock on several occasions which on its own or combined with the purchasing stockholders’ subsequent disposition of those shares, has resulted in such an ownership change, and could result in an additional ownership change in the future.

Upon the occurrence of an ownership change under Section 382 as outlined above, utilization of the NOL and research and development credit carryforwards become subject to an annual limitation under Section 382 of the Code, which is determined by first multiplying the value of our outstanding stock at the time of the ownership change by the applicable long-term, tax-exempt rate, which could be subject to additional adjustments. Any limitation may result in expiration of a portion of the NOL or research and development credit carryforwards before utilization. We completed an analysis through September 7, 2011, determined that an ownership change occurred on November 30, 2006, and adjusted our NOL and $15,000 of research and development tax credit carryforwards accordingly. Ownership changes that may have occurred subsequent to September 7, 2011, and future ownership changes, including any ownership changes resulting from this offering, may further limit our ability to utilize our remaining tax attributes.

Emerging Growth Company

On April 5, 2012, the Jumpstart Our Business Startups Act of 2012, or the JOBS Act, was enacted. Section 107 of the JOBS Act provides that an “emerging growth company” can take advantage of the extended transition period provided in Section 7(a)(2)(B) of the Securities Act of 1933, or the Securities Act, for complying with new or revised accounting standards. In other words, an “emerging growth company” can delay the adoption of certain accounting standards until those standards would otherwise apply to private companies. We have irrevocably elected not to avail ourselves of this extended transition period and, as a result, we will adopt new or revised accounting standards on the relevant dates on which adoption of such standards is required for other public companies.

We intend to take advantage of the reduced reporting requirements and to rely on certain other exemptions provided by the JOBS Act. Subject to certain conditions set forth in the JOBS Act, as an “emerging growth company,” the exemptions that we may rely on include, without limitation, exemptions from: (i) providing an auditor’s attestation report on our system of internal controls over financial reporting pursuant to Section 404(b) of the Sarbanes-Oxley Act and (ii) complying with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial statements, known as the auditor discussion and analysis.

We will remain an “emerging growth company” until the earliest of (i) the last day of the fiscal year in which we have total annual gross revenues of $1 billion or more, (ii) the last day of our fiscal year following the fifth anniversary of the date of the completion of this offering, (iii) the date on which we have issued more than $1 billion in non-convertible debt during the previous three years or (iv) the date on which we are deemed to be a large accelerated filer under the rules of the SEC.

 

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Results of Operations

Comparison of the Nine Months Ended September 30, 2013 and 2014

The following table summarizes our results of operations for the nine months ended September 30, 2013 and 2014:

 

		Nine Months Ended September 30,								Increase / (Decrease)
		2013				2014
		(unaudited)
		(in thousands)
Research and development expenses		$	9,723			$	12,436			$	2,713
General and administrative expenses			4,512				5,088				576
Other income (expense)			(344	)			(788	)			444

Research and development expenses. Research and development expenses were $9.7 million and $12.4 million for the nine months ended September 30, 2013 and 2014, respectively. The increase of $2.7 million was due primarily to a $2.4 million increase in regulatory and clinical activities related to the completion of our Phase 1 clinical trial of Resolaris and the initiation of our multi-national Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD in the European Union, a $1.0 million increase related to compensation expenses (including stock-based compensation) as a result of increased headcount across our research and development organization and a $0.9 million increase in pre-clinical expenditures, facilities and other research costs. These increases were offset by a decrease of $1.6 million related to the timing of manufacturing costs incurred in support of various Resolaris clinical development activities.

General and administrative expenses. General and administrative expenses were $4.5 million and $5.1 million for the nine months ended September 30, 2013 and 2014, respectively. The increase of $0.6 million was due primarily to a $1.3 million increase in personnel costs resulting from increased headcount in our executive leadership team and stock-based compensation and a $0.2 million increase in facility-related expenses, offset by a decrease of $0.4 million related to market studies that did not recur in 2014 and a decrease of $0.5 million of legal fees related to patent filings.

Other income (expense). Other income (expense) was $(0.3) million and $(0.8) million for the nine months ended September 30, 2013 and 2014, respectively. The increase of $0.4 million in other expense was primarily the result of additional interest expense related to the $5.0 million we borrowed under a loan agreement with Silicon Valley Bank in June 2014 and a $0.2 million increase in other expense related to increases in the fair value of outstanding warrant liabilities as the underlying preferred stock fair value increased.

Comparison of the Years Ended December 31, 2012 and 2013

The following table summarizes our results of operations for the years ended December 31, 2012 and 2013:

 

		Years Ended December 31,								Increase / (Decrease)
		2012				2013
		(in thousands)
Research and development expenses		$	7,745			$	13,832			$	6,087
General and administrative expenses			4,854				5,710				856
Other income (expense)			(261	)			(472	)			211

Research and development expenses. Research and development expenses were $7.7 million and $13.8 million for the years ended December 31, 2012 and 2013, respectively. The increase of $6.1 million was due primarily to an increase of $2.6 million of Resolaris manufacturing costs, an increase of $2.1 million for clinical, regulatory and travel costs related to our Phase 1 clinical trial of Resolaris, an increase of $0.8 million related to compensation expenses (including stock-based compensation) and an increase of $0.6 million for preclinical development activities, facilities and other research costs.

 

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General and administrative expenses. General and administrative expenses were $4.9 million and $5.7 million for the years ended December 31, 2012 and 2013, respectively. The increase of $0.9 million was due primarily to a $0.7 million increase in legal fees associated with patent filings and a $0.4 million increase in market studies, offset by a $0.2 million decrease in travel and related costs.

Other income (expense). Other income (expense) was $(0.3) million and $(0.5) million for the years ended December 31, 2012 and 2013, respectively. The increase of $0.2 million in other expense was primarily the result of additional interest expense related to the $5.0 million we borrowed under a loan agreement with Silicon Valley Bank in July 2013.

Liquidity and Capital Resources

We have incurred losses and negative cash flows from operations since our inception. As of September 30, 2014, we had an accumulated deficit of $104.1 million and we expect to continue to incur net losses for the foreseeable future. As of September 30, 2014, we had cash, cash equivalents and investments of $23.5 million. We believe that our existing cash, cash equivalents and investments as of September 30, 2014, together with the net proceeds from this offering, will be sufficient to meet our anticipated cash requirements through at least the next 12 months.

Sources of Liquidity

From our inception through September 30, 2014, we have funded our operations primarily with aggregate net proceeds of $94.9 million from the private placement of redeemable convertible preferred stock and convertible promissory notes, $10.0 million of commercial bank debt and a $2.0 million convertible promissory note issued to our landlord.

Debt Financing

In each of July 2013 and June 2014, we borrowed $5.0 million under a $10.0 million loan and security agreement with Silicon Valley Bank, or SVB, which we refer to as the SVB Loan. Beginning in July 2014, we are obligated to make equal payments of principal and interest through the maturity date of June 1, 2017. The interest rate is a per annum fixed rate of 5.0% and 5.88% for the $5.0 million drawn in each of July 2013 and June 2014, respectively. The final payment due in June 2017 includes an additional fee of $0.5 million. The SVB Loan is collateralized by all of our assets, other than our intellectual property, and contains customary affirmative and negative covenants, reporting requirements and events of default. In connection with the SVB Loan, we issued a warrant to purchase 118,624 shares of Series D redeemable convertible preferred stock at an exercise price of $2.529 per share. As of September 30, 2014, we have no available credit under the SVB Loan.

In December 2011, in conjunction with our facility lease, we issued a $2.0 million subordinated convertible unsecured promissory note to the venture arm of our landlord, BioMed Realty, L.P., which was subsequently transferred to its affiliate, BMV Direct RE LP. The convertible note carries an annual interest rate of 8.0% and matures at the earlier of (i) May 2015, (ii) a liquidation event, and (iii) the closing of an initial firm commitment underwritten public offering of our common stock pursuant to a registration statement under the Securities Act, unless previously converted. At any time prior to maturity, the holder may elect to convert the principal outstanding under the promissory note into shares of our Series D redeemable convertible preferred stock at the price of $2.662 per share. Upon conversion, all then accrued interest will be forgiven. As of September 30, 2014, the outstanding principal and accrued interest on the convertible note were $2.0 million and $0.4 million, respectively.

 

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Cash Flows

The following table sets forth a summary of the net cash flow activity for each of the periods set forth below:

 

		Years Ended December 31,								Nine Months Ended September 30,
		2012				2013				2013				2014
										(unaudited)
		(in thousands)
Net cash provided by (used in):
Operating activities		$	(11,378	)		$	(17,311	)		$	(13,000	)		$	(17,023	)
Investing activities			(598	)			(644	)			(348	)			(4,996	)
Financing activities			1,658				50,737				50,733				4,297
Net increase (decrease) in cash		$	(10,318	)		$	32,782			$	37,385			$	(17,722	)

Operating activities. Net cash used in operating activities was $11.4 million, $17.3 million, $13.0 million and $17.0 million for the years ended December 31, 2012 and 2013 and the nine months ended September 30, 2013 and 2014, respectively. The net cash used in operating activities in each of these periods was primarily due to our net losses. The primary differences between net cash used in operating activities and our net loss in each period primarily related to non-cash charges for depreciation, stock-based compensation and changes in our accounts payable and accrued expense accounts.

Investing activities. Net cash used in investing activities for the years ended December 31, 2012 and 2013 and the nine months ended September 30, 2013 was due to our purchases of property and equipment in each period. Net cash used in investing activities for the nine months ended September 30, 2014 consisted of $0.2 million of property and equipment purchases and $4.7 million of net purchases of investments, consisting primarily of corporate debt and commercial paper.

Financing activities. Net cash provided by financing activities was $1.7 million for the year ended December 31, 2012 and consisted primarily of net proceeds received from commercial bank debt. Net cash provided by financing activities for the year ended December 31, 2013 and the nine months ended September 30, 2013 was $50.7 million and consisted primarily of $38.7 million of net proceeds from the issuance of Series D redeemable convertible preferred stock, $9.5 million of net proceeds from the issuance of convertible notes that were converted into Series D redeemable convertible preferred stock and $2.5 million of net proceeds from the SVB Loan. Net cash provided by financing activities during the nine months ended September 30, 2014 consisted primarily of $5.0 million of proceeds from the SVB Loan offset by $0.8 million of principal payments on outstanding debt obligations.

Funding Requirements

We expect our expenses to increase in connection with our ongoing activities, particularly as we continue to advance Resolaris in clinical development, continue our research and development activities with respect to potential Physiocrine-based therapeutics, and seek marketing approval for Resolaris and other product candidates that we may develop. In addition, if we obtain marketing approval for any of our product candidates, we expect to incur significant commercialization expenses related to product sales, marketing, manufacturing and distribution. We currently have no sales or marketing capabilities and would need to expand our organization to support these activities. Furthermore, upon the completion of this offering, we expect to incur additional costs associated with operating as a public company. Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations. Our forecast of the period of time through which our financial resources will be adequate to support our operations is a forward-looking statement that involves risks and uncertainties, and actual results could vary materially.

 

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Our future capital requirements are difficult to forecast and will depend on many factors, including:

 

•

our ability to initiate, and the progress and results of, our planned clinical trials of Resolaris;

 

•

the scope, progress, results and costs of preclinical development, and clinical trials for our other product candidates;

 

•

the costs, timing and outcome of regulatory review of our product candidates;

 

•

the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending any intellectual property-related claims;

 

•

the costs and timing of future commercialization activities, including product manufacturing, marketing, sales and distribution, for any of our product candidates for which we receive marketing approval; and

 

•

the extent to which we acquire or in-license other products and technologies.

Until such time, if ever, as we can generate substantial product revenues, we expect to finance our cash needs through a combination of equity offerings, debt financings, collaborations, strategic partnerships and licensing arrangements. To the extent we raise additional capital through the sale of equity or convertible debt securities, the ownership interest of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of our common stockholders. Debt financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends. If we raise additional funds through collaborations, strategic partnerships or licensing arrangements with third parties, we may have to relinquish valuable rights to our product candidates, our other technologies, future revenue streams or research programs or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to develop and market our product candidates even if we would otherwise prefer to develop and market such product candidates ourselves.

Contractual Obligations and Commitments

The following table summarizes our contractual obligations as of December 31, 2013:

 

						Payments Due by Period
		Total				Less than 1 Year				1-3 Years				3-5 Years				More than 5 Years
		(in thousands)
Commercial bank debt, including interest and final payment obligations (1)		$	5,677			$	1,027			$	3,600			$	1,050			$	—
Convertible promissory note, including interest			2,544				—				2,544				—				—
Operating lease obligation (2)			2,002				571				1,200				231				—
Total		$	10,223			$	1,598			$	7,344			$	1,281			$	—

 

(1)	Amounts do not include the $5.0 million borrowed in June 2014 under our loan agreement with SVB. We will make principal and interest payments to SVB with respect to these June 2014 borrowings of $0.9 million in 2014, $1.8 million in 2015, $1.8 million in 2016 and $1.3 million in 2017.

(2)	Our operating lease obligations relate to our corporate headquarters in San Diego, California. We lease 17,083 square feet of office and laboratory space under an operating lease that expires in May 2017.

We enter into contracts in the normal course of business with clinical trial sites and clinical supply manufacturing organizations and with vendors for preclinical safety and research studies, research supplies and other services and products for operating purposes. These contracts generally provide for termination after a notice period, and therefore are cancelable contracts and not included in the table of contractual obligations and commitments.

 

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We may have payment obligations under our agreements with The Scripps Research Institute, or TSRI, certain of which are contingent upon future events such as our achievement of specified development, regulatory and commercial milestones, and we are required to make development milestone payments and royalty payments in connection with the sale of products developed under these agreements. As of December 31, 2013, we were unable to estimate the timing or likelihood of achieving the milestones or making future product sales and, therefore, any related payments are not included in the table above.

We are party to an amended and restated research funding and option agreement with TSRI, under which we provide funding to TSRI to conduct certain research activities related to aminoacyl tRNA synthetases. Under the research funding and option agreement, TSRI has granted us options to enter into license agreements to acquire rights and exclusive licenses to develop, make, have made, use, have used, import, have imported, offer to sell, sell and have sold certain licensed products, processes and services based on certain technology arising from the sponsored research activities. Pursuant to the terms of these license agreements, TSRI is entitled to receive tiered royalties as a percentage of net sales, ranging from the low to mid-single digits, with these royalty rates subject to adjustment under certain circumstances. Additionally, we have agreed to pay TSRI a percentage of non-royalty revenue we receive from our sublicensees or partners, with the amount owed decreasing if we enter into the applicable sublicense agreement or partnering agreement after meeting a specified clinical milestone. We are obligated to make payments to TSRI of up to an aggregate of $2.75 million under each license agreement upon the achievement of specific clinical and regulatory milestone events.

Recent Accounting Pronouncements

In June 2014, the Financial Accounting Standards Board, or FASB, issued Accounting Standards Update, or ASU, No. 2014-10, Development Stage Entities (Topic 915) Elimination of Certain Financial Reporting Requirements, Including an Amendment to Variable Interest Entities Guidance in Topic 810, Consolidation. This ASU, among other things: (i) eliminates the requirement to present inception-to-date information on the statements of income, cash flows, and stockholders’ equity, (ii) eliminates the need to label the financial statements as those of a development stage entity, (iii) eliminates the need to disclose a description of the development stage activities in which the entity is engaged and (iv) amends FASB ASC 275, Risks and Uncertainties, to clarify that information on risks and uncertainties for entities that have not commenced planned principal operations is required. The amendments in ASU No. 2014-10 related to the elimination of Topic 915 disclosures and the additional disclosure for Topic 275 are effective for public companies for annual and interim reporting periods beginning after December 15, 2014. We have early adopted this new guidance for our consolidated financial statements for the year ended December 31, 2013, and therefore have not labeled our consolidated financial statements as those of a development stage entity or included the previously required inception-to-date information.

In August 2014, the FASB issued ASU 2014-15, Disclosure of Uncertainties about an Entity’s Ability to Continue as a Going Concern. ASU 2014-15 requires management to evaluate relevant conditions, events and certain management plans that are known or reasonably knowable that when, considered in the aggregate, raise substantial doubt about the entity’s ability to continue as a going concern within one year after the date that the financial statements are issued, for both annual and interim periods. ASU 2014-15 also requires certain disclosures around management’s plans and evaluation, as well as the plans, if any, that are intended to mitigate those conditions or events that will alleviate the substantial doubt. ASU 2014-15 is effective for fiscal years ending after December 15, 2016. We are currently evaluating the impact that the adoption of ASU 2014-15 will have on our consolidated financial statements and related disclosures.

Off-Balance Sheet Arrangements

We did not have during the periods presented, and we do not currently have, any off-balance sheet arrangements, as defined in the rules and regulations of the SEC.

 

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Quantitative and Qualitative Disclosures about Market Risk

Interest Rate Risk

Our primary exposure to market risk is interest income sensitivity, which is affected by changes in the general level of U.S. interest rates. Due to the short-term duration of our investment portfolio and the low-risk profile of our investments, we would not expect our operating results or cash flows to be affected to any significant degree by the effect of a sudden change in market interest rates on our investment portfolio. A 10% change in interest rates on September 30, 2014 would not have had a material effect on the fair market value of our portfolio.

We do not believe that our cash, cash equivalents and investments have significant risk of default or illiquidity. While we believe our cash and cash equivalents do not contain excessive risk, we cannot provide absolute assurance that in the future our investments will not be subject to adverse changes in market value. In addition, we maintain significant amounts of cash and cash equivalents at one or more financial institutions that are in excess of federally insured limits.

Our debt obligations bear interest at fixed rates and therefore have no exposure to changes in interest rates.

Foreign Currency Exchange Risk

We incur expenses, including for CROs and clinical trial sites, outside the United States based on contractual obligations denominated in currencies other than the U.S. dollar, including Pounds Sterling. At the end of each reporting period, these liabilities are converted to U.S. dollars at the then-applicable foreign exchange rate. As a result, our business is affected by fluctuations in exchange rates between the U.S. dollar and foreign currencies. We do not enter into foreign currency hedging transactions to mitigate our exposure to foreign currency exchange risks. Exchange rate fluctuations may adversely affect our expenses, results of operations, financial position and cash flows. However, to date, these fluctuations have not been significant and a movement of 10% in the U.S. dollar to Pounds Sterling exchange rate would not have a material effect on our results of operations or financial condition.

Effects of Inflation

Inflation generally affects us by increasing our cost of labor, manufacturing, clinical trial, and other research and development and administration costs. We do not believe that inflation has had a material effect on our results of operations or financial condition during the periods presented.

 

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BUSINESS

Overview

We engage in the discovery and clinical development of innovative medicines for patients suffering from severe rare diseases using our knowledge of Physiocrine biology, a newly discovered set of physiological modulators. We have discovered approximately 300 Physiocrines (physio for life and crine for specific activity), a class of naturally-occurring proteins that we believe promote homeostasis, a fundamental process of restoring stressed or diseased tissue to a healthier state. Physiocrines are extracellular signaling regions of tRNA synthetases, an ancient family of enzymes that catalyze a key step in protein synthesis. We believe that Physiocrines have evolved over time to modulate important cellular pathways by interacting with various types of cells, including immune and stem cells. Approximately 100 of these proteins interact with the immune system, which we believe presents a significant therapeutic opportunity to restore affected tissues to a healthier state through natural immuno-modulation mechanisms. We successfully completed a Phase 1 clinical trial of Resolaris, our first development candidate from our Physiocrine discovery engine, and are currently conducting a multi-national exploratory Phase 1b/2 clinical trial of Resolaris in adult patients with facioscapulohumeral muscular dystrophy, or FSHD, a severe, rare genetic myopathy with an immune component, for which there are currently no approved treatments. By leveraging our Physiocrine discovery engine and our knowledge of rare diseases, we aim to build a proprietary pipeline of novel product candidates with the potential to treat severe, rare diseases characterized by immune dysregulation and independently commercialize our Physiocrine-based therapeutics.

Our scientists were the first to identify the Resokine pathway (reso for restoring muscle health and kine for specific activity), a cellular pathway in human skeletal muscle associated with activities arising from various Physiocrine regions of the histidine aminoacyl tRNA synthetase, or HARS. We believe that the Resokine pathway, among its various activities, modulates the immune system to promote tissue homeostasis. We observed that stimulation of this pathway through the introduction of Resolaris and its derivatives in rodent models of both severe inflammation and myopathy led to immuno-modulatory effects. A myopathy is a disease of the skeletal muscle, characterized by muscle fiber deterioration, muscle weakness and often an immune response in the affected muscle tissue. In particular, we have shown that stimulation of the Resokine pathway by Resolaris alters the expression or release of immune-related proteins released by cells in response to inflammation, immune responses and other cellular perturbations, from human cells. HARS, which contains the immuno-modulatory domain, is also released from human skeletal muscle. In addition to its immuno-modulatory properties, we believe the Resokine pathway may act on other physiological processes, including processes associated with stem cells, fibrosis and endothelial cells.

We are harnessing the Resokine pathway and its association in skeletal muscle with homeostasis to develop Resolaris as a first-in-class therapeutic for patients with rare myopathies with an immune component, or RMICs, for which there are limited or no approved treatments. In contrast to most current immunology drugs, which are engineered antagonists of immunological pathways, Resolaris is derived from a naturally occurring protein, HARS, which we believe has the potential to reset the immune system in diseased tissue to a more normal state while maintaining the immune system’s activity against exogenous, pathogen-based insults. Since the identification of the Resokine pathway, we have successfully advanced Resolaris through preclinical development, current Good Manufacturing Practice, or cGMP, manufacturing and an initial Phase 1 clinical trial. In the first quarter of 2014, we completed a double-blind, placebo-controlled Phase 1 clinical trial of Resolaris, in which we assessed its safety and tolerability in 32 healthy subjects. Resolaris was shown to be well tolerated at all doses tested, and no serious adverse events were reported. Based on the favorable clinical safety, pharmacokinetic and immunogenicity profile of Resolaris in this trial, we decided to advance Resolaris into clinical trials of RMIC patients.

We recently initiated a multi-national exploratory Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD in the European Union. This randomized, double-blind, placebo-controlled trial is designed to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of multiple intravenous doses of Resolaris in adults

 

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with FSHD. We also intend to explore pharmacodynamic changes in inflammatory immune responses in skeletal muscle, as assessed by quantitative magnetic resonance imaging, or MRI, and in peripheral blood, as assessed by levels of circulating immune proteins, such as cytokines and muscle enzymes, and ex vivo inflammatory immune proteins released from peripheral blood cells. Resolaris will be studied in three dose escalation cohorts (0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg). In the fourth quarter of 2014, we completed multiple dosing of the patients in the first dose cohort. We are currently enrolling the second dose cohort. Subject to our discussions with regulatory authorities and patient enrollment in accordance with our clinical development plans, we expect to report initial results from this clinical trial in the second half of 2015 for all three cohorts.

Our initial therapeutic efforts target rare disease indications in which patients suffer from the immune-related consequences of their genetic disease. We have identified over 20 distinct, molecularly definable RMIC indications, including FSHD and limb-girdle muscular dystrophies, that we believe Resolaris has the potential to treat. Additionally, we believe Physiocrine biology has potential therapeutic application in a variety of diseases characterized by tissue dysfunction, including severe diseases of the lung, gut, skin, brain and liver. We intend to leverage our Physiocrine expertise and our broad intellectual property portfolio, which we believe covers this entire class of potential protein therapeutics, to build a pipeline of product candidates that we expect to develop and commercialize independently for the treatment of various rare diseases.

We were founded in 2005 by Paul Schimmel, Ph.D. and Xiang-Lei Yang, Ph.D., two leading aminoacyl tRNA synthetase scientists at The Scripps Research Institute in San Diego, California. Our Executive Chairman and Chief Executive Officer, John D. Mendlein, Ph.D., was formerly the Chief Executive Officer of Adnexus Therapeutics, Inc. (acquired by Bristol-Myers Squibb Company) and Affinium Pharmaceuticals, Ltd. (acquired by Debiopharm Group), and held various roles at Aurora Biosciences Corporation (acquired by Vertex Pharmaceuticals Incorporated). We have assembled an executive team with broad experience in the discovery, development and commercialization of innovative therapeutics, including transformative therapies for rare genetic diseases such as Kalydeco, marketed by Vertex Pharmaceuticals Incorporated for the treatment of cystic fibrosis. We are advised by a Scientific Advisory Board comprised of leaders in the field of biology for medical applications, including our special advisor in immunology, Bruce Beutler, M.D., recipient of the 2011 Nobel Prize in Physiology or Medicine for his work in immunology. Our key investors include entities affiliated with Alta Partners, Cardinal Partners, Domain Associates, Polaris Venture Partners and Fidelity Management & Research Company.

Our Strategy

We aim to capitalize on Physiocrine biology, a new and important area of human biology, to develop first-in-class medicines to treat patients with severe diseases characterized by an immune component. Key elements of our strategy include the following:

 

•

Leverage our leadership position in Physiocrine biology to develop and commercialize novel, first-in-class medicines for patients affected by severe, rare diseases with significant unmet need. We focus on patients with severe, rare genetic diseases because we believe that the stimulation of Physiocrine pathways in these patients can restore diseased tissue to a more normal phenotype. Our strategy is to focus initially on indications where current treatment options are limited and our product candidates have the potential to provide transformative therapeutic benefit to patients given the severity of the diseases. We believe our initial focus on rare diseases will allow us to more effectively deploy investor capital for the independent development and commercialization of medicines for the benefit of patients and our stakeholders.

 

•

Rapidly and prudently pursue the development and commercialization of Resolaris to treat patients across multiple severe disease indications. We intend to expeditiously pursue the development and regulatory approval of Resolaris in multiple RMICs. We are currently evaluating Resolaris in a Phase 1b/2 clinical trial in adult patients with FSHD and expect to report results from this clinical trial in the second half of 2015. In addition, we plan to conduct clinical trials in early onset FSHD and other

 

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RMIC indications, including limb-girdle muscular dystrophy. We also intend to evaluate Resolaris in other rare diseases with an immune component. To bolster our clinical understanding of Resolaris, we may additionally evaluate Resolaris in more common diseases with an immune component.

 

•

Leverage our Physiocrine discovery engine to build a pipeline of first-in-class medicines to address severe conditions driven by immune or fibrotic pathways. Based on our understanding of the biology of Physiocrines, we believe that this class of naturally-occurring proteins has the potential to produce therapeutic benefits across a broad range of disease indications associated with an inappropriately amplified immune response, or where fibrosis contributes to disease associated with specific organs. We plan to leverage our discovery engine to identify other Physiocrine pathways of interest and select additional potential product candidates for preclinical and clinical investigation in a variety of disease settings on an organ-by-organ basis, which may include severe, currently inadequately treated diseases of the lung and liver.

 

•

Retain exclusive worldwide commercial rights to our product candidates to pursue autonomous commercialization. We intend to build a pipeline of product candidates, the rights to which we solely own or exclusively license, that we can commercialize independently through a relatively small, dedicated commercial organization focused on patient needs and directed at a limited number of physicians who specialize in the treatment of our target patient populations. While we do not expect to require pharmaceutical partners for commercialization of our product candidates, we may consider partnering for strategic purposes, including to enhance our pipeline efforts.

 

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Expand our knowledge and intellectual property position in Physiocrine biology by emphasizing continuous scientific and business advancements. We will continue to advance our scientific and therapeutic insights into Physiocrine biology through internally developed in vivo and in vitro screening systems in conjunction with genetic analysis and disease associations of Physiocrines, as well as in partnership with academic institutions and disease societies. We intend to leverage our leadership position in this field to broaden our intellectual property positions both in our most advanced programs and for additional therapeutic applications of Physiocrines. We will continue to vigorously prosecute and defend our intellectual property portfolio, as well as exploit our proprietary position to strategically advance our business.

 

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Build a world class organization oriented to patients and focused on rigorous scientific, clinical and industrial advancements. We have assembled a world class team with industry-recognized expertise in biology, medicine and the commercialization of innovative and important therapeutics. We intend to continue to build on our leadership position in Physiocrine and immunology-based therapeutics and to grow an organization and culture dedicated to the development and commercialization of medicines with the potential to transform the lives of patients with severe, rare diseases. We intend to maintain and expand our relationships with key opinion leaders, patient advocacy groups and other business partners, and to solicit input from payors and others in the healthcare industry, to identify and develop our product opportunities and to design our development programs in order to maximize the availability of our product candidates to patients.

Our Founding Principles

We embrace the following principles:

 

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We understand disease never takes a day off. Transformational science never sleeps in order to make meaningful medicines.

 

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With relentless determination, we aim to discover life-changing therapies for people with grave maladies where others fall short.

 

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We aim to develop medicines by orchestrating important physiological processes using novel biological and therapeutic mechanisms.

 

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We recruit and retain remarkable people to actualize our aspiration to achieve industry-admired results in all aspects of our business.

 

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We galvanize our teams using shared principles to accomplish our collective mission to make meaningful medicines with the potential to provide positive outcomes to patients and our stakeholders.

Our Pipeline—A New Set of Treatment Mechanisms for Patients

We believe that, as the first and only company engaged in the clinical development of therapeutics based on Physiocrine biology, we are positioned to develop and commercialize a pipeline based on a novel class of protein therapeutics, protected by intellectual property rights that we own or exclusively license, that modulate important physiological processes. Below is a summary of our discovery and product development pipeline:

 

(1)	The expected timing of the anticipated next milestones for our clinical programs for Resolaris in FSHD and LGMD is based on our current estimates and is subject to change based on a variety of factors discussed in this prospectus, including in the section entitled “Risk Factors.”

Our research suggests that Physiocrines act through basic mechanisms of innate and adaptive immunity, as well as other pathways, in a way that is distinct from existing classes of protein therapeutics. We believe Physiocrines have evolved, among other things, to balance the immune system, resolving inflammation naturally, in contrast to currently available immuno-modulatory therapeutics, which are engineered inhibitors of pro-inflammatory pathways. We intend to harness these mechanisms of Physiocrines to benefit patients with severe diseases in ways that we believe have advantages over traditional antibody and small molecule approaches.

Physiocrines: Harnessing a Newly Discovered Source of Innovative Therapeutics

The Promise of Physiocrine-Based Medicines in Promoting Homeostasis

Homeostasis, or the coordinated regulation of tissues within the body, is fundamental to the maintenance of the overall health of an organism and a key feature of multicellular life. Lack of homeostasis can lead to disease and death. The process of homeostasis was first described in 1865 by the French physiologist Claude Bernard. In the 150 years since this discovery, many proteins associated with homeostatic pathways have been discovered, ranging from insulin to erythropoietin, or EPO.

 

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Using our knowledge of bioinformatics, sequencing, proteomics and structural biology, we identified Physiocrines, a novel class of proteins that are present as biologically active signaling regions of the tRNA synthetases, an ancient protein family. We believe that Physiocrines are involved in orchestrating homeostatic activities to help the body restore diseased or damaged tissue to a healthier state. We have observed that certain Physiocrines exhibit previously undescribed extracellular activities that are involved in restoring and regulating tissues to promote health. We believe that physiological perturbations, such as stress or changes in physiological state, alter or induce the release of Physiocrines from cells or platelets in the human body. Physiocrines have been observed to be released from a wide variety of cells, including in response to such stimuli as starvation-induced apoptotic stress or the introduction of certain cellular ligands, including tumor necrosis factor alpha and vascular endothelial growth factor.

Physiocrine Biology Overview

The Discovery of Physiocrines

In 1999, our founder, Dr. Paul Schimmel, published in Science a structural and functional description of extracellular signaling regions of a specific tRNA synthetase. tRNA synthetases are an ancient family of enzymes that were generally thought to be involved only in protein synthesis. Since Dr. Schimmel’s discovery, numerous papers have been published on the alternative activities of tRNA synthetases. We refer to the extracellular signaling regions of tRNA synthetases illustrated in the figure below, along with other later-discovered or splice variant regions of tRNA synthetases, as Physiocrines. A splice variant is a variation of a gene transcript.

 

There are 20 known human cytosolic tRNA synthetases, each coding for one of the 20 amino acids. Amino acids, when bonded together, form full-length functional proteins. There about 15 potential Physiocrines per tRNA synthetase, including Physiocrine regions in a full length tRNA synthetase protein, splice variants from a tRNA synthetase gene, or proteolytic fragments from a full length protein. Physiocrines act by binding to various proteins important in extracellular activities, including G protein-coupled receptors, cytokine receptors, tyrosine kinase receptors and extracellular matrix proteins.

 

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Our founding mandate focused on the systematic interrogation of the tRNA synthetase gene family through bioinformatics and structural analysis. Our research, along with that of The Scripps Research Institute, revealed that although the genetic sequence of each of the 20 tRNA synthetase genes changed at multiple times over four billion years by the genetic mutation of tRNA synthetases, including the insertion of DNA sequences, protein synthesis, however, as characterized by tRNA synthetase activity, remained relatively unchanged over that period of time. As illustrated in the figure below, the structural diversity of proteins resulting from the inserted genetic material increased as living organisms became more complex and as fundamental physiological systems, including immunological, stem cell, muscular, circulatory, respiratory and neural systems, developed.

 

The results of this research suggested to us that tRNA synthetases retained a core function in protein synthesis over four billion years, while developing other important and diverse physiological functions associated with Physiocrines. We believe these functions could serve as a source of therapeutics directed at stimulating pathways involved in the restoration of a wide variety of tissues.

 

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The Function of Physiocrines in Fundamental Pathways of Life

Based on the research suggesting that Physiocrines are potentially important modulators of cellular pathways, we hypothesized that Physiocrines may play roles in immunology, stem cell biology, neurology, vascular biology, skeletal muscle biology, hepatic (liver) biology and metabolic biology. To test this, we expressed and purified over 200 Physiocrine regions across the family of 20 tRNA synthetase genes and evaluated these purified Physiocrines in numerous cell-based assays to determine their activity in several important human physiological pathways. Some of the data was published in July 2014 in Science, with the data categorized according to important areas of biology. The table below describes several key cellular pathways in which Physiocrines may present therapeutic opportunities:

 

Cellular Pathways		Number of Physiocrines		Potential Therapeutic Applications
Immunology		99		Rare Diseases with an Immune Component, Auto-immune, Oncology and Fibrosis
Stem Cells		129		Regenerative Medicine, Fibrosis and Oncology
Neurology		34		Neurodegenerative Diseases
Vascular		35		Cardiovascular Diseases, Oncology and Immunology
Skeletal Muscle		130		Skeletal Muscle Diseases
Hepatic		76		Liver Fibrosis
Metabolic		22		Diabetes and Obesity

Our current research includes efforts to understand the relationship of various Physiocrine pathways to health and disease and the potential for a particular Physiocrine pathway to provide a valuable therapeutic intervention point. To this end, we track international efforts related to gene sequencing of patients with rare phenotypes and genetic changes to tRNA synthetases, as well a number of cancers associated with tRNA synthetases and auto-immune diseases associated with antibodies to tRNA synthetases.

Physiocrine Pathways as Therapeutic Intervention Points

Our Initial Focus on Immuno-Modulation

Many important therapeutics act in connection with physiological pathways, including growth factor and differentiation pathway agonists, such as insulin and EPO; growth factor pathway antagonists, such as vascular endothelial growth factor antagonists; immune pathway antagonists, such as tumor necrosis factor antagonists; immune pathway agonists, such as interferon; and metabolic pathway modulators, such as glucagon-like peptide-1 (GLP-1). We are initially focused on the application of Physiocrines to immuno-modulation in rare diseases. We selected immuno-modulation as our initial area of focus for the following reasons:

 

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We believe immunology plays a significant role in most diseases;

 

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A number of Physiocrines have been shown to be differentially expressed in immune cells;

 

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A large number of Physiocrine pathways appear to relate to immunology, as at least seven different tRNA synthetase proteins are associated with certain immune-driven diseases; and

 

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Approximately 100 Physiocrines have demonstrated activity in various cell-based assays related to immunological pathways.

Additionally, we focus our immuno-modulator development efforts on indications that represent severe, rare diseases, particularly genetically based diseases, because:

 

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Our scientific understanding of Physiocrines as immuno-modulators intersected with multiple rare diseases;

 

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We believe patients with rare genetic diseases often face challenges related to the responses of their immune systems to changes in tissues that are caused by genetic mutations; and

 

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We believe the pathological phenotypes in rare diseases present an opportunity for us to therapeutically intervene with greater impact.

Advantages of Physiocrine-Based Therapeutics

Most current immunological drugs are engineered antagonists of immunological pathways, typically acting to lower elevated immune responses resulting from disease, as in the case of monoclonal antibodies acting against circulating signaling molecules, such as cytokines. Although these signaling molecules may be up-regulated by disease, their natural levels and fluctuations have evolved to include non-disease functions of the immune system, mediating a wide range of physiological activities, as opposed to evolving to cause disease. Our discovery and development efforts focus on therapeutics derived from naturally-occurring proteins. We believe that Physiocrines have naturally evolved to reset the immune system to control or reduce tissue damage while maintaining the immune system’s activity against exogenous pathogen based insults, and may possess the following advantages over engineered antagonists of immunological pathways:

 

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As proteins designed by nature to reset the immune system, Physiocrines may provide a unique mechanism to improve patient outcomes through their activity in either a single or multiple pathways;

 

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Physiocrines have the potential to reset the immune system across multiple pathways at the level of an immune cell, rather than lowering the levels of a single immune protein like most engineered antagonists;

 

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Physiocrines may potentially act as agonists at the level of the immune cell to reduce pro-inflammatory effects and induce resolution of inflammation;

 

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The therapeutic effects of Physiocrines may persist even after the Physiocrines have been cleared from circulation; and

 

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Physiocrines present the potential for fewer, if any, immuno-suppressive effects, as compared to engineered antagonistic immuno-modulators.

The Resokine Pathway and Resolaris, Our Product Candidate

Identification of the Resokine Pathway through In Vivo Screening Approaches

Our scientists discovered the Resokine pathway in human skeletal muscle using our in vivo screening systems in models of severe inflammation, combined with our knowledge of the effects of antibody binding to a specific tRNA synthetase in a population of patients with a particular rare myopathy. The Resokine pathway encompasses physiological activities, including potential immuno-modulatory and other muscle health activities, arising from various Physiocrine regions of the histidine aminoacyl tRNA synthetase, or HARS. Animal studies and human pathophysiological data have shown that antibody-based blockade of the Resokine pathway may lead to muscle tissue deterioration and immune cell invasion.

 

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First Demonstration of a Region of HARS as an Immuno-modulator

We conducted in vivo screening activities of a splice variant from HARS that we identified in our deep sequencing studies, which we refer to as the immuno-modulatory domain, or iMod domain, of HARS. The figure below depicts the iMod domain and other forms of HARS:

 

For our studies of the iMod domain, we selected a rodent model of severe inflammation induced by the administration of trinitrobenzene sulfonic acid, or TNBS, in which the inflammation is thought to be driven by excessive T-cell involvement in the gut, leading to the death of the study animals. Animals administered the iMod domain survived longer than those given either the vehicle control phosphate buffer solution, or PBS, or the approved drug control (Budesonide) (p<0.01), demonstrating the potential activity of the iMod domain as an immuno-modulator of excessive T-cell involvement. The results of this study are summarized in the graph below:

 

Additionally, we have demonstrated in the same rodent model of inflammation in the gut that at least two other related molecules, Resolaris and iModFc, both of which are derived from HARS and contain the iMod domain, are active in models of excessive T-cell involvement. Based on these observations, we believe that blockade of the activity of the iMod domain may contribute to excessive or inappropriate T-cell involvement in immune-driven diseases.

 

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Evidence of the Role of the Resokine Pathway in Rare Muscle and Lung Diseases

In 1983, Matthews and Bernstein published in Nature the observation that a rare myopathy patient possessed antibodies to a single tRNA synthetase, HARS. This condition is one example of anti-synthetase syndrome and is often referred to as Jo-1 antibody disease. Since then, it has been observed that patients with auto-antibodies to HARS (but not antibodies to the other 19 tRNA synthetases in the same patients) can develop both a debilitating myopathy characterized by weakness and skeletal muscle loss, and interstitial lung disease, or ILD, both of which are characterized by T-cell invasion. Numerous laboratories have verified the existence of anti-HARS antibodies, sometimes known as Jo-1 antibodies, as one of the manifestations of anti-synthetase syndrome.

Based on these observations, we chose to study the potential link between HARS antibodies and muscle disease in Jo-1 antibody positive anti-synthetase syndrome patients. Our scientists obtained serum samples from 18 of these patients to determine whether the Jo-1 antibodies specifically bound to the iMod domain. We determined that in each of the 18 Jo-1 antibody positive patients studied, a significant portion of Jo-1 antibody binding was to the iMod domain, compared to binding to other regions of HARS. We believe that in these patients, the binding of Jo-1 antibodies to the iMod domain blocked the immuno-modulatory properties of the iMod domain, therefore contributing to their myopathy and ILD. Independent laboratories have also observed in unrelated studies that the iMod domain is the primary Jo-1 antibody binding region in patients with anti-synthetase syndrome. The figure below illustrates the potential connection between Jo-1 antibody binding to the iMod domain and T-cell proliferation in diseased muscle and lung tissue.

 

 

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Additional Confirmatory Studies of the Blockade of the Resokine Pathway

We have conducted studies that suggest that antibody blockade of the Resokine pathway contributes to immune cell invasion in skeletal muscle and lung tissue. Recently published animal studies by a third party laboratory are consistent with our findings. In particular, in 2014, Sciorati et al. published on the effect in rat skeletal muscle of antibodies to the iMod domain produced by vaccination, generating additional evidence that the Resokine pathway plays a role in skeletal muscle health and the immune system. The Sciorati study demonstrated: (1) antibody generation to the iMod domain of HARS; (2) levels of creatine kinase, or CK, a biomarker of muscle destruction, increased in relation to antibody levels; (3) antibodies to the iMod domain correlated with an increase in muscle inflammation, as observed by MRI; and (4) the MRI signal corresponded to muscle destruction, as judged by histology. These data are illustrated in the figures below:

 

The data generated by Sciorati et al. are consistent with our conclusions that the Resokine pathway was reduced or blocked in Jo-1 antibody positive anti-synthetase syndrome patients as a result of antibodies against the iMod domain.

 

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Altering Excessive T-cell Invasion in Preclinical Studies of Resolaris in Skeletal Muscle

We also tested Resolaris in a rodent model in which statins, which are known to induce myopathies in humans and rodents, were administered to induce a severe, aggressive myopathy. In the study, animals were administered statins for two weeks, and at Day 8, treatment with Resolaris was started. After a week of treatment with Resolaris, we observed a change in the phenotype of the treated animals, from excessive immune cell invasion to nearly normal histology and immune cell levels, as compared to animals in the control group, as shown in the figure below:

 

Resolaris Mechanism of Action: T-cell Modulation and Other Potential Pathways

Our in vivo studies suggest that stimulation of the Resokine pathway combats pathophysiological changes in three established animal models of excessive T-cell involvement in which approved drugs have been tested. Our in vitro studies of Resolaris suggest that at least one of the activities of Resolaris includes a direct action on T-cells to reduce, but not completely block, cytokine release. This reduction also lasts for at least 24 hours after Resolaris has been removed from the T-cells. This suggests that the pharmacodynamic effect of Resolaris in vivo could be longer than the pharmacokinetics of the protein. It also suggests that there is at least one T-cell associated receptor for Resolaris, such as a cytokine or chemokine receptor.

 

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Additional cell-based assays show that specific regions of Resolaris may harbor additional activities similar to Physiocrine regions from the HARS gene, including those illustrated in the figure below. We are currently conducting additional studies regarding non-immuno-modulatory activities that may relate to the mechanism of action of Resolaris.

 

Additionally, we have looked for direct antagonist activities of Resolaris on certain cytokines. Resolaris does not appear to act as a direct ligand antagonist, but rather appears to act more globally at the level of immune cells and potentially other cell types. HARS is also released directly from human skeletal muscle in vitro, and blocking HARS with antibodies after stimulated release by insulin-like growth factor, or IGF-1, reduces the effect of IGF-1 in muscle differentiation.

Resolaris for the Treatment of Multiple Rare Myopathies with an Immune Component

Overview

We are developing Resolaris as a first-in-class intravenous protein therapeutic for the treatment of rare myopathies with an immune component, or RMICs. We have identified over 20 distinct, molecularly definable RMIC indications that we believe Resolaris has the potential to treat. In each of these indications, skeletal muscle tissue exhibits dysfunction and becomes subject to immune cell invasion, which contributes to the loss of function and deterioration of the muscle tissue. RMIC patients generally present with three common characteristics:

 

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aberrant protein expression (in the case of genetically based RMIC indications);

 

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immune cell invasion; and

 

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muscle cell damage and deterioration.

In normal muscle, muscle mass and function require a balance between muscle cell stress and damage and muscle cell regeneration and growth. The immune system helps maintain this balance by “cleaning up” damaged muscle cells after muscle damage and during the healing process. In RMIC diseases, the balance is tipped to favor chronic pathophysiological muscle deterioration and persistent immune cell invasion. In genetically based RMIC diseases, aberrant protein expression often occurs, as in the case of FSHD patients with inappropriate expression of a protein not normally expressed in muscle. As discussed above, in vivo rodent models of skeletal muscle deterioration and immune cell invasion have shown that Resolaris can combat immune cell invasion into the muscle and muscle deterioration. Conversely, experiments in rodents have shown that antibody blockade of the Resokine pathway can lead to immune cell invasion and muscle tissue deterioration.

 

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We intend to harness the body’s power to restore skeletal muscle after stress or damage in the development of Resolaris for RMIC patients who have limited or no approved treatment options. We believe Resolaris can offer a potential multi-pharmacologic therapeutic, synergystically modulating multiple pathways important to muscle health. Our proprietary position for Resolaris includes an issued U.S. patent covering the composition of matter of Resolaris, as well as various patent applications relating to specific methods of use of Resolaris and related proteins.

Resolaris: Potential Therapeutic Applications

We believe Resolaris will provide therapeutic benefit to patients in RMIC indications characterized by excessive immune cell involvement, particularly a type of T-cell known as CD8 T-cells. Dysregulated immune cell invasion can cause and exacerbate muscle damage and stress. For example, CD8 T-cells have been observed to contribute to muscle damage by the release of proteins that destroy or damage skeletal muscle cells. The table below describes RMIC indications in which the relationship between diseased muscle and the immune system has been observed by others, which we believe may be addressed by the proposed mechanism of action of Resolaris.

 

Disease Area		Type of RMIC		Molecular Definition of Disease (Estimated U.S. Population)		Immune Features		Potential Resolaris Mechanism of Action
Rare myopathies with an immune component (RMIC)		Genetic		Facioscapulohumoral muscular dystrophy, or FSHD (19,000)     3 genetic forms*		CD8 T-cell infiltration   Macrophage infiltration   Pro-inflammatory cytokine production, including: MCP-1, IL-6 and IL-12		In preclinical models in vivo, Resolaris reduces (i) the infiltration and accumulation of CD8 T-cells and macrophages and (ii) the expression of cytokines, including MCP-1, MMP9, IL-6 and others.   In vitro studies using Resolaris also demonstrate reduction of a variety of pro-inflammatory cytokines, including IFNg and IL-17A, as well as the activity of pro-inflammatory macrophages.
				Limb-girdle muscular dystrophy, or LGMD (16,000)   >20 genetic forms*		T-cell infiltration
				Duchenne muscular dystrophy, or DMD (5,600-18,000)     >50 genetic forms*		CD8 T-cell infiltration   Macrophage infiltration   MMP9, TIMP1, TNFa
				>10 undisclosed muscular dystrophies		To be determined
		Autoimmune		Sporadic Inclusion Body Myositis, or sIBM (3,400)   Myositis with at least one molecular marker (such as auto-anti-bodies)		CD8 T-cell infiltration   Macrophage infiltration   Pro-inflammatory cytokine production, including MCP-1

 

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*	By use of the term “genetic form,” we mean a molecularly defined marker that includes (1) changes in a chromosome structure, (2) different genes that are mutated or (3) a single gene with multiple points of mutation.

 

Legend:

IL-6: Interleutin-6

IL-12: Interleutin-12

MCP-1: Monocyte Chemotactic Protein 1

MMP9: Matrix Metallopeptidase 9

TIMP1: Tissue Inhibitor of Metalloproteinase-1

TNF-a: Tumor Necrosis Factor alpha

Resolaris: Our Clinical Development Program

We successfully completed a single ascending dose Phase 1 clinical trial in healthy subjects of Resolaris, our first development candidate from our Physiocrine discovery engine. We are currently conducting a multi-national Phase 1b/2 clinical trial of Resolaris in adult patients with facioscapulohumeral muscular dystrophy, or FSHD, a severe, rare genetic myopathy with an immune component, for which there are currently no approved treatments.

Phase 1 Clinical Trial in Healthy Subjects

The first administration in humans of a novel protein within a new class of therapeutics poses specific considerations relating to the safety and tolerability of the molecule. We currently anticipate that if approved, Resolaris would be chronically administered and therefore tolerability, as well as safety, will be important to its adoption. Tolerability effects that could impair drug administration have been observed for other proteins known to interact with cytokine receptors in the immune system, including approved interferons and interleukins. In the case of Resolaris, its proposed mechanism of action suggests that it may interact with receptors on immune cells. As a result, we elected to evaluate Resolaris in healthy subjects first to more rapidly and extensively assess the effects of dose on safety and tolerability.

In the first quarter of 2014, we completed a single ascending dose Phase 1 clinical trial of Resolaris to assess its safety and tolerability in healthy subjects. The planning and design of the trial were guided by the principles that this trial would be the first time that a Physiocrine has been administered to a human subject, and that the therapeutic use of immuno-modulatory drugs are often characterized by poor tolerability and common safety concerns. In particular, we designed this trial as a double-blind, placebo-controlled study in order to rigorously assess safety and tolerability, such as injection site reactions or systemic reactions, and to assess the pharmacokinetics, or PK, immunogenicity and biological activity of single doses of Resolaris in humans. In this trial, 32 healthy adult subjects were randomized to receive a 30 minute intravenous infusion of either placebo or a single dose of 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, or 3.0 mg/kg of Resolaris. Participants were randomly assigned to receive Resolaris or placebo on a 3:1 basis so that within each of the four cohorts, six subjects received Resolaris and two subjects received placebo, and overall, 24 healthy subjects were dosed with Resolaris and eight healthy subjects were dosed with placebo.

Resolaris was found to be well tolerated in all dose cohorts in our Phase 1 clinical trial. There were no serious adverse events or deaths, and the incidence of individual treatment emergent adverse events, or TEAEs, among all groups was low, with no relationship to Resolaris dose level. All TEAEs observed in the trial were mild in intensity and transient, and resolved without treatment-related pathological effects. TEAEs that were considered possibly related to Resolaris were predominantly nervous system symptoms, including single cases of dizziness, headache, and drowsiness. No local tolerability issues related to Resolaris were observed. None of the subjects in the trial reported the discomfort (fever and body aches) commonly observed following single dose administration of other therapeutic proteins that interact with cytokine receptors, such as interferon and granulocyte-colony stimulating factor.

We observed no significant changes from normal in over 30 cytokine and other immune-related protein assays after administration of 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, and 3.0 mg/kg of Resolaris in these healthy

 

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individuals. These results are consistent with the observed role of the Resokine pathway in resolving inflammation. Systemic exposure and C_max were dose proportional, mean total systemic clearance was low and the volume of distribution was small, resulting in a terminal half-life in plasma of approximately three to six hours across all dose levels. Low titer anti-drug antibodies were observed in five subjects out of 24 after administration of Resolaris. One subject out of 24 had similar low titer anti-drug antibodies prior to the administration of Resolaris. The PK of Resolaris was not altered in these subjects. Based on the favorable PK, safety, tolerability and immunogenicity profile of Resolaris in our Phase 1 clinical trial in healthy subjects, we have advanced Resolaris into clinical development in RMIC patients.

Resolaris in Facioscapulohumoral Muscular Dystrophy (FSHD)

Our clinical development of Resolaris first targets FSHD, a rare genetic myopathy for which there are no approved treatments. The primary clinical phenotype of FSHD is debilitating skeletal muscle weakness. The symptoms of FSHD develop in a descending pattern, starting with the face and upper body to the lower body and progressing in a “muscle by muscle” fashion. This is in contrast to other genetic myopathies such as Duchenne muscular dystrophy that affect muscles symmetrically often starting with the legs. These symptoms include musculoskeletal abnormalities such as abnormal protrusion of the shoulder blades or exaggerated bend of the lower spine and, often as the disease progresses, difficulty standing upright, lifting objects, reaching above shoulder level or using the shoulders to support various activities of daily life. Patients also suffer pelvic girdle and lower limb weakness, resulting in progressive difficulty arising from a seated position. Importantly, most patients eventually develop profound weakness in the lower leg and cannot manage to lift the foot of the affected side appropriately. This condition results in frequent falls and related injuries. In addition to muscle weakness, FSHD patients often experience debilitating fatigue and chronic pain. In early onset FSHD, a particularly severe form of FSHD that presents early in life (generally at six years of age or younger), patients often die in their 20s or 30s.

While estimates of FSHD prevalence vary, recent studies exploring the topic have identified average prevalence rates of approximately one in 17,000. Applying this rate to the U.S. population as of November 1, 2014 yields a domestic FSHD population of approximately 19,000. The disease is typically diagnosed by the presence of a characteristic pattern of muscle weakness and other clinical symptoms, as well as through genetic testing of the number of repeats of a specific DNA sequence at the end of Chromosome 4. In normal, unaffected individuals this chromosomal region has from 11 to 100 repeats of the applicable DNA sequence. Patients with late or adult onset FSHD typically have only one to ten of these repeats. Early onset FSHD occurs when patients have three or fewer repeats. Together, late onset FSHD and early onset FSHD are referred to as FSHD1. Another form of the disease, FSHD2, occurs in approximately 5% of FSHD patients, and is caused by mutations in the gene SCHMD1 located on Chromosome 18, together with fewer than 100 repeats of the applicable DNA sequence. In both FSHD1 and FSHD2, the genetic abnormality results in the expression of genes that are normally silent or inactive in skeletal muscle. Consequently, an unusual profile of proteins is produced, which has been linked to FSHD skeletal muscle immuno-pathology.

The FSHD immuno-pathology includes an infiltrative inflammatory process (usually dominated by CD8 T-cells and macrophages) that can also be observed by MRI in individual skeletal muscles that are in the early stages of disease. Longitudinal MRI studies in FSHD have recently shown that these muscle by muscle inflammatory changes directly precede the fatty infiltration that characterizes individual muscles that have been affected for a longer period of time. Once this fatty infiltration has progressed to a certain stage in the affected muscle, however, the level of inflammation as detected by MRI decreases. The degree of fatty infiltration correlates with a commonly used measure of functional status, the FSHD clinical severity score.

The inflammatory immune response in FSHD is reflected in individuals with FSHD through activated immune cells and elevated levels of circulating immune and skeletal muscle proteins present in the circulation. In particular, peripheral blood mononuclear cells from individuals with evidence of muscle inflammation also show evidence of activation in cell culture by spontaneously releasing high amounts of immune proteins into the culture medium compared to controls.

 

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There are currently no approved treatments for FSHD. The standard of care in management of the disease includes physical therapy and, in the presence of severe muscle weakness, orthotic devices or surgical interventions may be needed to maintain musculoskeletal stability.

Phase 1b/2 Clinical Trial

In the third quarter of 2014, we initiated a multi-national Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD in the European Union. The randomized, double-blind, placebo-controlled trial is designed to evaluate the safety, tolerability, PK and immunogenicity of multiple intravenous doses of Resolaris in adults 18 to 65 years of age with FSHD. We also intend to explore pharmacodynamics, or PD, changes in inflammatory immune responses in skeletal muscle, as assessed by quantitative MRI, and in peripheral blood, as assessed by measures of circulating immune proteins such as cytokines and muscle enzymes and ex vivo inflammatory immune proteins released from peripheral blood cells. In addition, we will assess changes in inflammation and fat cell infiltration into the affected muscle using quantitative MRI, and we intend to explore changes in muscle mass. We have received regulatory clearance to proceed with our trial at clinical sites in France, Italy and the Netherlands. These sites were selected based on their leadership and expertise in MRI as an assessment tool for FSHD patients. Additionally, in January 2015, we received clearance from the FDA to initiate our Phase 1b/2 clinical trial of Resolaris in adult patients with FSHD in the United States, subject to a partial clinical hold that prohibits the evaluation of Resolaris at doses higher than 3.0 mg/kg. We do not expect the partial clinical hold to have a material impact on the timeline for this clinical trial because we currently do not plan to evaluate Resolaris in doses higher than 3.0 mg/kg.

Resolaris will be studied in three dose escalation cohorts (0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg). Enrollment in subsequent cohorts will be subject to review and a recommendation to proceed by an independent Data Monitoring Board, or DMB. In each cohort, patients will be randomized to receive Resolaris or placebo at a ratio of 3:1 and will be dosed once per week over four weeks. We enrolled a total of four patients in the first cohort and expect to enroll eight patients each in the second and third cohorts. In the fourth quarter of 2014, we completed multiple dosing of the patients in the first dose cohort. We are currently enrolling the second dose cohort. Starting with the second cohort, inclusion criteria include the presence of at least one skeletal muscle in the lower extremities displaying an inflammatory immune response by MRI. Our protocol for this trial includes the option to add up to two additional cohorts comprised of 12 patients each.

Following the completion of dosing for the third cohort of this trial, we will receive and analyze unblinded safety data, MRI data and PD data from all three cohorts. Subject to our interactions with regulatory authorities and patient enrollment in accordance with our clinical development plans, we expect to report initial results from the trial in the second half of 2015.

In parallel with conducting our initial clinical trial in adults with FSHD, we are finalizing our plans to evaluate Resolaris in a multi-center, international trial of patients with early onset FSHD. This trial will be designed to assess the safety, tolerability, PK, immunogenicity, PD and clinical effectiveness of multiple intravenous doses of Resolaris in patients with early onset FSHD. Subject to our interactions with regulatory authorities, we expect to initiate this clinical trial in the third quarter of 2015.

In the fourth quarter of 2014, we submitted an application to the European Medicines Agency, or the EMA, for orphan medicinal product designation for Resolaris (ATYR1940) for the treatment of FSHD. We have received a positive opinion from the EMA’s Committee for Orphan Medicinal Products recommending the granting of this orphan designation. We are currently awaiting the final decision from the European Commission.

Other RMIC Indications for Resolaris

In addition to FSHD, we plan to address other genetic diseases in which immune cells invade diseased muscle. We plan to commence clinical trials of Resolaris in one or more genetic forms of limb-girdle muscular dystrophy, or LGMD, in adult patients in the fourth quarter of 2015.

 

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LGMD is a broad term used to describe over 20 rare genetic myopathies. The mutations typically create abnormal, malfunctioning proteins. These diseases are linked by the common distribution of their muscle weakness (e.g., predominantly in the proximal limb muscles and the pelvic and shoulder girdle muscles). As is the case with FSHD patients, LGMD patients typically suffer from:

 

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skeletal muscle weakness or compromised function in identifiable, specific muscles;

 

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skeletal muscle immune cell invasion in identifiable, specific muscles; and

 

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skeletal muscle deterioration in identifiable, specific muscles with insufficient muscle regeneration.

The LGMD class of diseases stems from deficits in proteins that are important for muscle integrity. Thus, the affected muscles are more fragile than normal muscle and are easily damaged, even in the setting of everyday stress. The associated immune response (inflammation) and consequent deterioration can be seen locally in muscle tissue by biopsy or imaging techniques, such as MRI. The muscle deterioration is also reflected systemically, with patients often displaying elevated levels of muscle proteins in their blood (e.g., CK) or urine (e.g., myoglobin).

The age of onset of LGMD is usually between ten and 30, with both genders affected equally. The disease inevitably gets worse over time, although progression is more rapid in some patients. The disease commonly leads to dependence on a wheelchair within twenty to thirty years of symptom onset, but there is high inter-patient variability, with some patients maintaining mobility. LGMD may eventually weaken the respiratory muscles, leading to illness or early death due to complications from this secondary manifestation. Individuals with cardiac involvement may succumb to heart failure.

No definitive treatments exist for any of the over 20 forms of LGMD. Clinical management is directed to prolong survival and improve quality of life, including avoiding obesity, promoting physical therapy and stretching exercises, using mechanical aids to help ambulation and mobility, surgical intervention for orthopedic complications, using respiratory aids when indicated, monitoring for cardiomyopathy in LGMD types with cardiac involvement, and social and emotional support and stimulation.

We are in the process of evaluating the various genetic forms of LGMD in order to select genetic forms that we believe will be most amenable to treatment with Resolaris, based on factors such as the characteristics of the associated immuno-pathology in skeletal muscle. We expect these forms of LGMD to include those that begin early in life and have rapidly progressive consequences, such as LGMD2C, in which symptoms are usually similar to early onset FSHD, with individuals losing the ability to walk between ages ten and 12 and life expectancy typically limited to the 20s or early 30s. Subject to our selection of one or more genetic forms of LGMD for clinical evaluation, we may apply for orphan designation for Resolaris in an LGMD indication in one or more territories, which may include the United States and Europe.

Resolaris in Rare Pulmonary Diseases with an Immune Component

As described above, the Resokine pathway may also play an important role in lung health. In the presence of naturally occurring antibodies to this pathway (as observed in patients with Jo-1 antibody disease), interstitial lung disease, or ILD, which is typically characterized by lymphocytic invasion, occurs in approximately 85% of affected individuals. Consistent with this observation in our studies, the murine equivalent of Resolaris has shown promising activity in an animal model of a form of ILD known as pulmonary fibrosis (induced by the chemotherapeutic agent, bleomycin), including the reduction of inflammation. Together these data suggest that Resolaris may have therapeutic application in ILD. We are in the process of assessing the causes of ILD, which include various drugs, environmental exposures and genetic diseases, some of which involve only the lung, and others of which also affect other organs. ILD is also associated with various connective tissue diseases, some of which also are complicated by myopathies. We intend to select for clinical evaluation a form of ILD in which the lung pathology appears to be amenable to the activities that we have observed for Resolaris, and expect to consider undertaking both open label and placebo-controlled randomized trials in ILD patients.

 

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Our Preclinical iModFc Program

We have initiated iModFc, a discovery program to leverage our knowledge of the Resokine pathway to explore options to vary exposure of the iMod domain through protein engineering. The program seeks to develop a potential therapeutic that we refer to as iModFc, which would possess immuno-modulatory activity but not Physiocrine regions of Resolaris related to stem cell/remodeling and endothelial pathways. We have conducted a series of experiments to understand how various product forms enhance exposure of the iMod domain. These modifications include, among other options, creating a potential therapeutic by fusing the immunoglobin Fc with two iMod domains from Resolaris or pegylation of Resolaris or its domains.

The Fc fusion experiments have begun to delineate how to modulate the exposure of Resolaris as well as providing insight into the immuno-modulatory activity. Initial experiments have indicated that Fc fusion proteins can increase exposure and maintain iMod domain activity. We believe the data from these studies will provide molecules to explore how enhanced exposure may increase the therapeutic benefit of our Physiocrine approach in immuno-modulatory therapeutic applications.

Our Physiocrine Discovery Engine

We plan to leverage our discovery engine to identify other Physiocrine pathways of interest and select additional potential product candidates for preclinical and clinical investigation in a variety of disease settings. The engine that drives our discovery efforts is based on our scientific investigation of Physiocrine pathways and their proteins, coupled with a process of identifying disease indications that may benefit from a Physiocrine therapeutic. Through a combination of deep sequencing and bioinformatics panning, augmented by proteomic analysis, we identified over 300 naturally-occurring Physiocrines. We then expressed and purified over 200 of these Physiocrines. Our strategy for identifying function and potential indications begins with developing a series of phenotypic assays for in vitro evaluations of function. Many of our purified Physiocrines were evaluated in numerous cell-based phenotypic assays that encompassed 14 distinct human cell types. In July 2014, a publication in Science described certain results from our research, along with the research of our collaborators at Scripps La Jolla, Scripps Florida, Stanford University and the Hong Kong University of Science and Technology.

A key step in the discovery engine requires mining data from rare disease patients and linking this to the data generated in our phenotypic profiling experiments either in vitro or in vivo. For example, with HARS we studied published reports regarding Jo-1 antibody patients, also known as anti-synthetase patients. These clinical phenotypes led us to consider additional roles that extracellular HARS plays in muscle and lung. Thus, Resolaris, a HARS derivative, was evaluated in a number of in vivo pharmacology models that portray immune-driven inflammatory processes, including myopathy. The ability to restore homeostasis in multiple pharmacology models prompted us to catalog a number of rare myopathies that are immune driven as indications for therapeutic intervention with Resolaris.

We believe our strategy of understanding Physiocrine function by using in vivo experiments early and often while using patient data to focus this in vivo exploration has been validated by Resolaris. Additionally, we believe our discovery engine can be applied to other members of the Physiocrine class to help identify additional indications that may benefit from therapeutic intervention with Physiocrines.

We believe the biology of Physiocrines presents a novel protein therapeutic development opportunity based on the modulation of important physiological processes applicable to multiple diseases. This “pathway” approach or “physiology first” paradigm as we call it, which leverages the understanding of a basic physiological process, has been used successfully to create some of the most important therapeutics in such diverse areas as oncology and ophthalmology. Given the breadth of our discoveries, we currently focus on Physiocrine pathways related to immune and regeneration responses to explore for product candidates with rare disease applications.

 

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Discovery Programs in Lung and Liver

In addition, we believe some Physiocrine pathways may relate to fibrosis. Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive physiological process. Immune cells and their secreted molecules have been shown to play a critical role in the fibrotic process in a number of human tissues, including liver, lung and others. Persistent or unregulated inflammation is a hallmark of many chronic diseases, and is implicated in the development of fibrosis. Extracellular factors such as cytokines and chemokines act in the development of fibrosis by activating and recruiting inflammatory cells to developing fibrotic lesions.

Numerous studies in mice have demonstrated that mice lacking certain immune factors have an attenuation of fibrosis in relevant pharmacology models. In addition, neutralization of various cytokines in vivo is therapeutically beneficial in these same models. Our scientists have generated data indicating that the mouse version of Resokine can inhibit the inflammatory processes and the subsequent generation of fibrosis in a mouse model of lung fibrosis. In this model of fibrosis, using Bleomycin as an inducing agent, an inflammatory cascade develops leading to severe fibrosis. This process is very similar to that seen in human ILD, and the model has been used to support the development by several companies worldwide, including InterMune Inc. (acquired by Roche), Shionogi Ltd. and GNI Group Ltd., of Pirfenidone, which was approved by the FDA in October 2014 for the treatment of idiopathic pulmonary fibrosis. Several subsets of human patients with antibodies to various synthetase proteins, called anti-synthetase syndrome, also develop ILD, including fibrosis. This phenotype includes patients with antibodies to HARS (Jo-1), KARS (KS) and AARS (PL-12), suggesting that, similar to myositis, antibodies to specific synthetases may be causal in lung fibrotic diseases.

Immune-mediated processes are also thought to be a driver in various forms of liver fibrosis. A connection between Physiocrines and fibrosis has also been demonstrated in functional knockout studies. In these experiments, conducted at aTyr, antibodies to individual mouse Physiocrines were induced in mice and the phenotypes related to the absence of the Physiocrine or blockade of its pathway were observed. Mice with antibodies to specific Physiocrines developed liver fibrosis and impaired liver function, as measured by decreased glycogen content, decreased albumin:globulin ratio and other functional features.

These experiments demonstrate that the absence of Physiocrines in rodents resulted in an in vivo phenotype characterized by inflammatory cell infiltration and fibrotic disease in both the lung and the liver. These data support the concept that Physiocrines may have the potential to inhibit inflammation in both the lung and the liver, as well as the subsequent development of fibrosis in these tissues. Accordingly, we are continuing to investigate potential therapeutic Physiocrines in each of these indications.

Other Potential Discovery Programs

We have applied our Physiocrine discovery engine to identify a variety of medical conditions that we believe may be due to altered Physiocrine function, and are associated with mutations of members of the tRNA synthetase gene family, as set forth in the table below:

 

tRNA Synthetase Gene		Type of Mutation		Phenotype
AARS		Heterozygous (two forms)		CMT2N
		Heterozygous		Sporadic Axonal CMT
		Heterozygous		dHMN/CMT variant
DARS		Compound Heterozygous		Hypomyelination
		Homozygous (two forms)		Hypomyelination
GARS		Heterozygous (three forms)		dSMA-V
		Heterozygous (two forms)		CMT2D/dSMA-V
		Heterozygous (two forms)		CMT2D
		Heterozygous (two forms)		CMT2
		Heterozygous		CMT2D/dHMN-V
		Heterozygous (three forms)		dHMN
		Compound Heterozygous		Non-compaction Cardiomyopathy

 

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tRNA Synthetase Gene		Type of Mutation		Phenotype
HARS		Homozygous		Usher Syndrome
		Heterozygous		Peripheral Neuropathy
KARS		Compound Heterozygous		CMTRIB
		Homozygous (two forms)		Deafness
LARS		Homozygous		Infantile Liver Failure (ILFS1)
MARS		Compound Heterozygous		Infantile Liver Failure (ILFS2)
		Heterozygous		CMT2A1
		Compound Heterozygous		Hereditary Spastic Paraplegia
QARS		Compound Heterozygous (two forms)		Microcephaly
RARS		Compound Heterozygous (three forms)		Hypomyelination
YARS		Heterozygous (three forms)		DI-CMTC

 

Legend:

“_”ARS		=		“amino acid code” Aminoacyl tRNA synthetase. Alanine is represented by the letter A, hence alanine aminoacyl tRNA synthetase is abbreviated to AARS.
CMT		=		Charcot-Marie-Tooth Disease
CMT2A1		=		Charcot-Marie-Tooth Disease Type 2A1
CMT2D		=		Charcot-Marie-Tooth Disease Type 2D
CMT2N		=		Charcot-Marie-Tooth Disease Type 2N
CMTRIB		=		Intermediate Charcot-Marie-Tooth Disease B
dHMN		=		Distal Hereditary Motor Neuropathies
DI-CMTC		=		Intermediate Charcot-Marie-Tooth Disease C
dSMA-V		=		Distal Spinal Muscular Atrophy Type V

In addition, the following table summarizes research published regarding a variety of medical conditions that appear to be associated with autoantibodies targeting various tRNA synthetases:

 

tRNA synthetase target		Anti-tRNA synthetase antibody					# Patients Studied					% with Muscle Inflammation					% with Lung involvement
HARS		Jo-1					308					78-100					84
AARS		PL-12					69					60					95
TARS		PL-7					21					84					84
IARS		OJ					9					100					55
NARS		KS					6					0					100
GARS		EJ					1					100					100
FARSA, FARSB		ZO					1					100					100

Competition

The biotechnology and pharmaceutical industries are intensely competitive. We will face competition with respect to Resolaris and any other protein therapeutics we may develop or commercialize in the future from pharmaceutical companies, biotechnology companies and universities and other research institutions. Our competitors may have substantially greater financial, technical and other resources, such as larger research and development staff and experienced marketing and manufacturing organizations. Additional mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated in our competitors. Competition may increase further as a result of advances in the commercial applicability of technologies and greater availability of capital for investment in these industries. Our competitors may succeed in developing, acquiring or licensing on an exclusive basis drug products that are more effective or less costly than any product candidate that we may develop.

 

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Although we believe we are the only company engaged in the discovery and development of therapeutics based on Physiocrine pathways, we are aware of other companies that are developing products that could compete as treatments for our targeted indications, as described below.

In the area of RMICs, we expect to face competition from a number of companies, academic institutions and other organizations, including Novartis AG, Nationwide Children’s Hospital in collaboration with The Myositis Association and Parent Project Muscular Dystrophy, Eli Lilly and Company and Regeneron Pharmaceuticals, Inc. in collaboration with Sanofi, Biogen Idec, Inc., PTC Therapeutics, Inc., Prosensa Therapeutics, Inc. (which has agreed to be acquired by BioMarin Pharmaceutical Inc.) and Sarepta Therapeutics, Inc., that are engaged in the clinical development of therapeutics to address muscle loss and muscle weakness in a variety of indications. Although there are currently no approved products for the treatment of FSHD, Acceleron Pharma Inc. is developing a clinical candidate, ACE-083, a locally acting protein therapeutic designed to increase muscle mass and strength in patients with neuromuscular disorders and other diseases characterized by a loss of muscle function, including FSHD. In addition, Facio Therapies recently announced its plans to screen chemical libraries to identify chemical compounds that will boost the expression of proteins known to repress one of the causal genes responsible for FSHD. In the area of LGMD, we are aware of a number of academic institutions engaged in the clinical development of therapeutics, including Genethon, a not-for-profit research laboratory created by the Association Française contre les Myopathies, or French Muscular Dystrophy Association, which has completed an experimental Phase 1 clinical trial in LGMD 2C using gene therapy; Nationwide Children’s Hospital, which is currently conducting a Phase 1/2a clinical trial of an AAV vector to transport the alpha-sarcoglycan gene into muscles in in LGMD 2D; and NeuroGen Brain and Spine Institute in India, which is currently conducting a Phase 1 clinical trial in an unspecified form of LGMD using stem cell therapy.

In the field of lung disease, including rare pulmonary diseases with an immune component, we expect to face competition from Pirfenidone, which is marketed by several companies worldwide, including InterMune Inc. (acquired by Roche), Shionogi Ltd. and GNI Group Ltd., as well as Nintedanib, a small molecule tyrosine-kinase inhibitor marketed by Boehringer Ingelheim, both of which were approved by the FDA in October 2014.

Research and License Agreements

The Scripps Research Institute

We are party to an amended and restated research funding and option agreement with The Scripps Research Institute, or TSRI. Under the agreement, we provide funding to TSRI to conduct certain research activities related to aminoacyl tRNA synthetases. The agreement renews automatically for successive 12 month periods starting on May 31^st of each year unless we provide written notice of our desire to terminate the agreement at least 30 days prior to the end of the applicable 12-month period. Under the agreement, the parties agree to update the amount of annual funding for such successive 12-month periods as mutually agreed in good faith by the parties. We have the right to terminate the agreement at any time upon six months’ written notice, and TSRI has the right to terminate the agreement if we fail to make any payment under the agreement within ten days of being notified by TSRI that such payment is overdue. Additionally, each party may terminate the agreement in the event of an uncured material breach by the other party or for insolvency of the other party.

Under the amended and restated research funding and option agreement, TSRI has granted us options to enter into license agreements to acquire rights and exclusive licenses to develop, make, have made, use, have used, import, have imported, offer to sell, sell and have sold certain licensed products, processes and services based on certain technology arising from the sponsored research activities. Pursuant to the terms of these license agreements, TSRI is entitled to receive tiered royalties as a percentage of net sales, ranging from the low to mid-single digits, with these royalty rates subject to increase if we challenge the validity or enforceability of any of the licensed patent rights under certain circumstances. The royalty rates are subject to reduction to the extent we need to obtain any rights from third parties to make, use, or sell the licensed products, processes or services, subject to a minimum floor in the single digits. Additionally, we have agreed to pay TSRI a percentage of non-

 

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royalty revenue we receive from our sublicensees or partners, with the amount owed decreasing if we enter into the applicable sublicense or partnering agreement after meeting a specified clinical milestone. In addition, we are obligated to make payments to TSRI of up to an aggregate of $2.75 million under each license agreement upon the achievement of specific clinical and regulatory milestone events.

Under the terms of the license agreements, we are obligated to use commercially reasonable efforts and diligence to develop and commercialize licensed products, processes and services and to obtain regulatory approvals as necessary.

We may terminate the license agreements upon mutual agreement with TSRI or unilaterally upon 90 days’ notice, and TSRI has the right to terminate the agreements under certain circumstances, including our uncured material breach of the agreements and if TSRI determines that we are not engaged in research, development, manufacturing, marketing or sublicensing activities reasonably appropriate to put the licensed patents into commercial use, and to make the licensed subject matter reasonably available to the public, in the countries covered by the license.

Pangu Biopharma

In October 2007, we formed Pangu BioPharma Limited, or Pangu BioPharma, a company registered in Hong Kong, to collaborate with the Hong Kong University of Science and Technology, or HKUST, on the discovery and development of aminoacyl tRNA synthetase protein therapeutics. We hold 98% of the outstanding shares of Pangu BioPharma, and HKUST holds the remaining outstanding shares. Beginning in July 2008, Pangu BioPharma, in collaboration with HKUST, entered into a series of three research grant agreements with the Government of the Hong Kong Special Administrative Region to carry out research in the discovery and development of Physiocrines. In December 2014, Pangu BioPharma renewed its annual joint research agreement with the HKUST R and D Corporation Limited, under which Pangu BioPharma agrees to fund research to be performed in 2015 under the agreement by HKUST R and D Corporation Limited with respect to development of aminoacyl tRNA synthetase protein therapeutics. Pangu BioPharma is the sole beneficial owner of all resulting intellectual property rights from the research performed under these agreements, subject to the right of HKUST R and D Corporation Limited to use certain background intellectual property of HKUST in conducting the research and, in the event Pangu BioPharma applies for individual funding of any work under the research programs, compliance with the terms and conditions of any written agreement covering ownership of such funded works. Pangu BioPharma funds the annual research on a quarterly basis. Either party may terminate the agreement during the annual period upon an uncured breach of the agreement by the other party. We are also party to a license agreement with Pangu BioPharma, pursuant to which Pangu BioPharma has granted us an exclusive, royalty-bearing license (with a right to sublicense) in and to certain of Pangu BioPharma’s solely and jointly owned patent rights and know-how to research, develop, manufacture, use, import, export, distribute, offer for sale, sell and have sold products incorporating such patent rights and know-how for any therapeutic, prognostic or diagnostic use throughout the world.

Patents and Proprietary Rights

We strive to protect the proprietary technologies that we believe are important to our business, including seeking and maintaining patent protection intended to cover the composition of matter of our product candidates, their methods of use, related technology and other inventions that are important to our business. As of December 2014, we own, or have exclusive licenses to, 13 issued U.S. and foreign patents and over 230 pending U.S. and foreign patent applications, including 12 allowed U.S. patent applications, with predicted expiration dates ranging from 2026 to 2034. In addition to patent protection, we also rely on trade secrets and careful monitoring of our proprietary information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

Our success will depend significantly on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business, defend and

 

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enforce our patents, maintain our licenses to use intellectual property owned by third parties, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and other proprietary rights of third parties. We also rely on know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen, and maintain our proprietary position in the field of Physiocrine therapeutics.

A third party may hold intellectual property, including patent rights, which is important or necessary to the development of our products. It may be necessary for us to use the patented or proprietary technology of third parties to commercialize our products, in which case we would be required to obtain a license from these third parties on commercially reasonable terms, or our business could be harmed, possibly materially.

We plan to continue to expand our intellectual property estate by filing patent applications directed to new methods of treatment, therapeutics and additional new product forms thereof with new therapeutic or pharmacokinetic properties. Specifically, we seek patent protection in the United States and internationally for novel compositions of matter covering our protein therapeutics, next generation product forms and the use of these compositions in a variety of therapies.

The patent positions of biopharmaceutical companies like us are generally uncertain and involve complex legal, scientific and factual questions. In addition, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance. Consequently, we do not know whether any of our product candidates will be protectable or remain protected by enforceable patents. We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient proprietary protection from competitors. Any patents that we hold may be challenged, circumvented or invalidated by third parties.

Because patent applications in the United States and certain other jurisdictions are maintained in secrecy for 18 months, and since publication of discoveries in the scientific or patent literature often lags behind actual discoveries, we cannot be certain of the priority of inventions covered by pending patent applications. Moreover, we may have to participate in interference proceedings declared by the United States Patent and Trademark Office, or USPTO, or a foreign patent office to determine priority of invention or in post-grant challenge proceedings, such as oppositions, that challenge priority of invention or other features of patentability. Such proceedings could result in us incurring substantial costs, even if the eventual outcome is favorable to us.

The patent portfolios for our most advanced programs are summarized below.

Resolaris. Our Resolaris patent portfolio is comprised of a number of patent families and includes U.S. Patent No. 8,835,387 covering Resolaris, which issued on September 16, 2014 and is predicted to expire in 2033. This patent family is jointly owned by us and Pangu Biopharma. Patent applications in the same family as U.S. Patent No. 8,835,387 are pending in a variety of worldwide jurisdictions, including the United States, Australia, Brazil, Canada, China, Europe, India, Japan, Korea, Mexico, New Zealand, Russia and South Africa. The Resolaris patent portfolio also encompasses additional issued patents and pending patent applications that cover Resolaris and related proteins; these patents and patent applications are wholly owned by us. This second patent family includes Australian Patent No. 2010327926, which issued August 21, 2014, and related applications that are pending in the United States, Australia, Canada, Europe, China, Japan, and Hong Kong. Patents that issue from these applications, if any, are expected to expire in 2030. Also included with the Resolaris™ patent portfolio are pending patent applications to specific methods of use of Resolaris and related proteins, and disease polymorphisms of HARS. These applications have been filed in the United States as U.S. provisional applications and in some cases under the Patent Cooperation Treaty, or PCT. U.S. provisional applications may be used to establish non-provisional U.S. applications, PCT applications and other national filings worldwide. PCT applications are eligible for filing in most worldwide jurisdictions, including the United States. If issued, these patents are predicted to expire between 2033 and 2034.

iModFc. Our iModFc patent portfolio, which covers derivatives of Resolaris, including the iMod domain, related splice variants, and next-generation product forms with modified therapeutic activity or pharmacokinetic

 

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characteristics, is comprised of a number of patent families and includes U.S. Patent No. 8,404,242, and U.S. Patent No 8,753,638, which issued on March 26, 2013 and June 17, 2014, respectively, and are expected to expire in 2031 and 2030. This patent family is jointly owned by us and Pangu Biopharma, and includes pending applications in United States, Australia, Canada, Europe, China, Japan, and Hong Kong. The iModFc patent family also includes patent applications filed on related splice variants of HARS. This patent family includes applications that are pending in the United States, Australia, Canada, Europe, China, India, Japan, Korea, New Zealand, Russia and Hong Kong. This patent family is jointly owned by us, and our subsidiary Pangu Biopharma. Also included within the iModFc patent portfolio are pending applications to specific product forms of iModFc, Resolaris and other HARS splice variants which include patent families to Fc fusion proteins, pegylated forms and variants with substituted D amino acids. These applications have been filed in the United States as U.S. provisional applications and in some cases under the PCT. If issued, these patents are predicted to expire between 2033 and 2034.

Our pipeline of Physiocrines is covered by a series of 21 patent families, which covers all 20 human cytosolic tRNA synthetases. These cases are jointly owned by us and Pangu Biopharma, and include pending applications in the United States, Australia, Canada, India, Europe, China and Japan. Patents that issue from these applications, if any, would be expected to expire in 2031. Additional patent applications have also been separately filed on GARS (Glycyl-tRNA synthetase), DARS (Aspartyl-tRNA synthetase), YARS (tyrosyl-tRNA synthetase), and other tRNA synthetases, and any patents issuing from these patent applications would be expected to expire between 2026 and 2030. We have also exclusively in-licensed from TSRI patents and patent applications related to YARS and specific monomeric forms of tRNA synthetases.

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is generally 20 years from the earliest date of filing the non-provisional patent application from which the patent issued.

In the United States, the patent term of a patent that covers a drug approved by the U.S. Food and Drug Administration, or FDA, may also be eligible for patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review process. The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of the patent. The length of the patent term extension is related to the length of time the drug is under regulatory review. Patent extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended. Similar provisions are available in Europe and other non-United States jurisdictions to extend the term of a patent that covers an approved drug. In the future, if and when our pharmaceutical products receive FDA approval, we expect to apply for patent term extensions on patents covering those products. We intend to seek patent term extensions to any of our issued patents in any jurisdiction where these are available, however there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.

We also rely on trade secret protection for our confidential and proprietary information. Although we take steps to protect our proprietary information and trade secrets, including through contractual means with our employees and consultants, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our trade secrets. It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us. These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. In the case of employees, the agreements provide that all inventions conceived by the individual, and which are related to our current or planned business or research and development or made during normal working hours, on our premises or using our equipment or proprietary information, are our exclusive property.

 

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Manufacturing

We currently contract with third parties for the manufacturing and testing of our product candidates for preclinical studies and clinical trials and intend to do so in the future. We do not own or operate manufacturing facilities for the production of clinical quantities of our product candidates. We currently have no plans to build our own clinical or commercial scale manufacturing capabilities. The use of contracted manufacturing and reliance on collaboration partners is relatively cost-efficient and has eliminated the need for our direct investment in manufacturing facilities and additional staff early in development. Although we rely on contract manufacturers, we have personnel with extensive manufacturing experience to oversee our contract manufacturers.

Resolaris is produced in recombinant bacteria and then purified and packaged for clinical use. The active pharmaceutical ingredient for Resolaris is currently manufactured in India by Syngene International Limited, or Syngene, pursuant to a Master Services Agreement and a Quality Agreement executed in November 2012. We have a non-exclusive license to the cell line used to produce the active pharmaceutical ingredient for Resolaris. All other raw materials for Resolaris are commercially available. We intend to continue to work with Syngene for the production of Resolaris for preclinical studies and clinical testing up to pivotal trials. We contract with other third parties to conduct fill and finish and labeling, as well as for the storage and distribution of Resolaris to clinical sites and plan to do so for other product candidates that we may develop.

To date, our third-party manufacturers have met our manufacturing requirements for clinical development, and we expect that our current third-party manufacturers are capable of providing sufficient quantities of our product candidates to meet anticipated clinical development needs through to the start of the pivotal clinical trials.

To meet our projected needs for the pivotal clinical trials and larger scale commercial manufacturing, we are currently working with Fujifilm Diosynth Biotechnologies UK Limited, or Fujifilm, to develop a scaled up manufacturing process for Resolaris. Additionally, we are currently negotiating with alternative fill-finish and labelling contract manufacturing organizations, or CMOs, to enable the commercial production and supply of Resolaris. We believe that Fujifilm and these alternative CMOs can satisfy our clinical, regulatory and commercial requirements for Resolaris. We cannot be certain, however, that the transfer and commercial scale up of the manufacturing process for Resolaris will not result in significant delay or add material additional costs.

Sales and Marketing

We currently intend to build the commercial infrastructure in the United States and Europe necessary to effectively support the commercialization of all of our product candidates, if and when we believe a regulatory approval of the first of such product candidates in a particular geographic market appears imminent. The commercial infrastructure for products directed at rare disease indications typically consists of a targeted, specialty sales force that calls on a limited and focused group of physicians supported by sales management, medical liaisons, internal sales support, an internal marketing group, and distribution support. One challenge unique to commercializing therapies for rare diseases is the difficulty in identifying eligible patients due to the very small and sometimes heterogeneous disease populations. Our management team is experienced in maximizing patient identification for both clinical development and commercialization purposes in rare diseases.

Additional capabilities important to the marketing of therapeutics for rare diseases include the management of key accounts such as managed care organizations, group-purchasing organizations, specialty pharmacies, and government accounts. To develop the appropriate commercial infrastructure, we will have to invest significant amounts of financial and management resources, some of which will be committed prior to any confirmation that any of our product candidates will be approved.

Although we currently intend to commercialize Resolaris and any other product candidates that we may develop on our own, we may elect in the future to utilize strategic partners, distributors, or contract sales forces to assist in the commercialization of our products in selected geographic locations or for particular indications.

 

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Government Regulation

Government authorities in the United States, including federal, state, and local authorities, and in other countries, extensively regulate, among other things, the manufacturing, research and clinical development, marketing, labeling and packaging, storage, distribution, post-approval monitoring and reporting, advertising and promotion, pricing, and export and import of pharmaceutical and biological products, such as those we are developing. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local, and foreign statutes and regulations require the expenditure of substantial time and financial resources.

U.S. Government Regulation

In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and its implementing regulations, and biologics under the FDCA and the Public Health Service Act, or PHSA, and its implementing regulations. FDA approval is required before any new unapproved drug or biologic or dosage form, including a new use of a previously approved drug, can be marketed in the United States. Drugs and biologics are also subject to other federal, state, and local statutes and regulations. If we fail to comply with applicable FDA or other requirements at any time during the product development process, clinical testing, the approval process or after approval, we may become subject to administrative or judicial sanctions. These sanctions could include the FDA’s refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties or criminal prosecution. Any FDA enforcement action could have a material adverse effect on us.

The process required by the FDA before product candidates may be marketed in the United States generally involves the following:

 

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completion of extensive preclinical laboratory tests and preclinical animal studies, all performed in accordance with the Good Laboratory Practices, or GLP, regulations;

 

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submission to the FDA of an investigational new drug application, or IND, which must become effective before human clinical trials may begin and must be updated annually;

 

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approval by an independent institutional review board, or IRB, or ethics committee representing each clinical site before each clinical trial may be initiated;

 

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performance of adequate and well-controlled human clinical trials to establish the safety and efficacy of the product candidate for each proposed indication;

 

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preparation of and submission to the FDA of a biologics license application, or BLA, or a new drug application, or NDA, after completion of all pivotal clinical trials;

 

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potential review of the product application by an FDA advisory committee, where appropriate and if applicable;

 

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a determination by the FDA within 60 days of its receipt of a BLA or NDA to file the application for review;

 

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satisfactory completion of an FDA pre-approval inspection of the manufacturing facilities where the proposed product is produced to assess compliance with current Good Manufacturing Practices, or cGMP; and

 

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FDA review and approval of a BLA or NDA prior to any commercial marketing or sale of the product in the United States.

The preclinical and clinical testing and approval process requires substantial time, effort, and financial resources, and we cannot be certain that any approvals for our product candidates will be granted on a timely basis, if at all.

An IND is a request for authorization from the FDA to administer an investigational new drug product to humans in clinical trials. The central focus of an IND submission is on the general investigational plan and the protocol(s) for human trials. The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product; chemistry,

 

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manufacturing, and controls information; and any available human data or literature to support the use of the investigational new drug. An IND must become effective before human clinical trials may begin. An IND will automatically become effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to the proposed clinical trials. In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before clinical trials can begin. Accordingly, submission of an IND may or may not result in the FDA allowing clinical trials to commence. The FDA may impose a clinical hold at any time during clinical trials and may impose a partial clinical hold that would limit trials, for example, to certain doses or for a certain length of time.

Clinical Trials

Clinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigators in accordance with Good Clinical Practices, or GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety, and the efficacy criteria to be evaluated. A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND. Additionally, approval must also be obtained from each clinical trial site’s institutional review board, or IRB, before the trials may be initiated, and the IRB must monitor the trial until completed. There are also requirements governing the reporting of ongoing clinical trials and clinical trial results to public registries.

The clinical investigation of a drug is generally divided into three or four phases. Although the phases are usually conducted sequentially, they may overlap or be combined.

 

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Phase 1. The drug is initially introduced into healthy human subjects or patients with the target disease or condition. These studies are designed to evaluate the safety, dosage tolerance, metabolism and pharmacologic actions of the investigational new drug in humans, the side effects associated with increasing doses, and if possible, to gain early evidence on effectiveness.

 

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Phase 2. The drug is administered to a limited patient population to evaluate dosage tolerance and optimal dosage, identify possible adverse side effects and safety risks, and preliminarily evaluate efficacy.

 

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Phase 3. The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites to generate enough data to statistically evaluate dosage, clinical effectiveness and safety, to establish the overall benefit-risk relationship of the investigational new drug product, and to provide an adequate basis for product approval.

 

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Phase 4. In some cases, the FDA may condition approval of a BLA or NDA for a product candidate on the sponsor’s agreement to conduct additional clinical trials after approval. In other cases, a sponsor may voluntarily conduct additional clinical trials after approval to gain more information about the drug. Such post-approval studies are typically referred to as Phase 4 clinical trials.

A pivotal trial is a clinical trial that adequately meets regulatory agency requirements for the evaluation of a drug candidate’s efficacy and safety such that it can be used to justify the approval of the product. Generally, pivotal trials are Phase 3 trials, but the FDA may accept results from Phase 2 clinical trials if the trial design provides a well-controlled and reliable assessment of clinical benefit, particularly in situations where there is an unmet medical need and the results are sufficiently robust.

Sponsors must also report to the FDA, within certain timeframes, serious and unexpected adverse reactions, any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator’s brochure, or any findings from other studies or animal or in vitro testing that suggest a significant risk in humans exposed to the product candidate. The FDA, the IRB, or the clinical trial sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk. Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring

 

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board or committee. This group provides authorization for whether or not a trial may move forward at designated check points based on access to certain data from the trial. We may also suspend or terminate a clinical trial based on evolving business objectives or competitive climate.

The clinical trial process can take three to ten years or more to complete, and there can be no assurance that the data collected will support FDA approval or licensure of the product. Results from one trial are not necessarily predictive of results from later trials.

Submission of a BLA or NDA to the FDA

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, detailed investigational new drug product information is submitted to the FDA in the form of a BLA or NDA requesting approval to market the product for one or more indications. Under federal law, the submission of most BLAs and NDAs is subject to an application user fee. For fiscal year 2015, the application user fee exceeds $2.3 million, and the sponsor of an approved BLA or NDA is also subject to annual product and establishment user fees, set at $110,370 per product and $569,200 per establishment. These fees are typically increased annually. Applications for orphan drug products are exempted from the BLA and NDA user fees and may be exempted from product and establishment user fees, unless the application includes an indication for other than a rare disease or condition.

A BLA or NDA must include all relevant data available from pertinent preclinical studies and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things. Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including trials initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the investigational new drug product to the satisfaction of the FDA.

Once a BLA or NDA has been submitted, the FDA’s goal is to review the application within ten months after it accepts the application for filing, or, if the application relates to an unmet medical need in a serious or life-threatening indication, six months after the FDA accepts the application for filing. The review process is often significantly extended by the FDA’s requests for additional information or clarification.

Before approving a BLA or NDA, the FDA typically will inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving a BLA or NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

The FDA is required to refer an application for a novel drug to an advisory committee or explain why such referral was not made. Typically, an advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

The FDA’s Decision on a BLA or NDA

After the FDA evaluates the BLA or NDA and conducts inspections of manufacturing facilities where the product will be produced, it may issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete and the application is not ready for approval. A Complete Response Letter may require additional clinical data or an additional pivotal Phase 3 clinical trial(s), or other significant, expensive and time-consuming requirements related to clinical trials, preclinical studies or manufacturing. Even if such additional information is submitted, the FDA may ultimately

 

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decide that the BLA or NDA does not satisfy the criteria for approval. The FDA could also approve the BLA or NDA with a Risk Evaluation and Mitigation Strategy, or REMS, plan to mitigate risks, which could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling, development of adequate controls and specifications, or a commitment to conduct one or more post-market studies or clinical trials. Such post-market testing may include Phase 4 clinical trials and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization. Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

Expedited Review and Accelerated Approval Programs

A sponsor may seek approval of its product candidate under programs designed to accelerate FDA’s review and approval of BLAs and NDAs. For example, Fast Track Designation may be granted to a drug intended for treatment of a serious or life-threatening disease or condition that has potential to address unmet medical needs for the disease or condition. The key benefits of fast track designation are more frequent interactions with the FDA during development and testing, the eligibility for priority review, and rolling review, which is submission of portions of an application before the complete marketing application is submitted. Based on results of the Phase 3 clinical trial(s) submitted in a BLA or NDA, upon the request of an applicant, the FDA may grant the BLA or NDA a priority review designation, which sets the target date for FDA action on the application at six months after the FDA accepts the application for filing. Priority review is granted where there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition. If criteria are not met for priority review, the application is subject to the standard FDA review period of ten months after FDA accepts the application for filing. Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.

Under the accelerated approval program, the FDA may approve a BLA or NDA on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. Post-marketing trials or completion of ongoing trials after marketing approval are generally required to verify the drug’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit. In addition, the Food and Drug Administration Safety and Innovation Act, or FDASIA, which was enacted and signed into law in 2012, established the new Breakthrough Therapy designation. A sponsor may seek FDA designation of its product candidate as a breakthrough therapy if the drug is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

Post-Approval Requirements

Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing, annual user fee requirements for any marketed products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data.

Drug manufacturers are subject to periodic unannounced inspections by the FDA and state agencies for compliance with cGMP requirements. Changes to the manufacturing process are strictly regulated, and,

 

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depending on the significance of the change, may require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon us and any third-party manufacturers that we may decide to use. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.

We rely, and expect to continue to rely, on third parties for the production of clinical quantities of our product candidates, and expect to rely in the future on third parties for the production of commercial quantities. Future FDA and state inspections may identify compliance issues at our facilities or at the facilities of our contract manufacturers that may disrupt production or distribution, or require substantial resources to correct. In addition, discovery of previously unknown problems with a product or the failure to comply with applicable requirements may result in restrictions on a product, manufacturer or holder of an approved BLA or NDA, including withdrawal or recall of the product from the market or other voluntary, FDA-initiated or judicial action that could delay or prohibit further marketing. Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

 

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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;

 

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fines, warning letters or holds on post-approval clinical trials;

 

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refusal of the FDA to approve pending BLAs or NDAs or supplements to approved BLAs or NDAs, or suspension or revocation of product license approvals;

 

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product seizure or detention, or refusal to permit the import or export of products; or

 

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injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates marketing, labeling, advertising, and promotion of products that are placed on the market. Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

Orphan Designation and Exclusivity

The FDA may grant orphan drug designation to drugs intended to treat a rare disease or condition that affects fewer than 200,000 individuals in the United States, or if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making the drug for this type of disease or condition will be recovered from sales in the United States.

Orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages, and user-fee waivers. In addition, if a product receives FDA approval for the indication for which it has orphan designation, the product is entitled to orphan drug exclusivity, which means the FDA may not approve any other application to market the same drug for the same indication for a period of seven years, except in limited circumstances, such as a showing of clinical superiority over the product with orphan exclusivity.

 

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Pediatric Trials and Exclusivity

BLAs and NDAs must contain data, or a proposal for post-marketing activity, to assess the safety and effectiveness of an investigational new drug product for the claimed indications in all relevant pediatric populations in order to support dosing and administration for each pediatric subpopulation for which the drug is safe and effective. The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults or full or partial waivers if certain criteria are met. Discussions about pediatric development plans can be discussed with the FDA at any time, but usually occur any time between the end-of-Phase 2 meeting and submission of the BLA or NDA. The requirements for pediatric data do not apply to any drug for an indication for which orphan designation has been granted.

Pediatric exclusivity is another type of non-patent exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the five-year and three-year non-patent and orphan exclusivity. This six-month exclusivity may be granted if a BLA or NDA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data. The data do not need to show the product to be effective in the pediatric population studied; rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted. If reports of FDA-requested pediatric trials are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patent protection covering the product are extended by six months. This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot accept or approve another application relying on the BLA or NDA sponsor’s data.

Patent Term Restoration

Depending upon the timing, duration, and specifics of the FDA approval of the use of our product candidates, some of our U.S. patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of a BLA or NDA, plus the time between the submission date and the approval of that application. Only one patent applicable to an approved product is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent and within 60 days of the product’s approval. The U.S. Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration. In the future, we may apply for restoration of patent term for one of our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant BLA or NDA.

Biosimilars and Exclusivity

The Patient Protection and Affordable Care Act, or Affordable Care Act, signed into law on March 23, 2010, includes a subtitle called the Biologics Price Competition and Innovation Act of 2009, or BPCI Act, which created an abbreviated approval pathway for biological products shown to be similar to, or interchangeable with, an FDA-licensed reference biological product. This amendment to the PHSA attempts to minimize duplicative testing. Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical trial or trials. Interchangeability requires that a product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic. However, complexities associated with the larger, and often more complex, structure of biological products, as well as the process by which such products are manufactured, pose significant hurdles to implementation that are still being worked out by the FDA.

 

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A reference biologic is granted twelve years of exclusivity from the time of first licensure of the reference product. The first biologic product submitted under the abbreviated approval pathway that is determined to be interchangeable with the reference product has exclusivity against other biologics submitting under the abbreviated approval pathway for the lesser of (i) one year after the first commercial marketing, (ii) eighteen months after approval if there is no legal challenge, (iii) eighteen months after the resolution in the applicant’s favor of a lawsuit challenging the biologics’ patents if an application has been submitted, or (iv) 42 months after the application has been approved if a lawsuit is ongoing within the 42-month period.

Abbreviated New Drug Applications for Generic Drugs

In 1984, with passage of the Hatch-Waxman Amendments, Congress authorized the FDA to approve generic drugs that are the same as drugs previously approved by the FDA under the NDA provisions of the statute. To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application, or ANDA, to the agency. In support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference listed drug, or RLD.

Specifically, in order for an ANDA to be approved, the FDA must find that the generic version is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, and the strength of the drug. At the same time, the FDA must also determine that the generic drug is “bioequivalent” to the innovator drug. Under the statute, a generic drug is bioequivalent to an RLD if “the rate and extent of absorption of the [generic] drug do not show a significant difference from the rate and extent of absorption of the listed drug. . . .”

Upon approval of an ANDA, the FDA indicates that the generic product is “therapeutically equivalent” to the RLD and it assigns a therapeutic equivalence rating to the approved generic drug in its publication “Approved Drug Products with Therapeutic Equivalence Evaluations,” also referred to as the “Orange Book.” Physicians and pharmacists consider an “AB” therapeutic equivalence rating to mean that a generic drug is fully substitutable for the RLD. In addition, by operation of certain state laws and numerous health insurance programs, the FDA’s designation of an “AB” rating often results in substitution of the generic drug without the knowledge or consent of either the prescribing physician or patient.

The FDCA provides a period of five years of non-patent exclusivity for a new drug containing a new chemical entity. In cases where such exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the applicant may submit its application four years following the original product approval. The FDCA also provides for a period of three years of exclusivity if the NDA includes reports of one or more new clinical investigations, other than bioavailability or bioequivalence studies, that were conducted by or for the applicant and are essential to the approval of the application. This three-year exclusivity period often protects changes to a previously approved drug product, such as a new dosage form, route of administration, combination or indication.

Hatch-Waxman Patent Certification and the 30-Month Stay

Upon approval of an NDA or a supplement thereto, NDA sponsors are required to list with the FDA each patent with claims that cover the applicant’s product or a method of using the product. Each of the patents listed by the NDA sponsor is published in the Orange Book. When an ANDA applicant files its application with the FDA, the applicant is required to certify to the FDA concerning any patents listed for the reference product in the Orange Book, except for patents covering methods of use for which the ANDA applicant is not seeking approval.

Specifically, the applicant must certify with respect to each patent that:

 

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the required patent information has not been filed;

 

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the listed patent has expired;

 

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the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration; or

 

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the listed patent is invalid, unenforceable or will not be infringed by the new product.

A certification that the new product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is called a Paragraph IV certification. If the applicant does not challenge the listed patents or indicates that it is not seeking approval of a patented method of use, the ANDA application will not be approved until all the listed patents claiming the referenced product have expired.

If the ANDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA and patent holders once the ANDA has been accepted for filing by the FDA. The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification. The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA until the earlier of 30 months after the receipt of the Paragraph IV notice, expiration of the patent, or a decision in the infringement case that is favorable to the ANDA applicant.

European Union/Rest of World Government Regulation

In addition to regulations in the United States, we will be subject to a variety of regulations in other jurisdictions governing, among other things, clinical trials and any commercial sales and distribution of our products. The cost of establishing a regulatory compliance system for numerous varying jurisdictions can be very significant. Although many of the issues discussed above with respect to the United States apply similarly in the context of the European Union and in other jurisdictions, the approval process varies between countries and jurisdictions and can involve additional product testing and additional administrative review periods. The time required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to obtain FDA approval. Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.

Whether or not we obtain FDA approval for a product, we must obtain the requisite approvals from regulatory authorities in foreign countries prior to the commencement of clinical trials or marketing of the product in those countries. Certain countries outside of the United States have a similar process that requires the submission of a clinical trial application much like the IND prior to the commencement of human clinical trials. In the European Union, for example, a clinical trial application, or CTA, must be submitted for each clinical protocol to each country’s national health authority and an independent ethics committee, much like the FDA and IRB, respectively. Once the CTA is accepted in accordance with a country’s requirements, the clinical trial may proceed.

The requirements and process governing the conduct of clinical trials vary from country to country. In all cases, the clinical trials are conducted in accordance with cGCP, the applicable regulatory requirements, and the ethical principles that have their origin in the Declaration of Helsinki.

To obtain regulatory approval of an investigational medicinal product under European Union regulatory systems, we must submit a marketing authorization application. The content of the BLA or NDA filed in the United States is similar to that required in the European Union, with the exception of, among other things, country-specific document requirements.

For other countries outside of the European Union, such as countries in Eastern Europe, Latin America or Asia, the requirements governing product licensing, pricing, and reimbursement vary from country to country.

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biologic products. If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Authorization Procedures in the European Union

Medicines can be authorized in the European Union by using either the centralized authorization procedure or national authorization procedures.

 

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Centralized procedure. The EMA implemented the centralized procedure for the approval of human medicines to facilitate marketing authorizations that are valid throughout the European Economic Area, or EEA, which is comprised of the 28 member states of the European Union plus Norway, Iceland, and Lichtenstein. This procedure results in a single marketing authorization issued by the EMA that is valid across the EEA. The centralized procedure is compulsory for human medicines that are: derived from biotechnology processes, such as genetic engineering, contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative disorders or autoimmune diseases and other immune dysfunctions, and officially designated orphan medicines.

 

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For medicines that do not fall within these categories, an applicant has the option of submitting an application for a centralized marketing authorization to the European Commission following a favorable opinion by the EMA, as long as the medicine concerned is a significant therapeutic, scientific or technical innovation, or if its authorization would be in the interest of public health.

 

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National authorization procedures. There are also two other possible routes to authorize medicinal products in several European Union countries, which are available for investigational medicinal products that fall outside the scope of the centralized procedure:

 

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Decentralized procedure. Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one European Union country of medicinal products that have not yet been authorized in any European Union country and that do not fall within the mandatory scope of the centralized procedure.

 

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Mutual recognition procedure. In the mutual recognition procedure, a medicine is first authorized in one European Union Member State, in accordance with the national procedures of that country. Following this, further marketing authorizations can be sought from other European Union countries in a procedure whereby the countries concerned agree to recognize the validity of the original, national marketing authorization.

In some cases, a Pediatric Investigation Plan, or PIP, or a request for waiver or deferral, is required for submission prior to submitting a marketing authorization application. A PIP describes, among other things, proposed pediatric trials and their timing relative to clinical trials in adults.

New Chemical Entity Exclusivity

In the European Union, new chemical entities, sometimes referred to as new active substances, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity. This data exclusivity, if granted, prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a generic (abbreviated) application for eight years, after which generic marketing authorization can be submitted, and the innovator’s data may be referenced, but not approved for two years. The overall ten-year period will be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

 

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Orphan Designation and Exclusivity

In the European Union, the EMA’s Committee for Orphan Medicinal Products, or COMP, grants orphan drug designation to promote the development of products that are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions that affect not more than 5 in 10,000 persons in the European Union Community, or when, without incentives, it is unlikely that sales of such products in the European Union would be sufficient to justify the necessary investment in developing the products. Additionally, orphan drug designation is only available where no satisfactory method of diagnosis, prevention, or treatment of the condition has been authorized (or the product would be a significant benefit to those affected).

In the European Union, orphan drug designation entitles a party to financial incentives such as reduction of fees or fee waivers and ten years of market exclusivity is granted following medicinal product approval. This period may be reduced to six years if the orphan drug designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity. Market exclusivity would not prevent the approval of a similar drug that is shown to be safer, more effective or otherwise clinically superior.

Orphan drug designation must be requested before submitting an application for marketing approval. Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

Exceptional Circumstances/Conditional Approval

Orphan drugs or drugs with unmet medical needs may be eligible for European Union approval under exceptional circumstances or with conditional approval. Approval under exceptional circumstances may be applicable to orphan products and is used when an applicant is unable to provide comprehensive data on the efficacy and safety under normal conditions of use because the indication for which the product is intended is encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, when the present state of scientific knowledge does not allow comprehensive information to be provided, or when it is medically unethical to collect such information. Conditional marketing authorization may be applicable to orphan medicinal products, medicinal products for seriously debilitating or life-threatening diseases, or medicinal products to be used in emergency situations in response to recognized public threats. Conditional marketing authorization can be granted on the basis of less complete data than is normally required in order to meet unmet medical needs and in the interest of public health, provided the risk-benefit balance is positive, it is likely that the applicant will be able to provide the comprehensive clinical data, and unmet medical needs will be fulfilled. Conditional marketing authorization is subject to certain specific obligations to be reviewed annually.

Accelerated Review

Under the centralized procedure in the European Union, the maximum timeframe for the evaluation of a marketing authorization application is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the EMA’s Committee for Medicinal Products for Human Use, or CHMP). Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation. In this circumstance, EMA ensures that the opinion of the CHMP is given within 150 days, excluding clock stops.

Pharmaceutical Coverage, Pricing and Reimbursement

Significant uncertainty exists as to the coverage and reimbursement status of any products for which we obtain regulatory approval. In the United States and markets in other countries, sales of any products for which we receive regulatory approval for commercial sale will depend in part on the availability of coverage and reimbursement from third-party payors. Third-party payors include government authorities, managed care providers, private health insurers and other organizations. The process for determining whether a payor will

 

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provide coverage for a product may be separate from the process for setting the reimbursement rate that the payor will pay for the product. Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the FDA-approved products for a particular indication. Moreover, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Adequate third- party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.

Third-party payors are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy. In order to obtain coverage and reimbursement for any product that might be approved for sale, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of our products, in addition to the costs required to obtain regulatory approvals. Our product candidates may not be considered medically necessary or cost-effective. If third-party payors do not consider a product to be cost-effective compared to other available therapies, they may not cover the product after approval as a benefit under their plans or, if they do, the level of payment may not be sufficient to allow a company to sell its products at a profit.

The U.S. government, state legislatures and foreign governments have shown significant interest in implementing cost containment programs to limit the growth of government-paid health care costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs. By way of example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, collectively, the Healthcare Reform Law, contains provisions that may reduce the profitability of drug products, including, for example, increased rebates for drugs sold to Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies’ share of sales to federal health care programs. Adoption of government controls and measures, and tightening of restrictive policies in jurisdictions with existing controls and measures, could limit payments for pharmaceuticals.

In the European Community, governments influence the price of pharmaceutical products through their pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers. Some jurisdictions operate positive and negative list systems under which products may only be marketed once a reimbursement price has been agreed to by the government. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost-effectiveness of a particular product candidate to currently available therapies. Other member states allow companies to fix their own prices for medicines, but monitor and control company profits. The downward pressure on health care costs in general, particularly prescription drugs, has become very intense. As a result, increasingly high barriers are being erected to the entry of new products. In addition, in some countries, cross-border imports from low-priced markets exert a commercial pressure on pricing within a country.

The marketability of any products for which we receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement. In addition, an increasing emphasis on cost containment measures in the United States and other countries has increased and we expect will continue to increase the pressure on pharmaceutical pricing. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

 

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Other Healthcare Laws and Compliance Requirements

If we obtain regulatory approval for any of our product candidates, we may be subject to various federal and state laws targeting fraud and abuse in the healthcare industry. These laws may impact, among other things, our proposed sales, marketing and education programs. In addition, we may be subject to patient privacy regulation by both the federal government and the states in which we conduct our business. The laws that may affect our ability to operate include:

 

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the federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, to induce, or in return for, the purchase or recommendation of an item or service reimbursable under a federal healthcare program, such as the Medicare and Medicaid programs;

 

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federal civil and criminal false claims laws and civil monetary penalty laws, which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other third-party payors that are false or fraudulent;

 

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the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new federal criminal statutes that prohibit executing a scheme to defraud any healthcare benefit program and making false statements relating to healthcare matters;

 

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the federal transparency laws, including the federal Physician Payment Sunshine Act, that requires drug and biologics manufacturers to disclose payments and other transfers of value provided to physicians and teaching hospitals;

 

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HIPAA, as amended by the Health Information Technology and Clinical Health Act, or HITECH, and its implementing regulations, which imposes certain requirements relating to the privacy, security and transmission of individually identifiable health information; and

 

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state law equivalents of each of the above federal laws, such as anti-kickback and false claims laws that may apply to items or services reimbursed by any third-party payor, including commercial insurers, and state laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

The Healthcare Reform Law broadened the reach of the fraud and abuse laws by, among other things, amending the intent requirement of the federal Anti-Kickback Statute and the applicable criminal healthcare fraud statutes contained within 42 U.S.C. § 1320a-7b, effective March 23, 2010. Pursuant to the statutory amendment, a person or entity no longer needs to have actual knowledge of this statute or specific intent to violate it in order to have committed a violation. In addition, the Healthcare Reform Law provides that the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act or the civil monetary penalties statute. Many states have adopted laws similar to the federal Anti-Kickback Statute, some of which apply to the referral of patients for healthcare items or services reimbursed by any source, not only the Medicare and Medicaid programs.

We are also subject to the U.S. Foreign Corrupt Practices Act, or FCPA, which prohibits improper payments or offers of payments to foreign governments and their officials for the purpose of obtaining or retaining business. Safeguards we implement to discourage improper payments or offers of payments by our employees, consultants, and others may be ineffective, and violations of the FCPA and similar laws may result in severe criminal or civil sanctions, or other liabilities or proceedings against us, any of which would likely harm our reputation, business, financial condition and result of operations.

If our operations are found to be in violation of any of the laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including civil and criminal penalties, exclusion from

 

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participation in government healthcare programs, such as Medicare and Medicaid and imprisonment, damages, fines and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

Our Advisors

Scientific Advisory Board

We have assembled a world-class scientific advisory board with expertise in biology for medical applications. The members of our scientific advisory board have made significant scientific contributions in their individual fields, have published in top-tier journals and have been recognized with numerous awards and distinctions, including the Nobel Prize in Physiology or Medicine. Members of our scientific advisory board provide strategic advice to us in such fields as proteomics, translational research and molecular biology, and perform such other services as may be mutually determined by us and the scientific advisory board member. Our scientific advisory board meets on an as-needed basis, based on our need for advice in their respective fields of expertise from time to time.

 

Name		Affiliation
Susan L. Ackerman, Ph.D.		Professor, The Jackson Laboratory and Howard Hughes Medical Institute Investigator
Bruce Beutler, M.D.		Founding Director, Center for the Genetics of Host Defense, UT Southwestern Medical Center
Floyd Bloom, M.D.		Professor Emeritus, Molecular and Cellular Neuroscience Department, The Scripps Research Institute
Benjamin F. Cravatt, Ph.D.		Professor and Chairman of the Department of Chemical Physiology, The Scripps Research Institute
Nancy Ip, Ph.D.		Dean of Science and Director of the State Key Laboratory of Molecular Neuroscience at Hong Kong University of Science and Technology
Osamu Nureki, Ph.D.		Professor, Department of Biological Sciences, Graduate School of Science, The University of Tokyo
Wing Hung Wong, Ph.D.		Stephen R. Pierce Family Goldman Sachs Professor in Science and Human Health; Professor of Statistics, Stanford University

Therapeutic Advisory Board

We have convened a select group of experienced drug discovery leaders to guide our discovery and development of innovative Physiocrine-based medicines. Our therapeutic advisory board members have extensive drug development expertise in both biotechnology company and pharmaceutical company settings. They have repeatedly demonstrated their ability to build high quality research and development organizations and to transform promising research into products. Members of our therapeutic advisory board provide strategic advice to us in the areas of translational and clinical research and perform such other services as may be mutually determined by us and the therapeutic advisory board member. Our therapeutic advisory board generally meets once per year.

 

Name		Affiliation
Thomas O. Daniel, M.D.		President, Research and Early Development, Celgene Corporation
R. Alan Ezekowitz, M.D., Ph.D.		Advisor, Cardinal Partners; President, Chief Executive Officer and Co-Founder, Abide Therapeutics, Inc.
L. Patrick Gage, Ph.D.		Chairman, Cytokinetics Inc.; Executive Chairman, Virdante Pharmaceuticals, Inc.

 

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Name		Affiliation
Richard Heyman, Ph.D.		Chief Executive Officer, Seragon Pharmaceuticals, Inc.
Keith James, Ph.D.		President, Ferring Research Institute Inc.; Senior Vice President, Research and Development, Ferring Pharmaceuticals Inc.
Paul Negulescu, Ph.D.		Vice President, Research, Vertex Pharmaceuticals Incorporated
Timothy Rink, MA., M.D., Sc.D.		Director, Kymab Ltd.; Director, Santhera Pharmaceuticals Holding AG; Director, Stevanage Bioscience Catalyst
Wendell Wierenga, Ph.D.		Director, Apricus Biosciences, Inc., Concert Pharmaceuticals, Inc. and Ocera Therapeutics, Inc.
Doug Williams, Ph.D.		Executive Vice President, Research and Development, Biogen Idec Inc.

Employees

As of January 1, 2015, we had 46 full-time employees. None of our employees are represented by labor unions or covered by collective bargaining agreements. We consider our relationship with our employees to be good.

Facilities

Our administrative offices and research laboratory are located in San Diego, California. We lease approximately 17,083 square feet of office and laboratory space under a lease that currently expires in May 2017. We believe that our facility is sufficient to meet our needs and that suitable additional space will be available as and when needed.

Legal Proceedings

We are not a party to any material legal proceedings at this time. From time to time, we may be subject to various legal proceedings and claims that arise in the ordinary course of our business activities. Although the results of litigation and claims cannot be predicted with certainty, as of the date of this prospectus, we do not believe we are party to any claim or litigation the outcome of which, if determined adversely to us, would individually or in the aggregate be reasonably expected to have a material adverse effect on our business. Regardless of the outcome, litigation can have an adverse impact on us because of defense and settlement costs, diversion of management resources and other factors.

 

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MANAGEMENT

Executive Officers and Directors

The following table sets forth information regarding our executive officers and directors, including their ages as of January 1, 2015:

 

Name		Age				Position
Executive Officers:
John D. Mendlein, Ph.D.			55			Chief Executive Officer and Executive Chairman, Board of Directors
Frederic Chereau			48			President and Chief Operating Officer
David M. Weiner, M.D.			50			Chief Medical Officer
Melissa A. Ashlock, M.D.			56			Vice President, External Scientific Alliances and Human Genetics
John C. McKew, Ph.D.			50			Vice President, Research
Fred Ramsdell, Ph.D.			54			Vice President, Immunology
Kelly Blackburn			50			Vice President, Clinical Affairs
Andrew Cubitt, Ph.D.			51			Vice President, Product Protection
Holly D. Chrzanowski			49			Vice President, Enterprise Talent and Organization
Non-Management Directors:
John K. Clarke			61			Chairman of the Board
James C. Blair, Ph.D.			75			Director
Kathryn E. Falberg			54			Director
Amir H. Nashat, Sc.D.			41			Director
Edward Penhoet, Ph.D.			74			Director
Paul Schimmel, Ph.D.			74			Director

 

(1)	Member of the audit committee.

(2)	Member of the compensation committee.

(3)	Member of the nominating and corporate governance committee.

John D. Mendlein, Ph.D. has served as our Executive Chairman since July 2010 and as our Chief Executive Officer since September 2011. Dr. Mendlein is Vice Chairman of the Board of Fate Therapeutics, Inc., a biopharmaceutical company, and also holds board positions with Moderna Therapeutics, Inc., Pronutria Biosciences, Inc. and the BIO (Biotechnology Industry Organization) emerging companies board. Dr. Mendlein previously served as the Chief Executive Officer of Adnexus Therapeutics, Inc., a biopharmaceutical company, from 2005 to 2008, which was purchased by Bristol-Myers Squibb Company in 2008. Dr. Mendlein also served on the board of directors of Monogram Biosciences, Inc., an HIV and oncology diagnostic company that was acquired by Laboratory Corporation of America Holdings in 2009. Before that, he served as Chairman and Chief Executive Officer of Affinium Pharmaceuticals, Ltd. (acquired by Debiopharm Group) from 2000 to 2005, and as a board member, General Counsel and Chief Knowledge Officer at Aurora Bioscience Corporation from August 1996 to September 2001. Dr. Mendlein holds a Ph.D. in physiology and biophysics from the University of California, Los Angeles, a J.D. from the University of California, Hastings College of the Law, and a B.S. in biology from the University of Miami. Dr. Mendlein is the author or inventor of over 100 publications and patent properties, including a number of patents associated with our company. We believe Dr. Mendlein is qualified to serve on our board of directors due to his extensive leadership, executive, managerial, business and pharmaceutical company experience, as well as his day-to-day management and intimate knowledge of our business and operations.

Frederic Chereau has served as our President and Chief Operating Officer since January 2014. From September 2012 to December 2013, Mr. Chereau was Senior Vice President, Global Angioedema Franchise Lead at Shire plc, a global biopharmaceuticals company. Prior to that, from October 2008 to September 2012, he served as President and Chief Executive Officer of Pervasis Therapeutics, Inc., a clinical-stage therapeutics company. Before Pervasis, Mr. Chereau worked at Genzyme from 1999 to 2008, where he held various roles,

 

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including Vice President and General Manager of the Cardiovascular Business Unit. Mr. Chereau holds B.S. in physics from the University of Paris, an M.A. in management from La Rochelle Business School in France and an M.B.A. from INSEAD, Fontainebleau, France and Singapore.

David M. Weiner, M.D. has served as our Chief Medical Officer since March 2014. Prior to that, he served as the Chief Medical Officer of Proteostasis Therapeutics, Inc., a clinical-stage therapeutics company, from September 2012 to March 2014 and its interim Chief Executive Officer from July 2013 to March 2014. From 2009 to 2011, Dr. Weiner was Vice President and head of early clinical development, Neurodegenerative Disease at Merck Serono S.A., a global pharmaceutical company. Dr. Weiner’s clinical experience includes a faculty appointment in Neuroscience and Psychiatry at the University of California, San Diego. He trained in neurology at New York Hospital, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, after completing a medical internship at St. Vincent’s Catholic Medical Center in New York. Dr. Weiner holds a B.A. in biopsychology from Brandeis University and an M.D. from the State University of New York at Buffalo.

Melissa A. Ashlock, M.D. has served as our Vice President, External Scientific Alliances and Human Genetics since May 2011. She also provides consulting services to BioMarin Pharmaceutical Inc., a global biopharmaceutical company. Since 1999, Dr. Ashlock has been involved with the Cystic Fibrosis Foundation (CFF), holding positions including Vice President of Drug Discovery for its therapeutics affiliate. Dr. Ashlock served as a consultant with Vertex Pharmaceuticals Incorporated, a global biotechnology company, from March 2011 to June 2011, with John J. Flatley Company in their cystic fibrosis research lab, from January 2011 to June 2011, with Galapagos NV, a clinical-stage biotechnology company, from April 2010 to April 2011, and with Therapeutics for Rare and Neglected Diseases Program, National Institutes of Health, from March 2009 to February 2010. She completed her internship and medical residency in adult internal medicine at New York Hospital (Cornell University Medical College) and Mary Hitchcock Memorial Hospital (Dartmouth Medical School), respectively. Dr. Ashlock, who has also published under the name Melissa Rosenfeld, M.D., has been co-inventor or author of more than 50 issued patents and publications. Dr. Ashlock holds a B.S. in biochemistry from Purdue University and an M.D. from Weill Cornell Medical College. She also holds a license to practice medicine (1989 to present, State of Maryland).

John C. McKew, Ph.D. has served as our Vice President, Research since October 2014. Prior to that, from October 2010 to October 2014, Dr. McKew served as the acting scientific director of the Division of Preclinical Innovation at the National Center for Advancing Translational Sciences (NCATS) within the National Institutes of Health (NIH). Before joining the NIH, from October 1993 to January 2011, Dr. McKew held a director level position at Wyeth Research in Cambridge, Massachusetts. Dr. McKew held post-doctoral research positions at the University of Geneva and Firmenich, SA and is currently an Adjunct Associate Professor at the Boston University School of Medicine. He holds B.S. degrees in chemistry and biochemistry from the State University of New York at Stony Brook and a Ph.D. in chemistry from the University of California, Davis.

Fred Ramsdell, Ph.D. has served as our Vice President, Immunology since June 2014 and provided consulting services to us from May 2014 to June 2014. Prior to that, from October 2008 to May 2014, Dr. Ramsdell served as Scientific Director, Discovery Immunology at Novo Nordisk, A/S, a global healthcare company. He conducted post-doctoral studies at the National Institutes of Health, researching a variety of questions regarding immune cell function and tolerance. He has a number of publications in high import journals. He holds a B.S. in biochemistry and cell biology from the University of California, San Diego and a Ph.D. in microbiology and immunology from the University of California, Los Angeles.

Kelly Blackburn has served as our Vice President, Clinical Affairs since July 2013. Prior to that, from September 2012 to July 2013, she was a consultant for the Company. From September 2006 to September 2012, Ms. Blackburn was the Vice President, Clinical Development Operations at Vertex Pharmaceuticals Incorporated. She also served as a director for Vertex Pharmaceuticals Incorporated, a global biotechnology company, from September 2006 to September 2012. Ms. Blackburn holds a B.S. in biochemistry from University of New Hampshire, an M.H.A. from Quinnipiac College and an M.Ed. from Cambridge College.

 

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Andrew Cubitt, Ph.D. has served as our Vice President, Product Protection since September 2011 and provided consulting services to us from January 2011 to September 2011. Prior to that, from 2009 to 2011, he worked as a senior patent agent for the Global Patent Group LLC, a patent consulting firm. He cofounded Anaptys Biosciences, an antibody company, in 2005 and served as executive director of corporate development until 2009. He also served as senior manager, technology and intellectual property at Aurora Bioscience Corporation. Dr. Cubitt did his postdoctoral training at Weill Cornell Medical College in New York. He holds a Ph.D. in biochemistry from the University of Sheffield and a B.Sc. in medical biochemistry from the University of Birmingham.

Holly D. Chrzanowski has served as our Vice President, Enterprise Talent and Organization since April 2013 and provided consulting services to us from 2012 to 2013. Prior to joining aTyr, she operated her own human resources consulting practice, HC Consulting, for 12 years. She also served as a Director, Human Resources at Vertex Pharmaceuticals Incorporated as a consultant and Senior Manager, Human Resources at Aurora Biosciences Corporation. She holds a B.A. in political science from California State University at Long Beach.

John K. Clarke has served as Chairman of our Board of Directors since September 2005. Mr. Clarke is Managing General Partner of Cardinal Partners, a venture capital partnership focused on healthcare investing. He co-founded Cardinal Partners in 1997 and has served as President of CHP Management, Inc. since that time. He currently serves as Chairman of the Board of Directors of Alnylam Pharmaceuticals, Inc. and as a director of Momenta Pharmaceuticals, Inc. and Rib-X Pharmaceuticals Inc. He has also served as a director for Verastem, Inc., Sirtris Pharmaceuticals, Inc. (acquired by GlaxoSmithKline), TechRx Technology Services Corporation (acquired by NDCHealth) and Visicu, Inc. (acquired by Phillips Electronics). Mr. Clarke holds an A.B. in economics and biology from Harvard University and an M.B.A. from the Wharton School at the University of Pennsylvania. We believe Mr. Clarke is qualified to serve on our board of directors due to his extensive experience within the field of drug discovery and development and his broad leadership experience on various public and private company boards.

James C. Blair, Ph.D. has served as a director since December 2010. Dr. Blair has been a Partner of Domain Associates, a venture capital firm with a focus on life sciences, since the company’s founding in 1985. Present board memberships include Clovis Oncology, Inc., as well as numerous private company boards. He previously served on the boards of Zogenix, Inc., Cadence Pharmaceuticals, Inc. and Five Prime Therapeutics, Inc. Dr. Blair currently serves on the board of directors of the Prostate Cancer Foundation and the Sanford-Burnham Medical Research Institute. He is also on the advisory boards of the Department of Molecular Biology at Princeton University, the USC Stevens Institute for Innovation, and the Division of Chemistry and Chemical Engineering at the California Institute of Technology. Dr. Blair holds a B.S.E. in electrical engineering from Princeton University and an M.S.E. and Ph.D. in electrical engineering from the University of Pennsylvania. We believe Dr. Blair is qualified to serve on our board of directors due to his experience in the life science industry and his years of business and leadership experience.

Kathryn E. Falberg has served as a director since July 2014. Ms. Falberg most recently served as Executive Vice President and Chief Financial Officer of Jazz Pharmaceuticals PLC, a biopharmaceutical company, from 2009 to 2014. From 1995 to 2001, Ms. Falberg was with Amgen Inc., where she served as Senior Vice President, Finance and Strategy, Chief Financial Officer, and before that as Vice President, Controller and Chief Accounting Officer, and Vice President, Treasurer. Ms. Falberg currently serves on the board of directors and is the Audit Committee Chair of Halozyme Therapeutics, Inc., a biopharmaceutical company and Medivation, Inc., a biopharmaceutical company, as well as at the private medical diagnostics company, Ariosa Diagnostics, Inc. Ms. Falberg holds a B.A. in economics and an M.B.A. in finance from the University of California, Los Angeles. We believe Ms. Falberg is qualified to serve on our board of directors due to her extensive background in financial and accounting matters for public companies and her leadership experience in the biotechnology industry.

 

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Amir H. Nashat, Sc.D. has served as a director since November 2006. He is also a Managing General Partner at Polaris Venture Partners, a venture capital firm. He joined Polaris in April 2002 and focuses on investments in healthcare, consumer products and energy. Dr. Nashat is currently a director of Receptos, Inc., Fate Therapeutics, Inc. and BIND Therapeutics, Inc., as well as a director of several private companies. Additionally, Dr. Nashat has served as a director of Adnexus Therapeutics, Inc. (acquired by Bristol-Myers Squibb Company) and other private companies. Dr. Nashat holds a Sc.D. in chemical engineering from the Massachusetts Institute of Technology with a minor in biology and an M.S. and B.S. in materials science and mechanical engineering from the University of California, Berkeley. We believe Dr. Nashat is qualified to serve on our board of directors due to his extensive experience within the field of drug discovery and development, his broad leadership experience on various boards, and his financial expertise with life sciences companies.

Edward Penhoet, Ph.D. has served as a director since September 2005. Dr. Penhoet joined Alta Partners Management VIII, LLC, a venture capital fund investing in biotherapeutics, drug discovery and medical device companies, in 2000 as a Director and has served there full time since 2008. He currently serves on the board of directors of CymaBay Therapeutics, Inc., Immune Design Corp. and Scynexis, Inc. and formerly served on the board of directors of ChemoCentryx, Inc., Veloxis Pharmaceuticals A/S and Zymogenetics, Inc. Dr. Penhoet was co-founder of Chiron Corporation, and served as its President and Chief Executive Officer from its formation in 1981 until April 1998. For ten years prior to founding Chiron, Dr. Penhoet was a faculty member of the Biochemistry Department of the University of California, Berkeley and is the immediate past Dean of the School of Public Health at the University of California, Berkeley. Dr. Penhoet holds an A.B. in biology from Stanford University and a Ph.D. in biochemistry from the University of Washington. We believe Dr. Penhoet is qualified to serve on our board of directors due to his in-depth knowledge and experience in both operating and investing in biopharmaceutical companies and his broad leadership on various boards.

Paul Schimmel, Ph.D. has served as a director since September 2005. Dr. Schimmel is an Ernest and Jean Hahn Professor at The Skaggs Institute for Chemical Biology at The Scripps Research Institute. He was formerly the John D. and Catherine T. MacArthur Professor of Biochemistry and Biophysics in the Department of Biology at the Massachusetts Institute of Technology. Dr. Schimmel holds a B.A. in biochemistry and biophysics from Ohio Wesleyan University and a Ph.D. from the Massachusetts Institute of Technology. We believe Dr. Schimmel is qualified to serve on our board of directors due to his role as one of our scientific founders and his discoveries and scientific leadership in the field of Physiocrine biology and other areas important to the development of therapeutics.

Principal Accounting Officer

Below is the biography of Stan Blackburn, our principal financial and accounting officer, who serves as a consultant:

Stan Blackburn has served as our Acting Chief Financial Officer as a consultant since October 2008. Mr. Blackburn has provided senior financial consulting services to early stage life science and technology companies through his firm BlackFord Partners, Inc. for over 13 years and as an independent consultant for over 25 years. He worked as a certified public accountant with Arthur Andersen & Company for over nine years. He holds a B.S. in accountancy from the University of Illinois.

Composition of Our Board of Directors

Our board of directors currently consists of seven members, all of whom were elected pursuant to the provisions of a stockholders’ agreement, which will terminate immediately prior to the completion of this offering. Upon the termination of these provisions, there will be no contractual obligations regarding the election of our directors. Our nominating and corporate governance committee and board of directors may consider a broad range of factors relating to the qualifications and background of director nominees, which may include diversity and is not limited to race, gender or national origin. We have no formal policy regarding board

 

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diversity. Our nominating and corporate governance committee’s and board of directors’ priority in selecting board members is identification of persons who will further the interests of our stockholders through his or her established record of professional accomplishment, the ability to contribute positively to the collaborative culture among board members, knowledge of our business, understanding of the competitive landscape and professional and personal experiences and expertise relevant to our business strategy. Our directors hold office until their successors have been elected and qualified or until the earlier of their resignation or removal.

Our amended and restated certificate of incorporation and amended and restated bylaws that will become effective upon the completion of this offering also provide that our directors may be removed only for cause by the affirmative vote of the holders of at least     % of the votes that all our stockholders would be entitled to cast in an annual election of directors, and that any vacancy on our board of directors, including a vacancy resulting from an enlargement of our board of directors, may be filled only by vote of a majority of our directors then in office

Director Independence. Our board of directors has determined that all members of our board of directors, except Dr. Mendlein, are independent, as determined in accordance with the rules of The NASDAQ Stock Market and the Securities and Exchange Commission, or SEC. In making such independence determination, our board of directors considered the relationships that each non-employee director has with us and all other facts and circumstances that our board of directors deemed relevant in determining their independence, including the beneficial ownership of our capital stock by each non-employee director. In considering the independence of the directors listed above, our board of directors considered the association of our directors with the holders of more than five percent of our common stock. Upon the completion of this offering, we expect that the composition and functioning of our board of directors and each of our committees will comply with all applicable requirements of The NASDAQ Stock Market and the rules and regulations of the SEC. There are no family relationships among any of our directors or executive officers.

Staggered Board. In accordance with the terms of our amended and restated certificate of incorporation and amended and restated bylaws that will become effective upon the completion of this offering, our board of directors will be divided into three classes, Class I, Class II and Class III, with each class serving staggered three-year terms. Upon the expiration of the term of a class of directors, directors in that class will be eligible to be elected for a new three-year term at the annual meeting of stockholders in the year in which their term expires.

 

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Our Class I directors will be             ,             and             ;

 

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Our Class II directors will be             and             ; and

 

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Our Class III directors will be             and             .

Our amended and restated certificate of incorporation and amended and restated bylaws that will become effective upon the completion of this offering provide that the authorized number of directors may be changed only by resolution of our board of directors.

The division of our board of directors into three classes with staggered three-year terms may delay or prevent stockholder efforts to effect a change of our management or a change in control.

Leadership Structure of the Board

Our board of directors believes that the decision as to who should serve as Chairman, Executive Chairman and Chief Executive Officer is the proper responsibility of the board of directors. Our amended and restated bylaws that will be in effect upon the completion of this offering will not require our Executive Chairman, Chairman and Chief Executive Officer positions to be separate and our board of directors will carefully consider the advantages and disadvantages of such separation or combination. At the present time, our board of directors believes the interests of all stockholders are best served through a leadership model with a combined Executive

 

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Chairman and Chief Executive Officer position and an independent Chairman. Our Executive Chairman and Chief Executive Officer focuses on our day-to-day operations, while our independent Chairman serves as our lead independent director. Our independent Chairman leads our board of directors in its fundamental role of providing advice to and independent oversight of management.

Board’s Role in Risk Oversight

We face a number of risks, including risks relating to our financial condition, development and commercialization activities, operations and intellectual property as more fully discussed under “Risk Factors” in this prospectus. Management is responsible for the day-to-day management of risks we face, while our board of directors, as a whole and through its committees, has responsibility for the oversight of risk management. In its risk oversight role, our board of directors has the responsibility to satisfy itself that the risk management processes designed and implemented by management are adequate and functioning as designed.

The role of our board of directors in overseeing the management of our risks is conducted primarily through committees of our board of directors, as disclosed in the descriptions of each of the committees below and in the charters of each of the committees. The full board of directors (or the appropriate board committee in the case of risks that are under the purview of a particular committee) discusses with management our major risk exposures, their potential impact on our company, and the steps we take to manage them. When a board committee is responsible for evaluating and overseeing the management of a particular risk or risks, the chairman of the relevant committee reports on the discussion to the full board of directors during the committee reports portion of the next board meeting. This enables our board of directors and its committees to coordinate the risk oversight role, particularly with respect to risk interrelationships.

Board Committees

Our board of directors has established an audit committee, a compensation committee and a nominating and governance committee. The composition of each committee set forth below will be effective upon the closing of this offering. Each committee will operate under a charter approved by our board. Following this offering, copies of each committee’s charter will be posted on the Corporate Governance section of our website, at www.atyrpharma.com.

Audit Committee

            ,              and             currently serve on the audit committee, which is chaired by             . Under the applicable NASDAQ rules, we are permitted to phase in our compliance with the independent audit committee requirements set forth in NASDAQ Marketplace Rule 5605(c)(2)(A)(ii) on the same schedule as we are permitted to phase in our compliance with the independent audit committee requirement pursuant to Rule 10A-3(b)(1)(iv)(A) under the Securities Exchange Act of 1934, as amended, or the Exchange Act, which require (1) one independent member at the time of listing; (2) a majority of independent members within 90 days of listing; and (3) all independent members within one year of listing. Our board of directors has determined that each of             ,             and             is an independent director under the NASDAQ Marketplace Rules and Rule 10A-3 of the Exchange Act. We believe that the composition of our audit committee will comply with applicable rules of The NASDAQ Stock Market under the phase-in schedule described above. Our board of directors has designated             as an “audit committee financial expert,” as defined under the applicable rules of the Securities and Exchange Commission. The audit committee’s responsibilities include:

 

•

appointing, approving the compensation of, and assessing the independence of our independent registered public accounting firm;

 

•

approving auditing and permissible non-audit services, and the terms of such services, to be provided by our independent registered public accounting firm;

 

•

reviewing the internal audit plan with the independent registered public accounting firm and members of management responsible for preparing our financial statements;

 

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•

reviewing and discussing with management and the independent registered public accounting firm our annual and quarterly financial statements and related disclosures as well as critical accounting policies and practices used by us;

 

•

reviewing the adequacy of our internal control over financial reporting;

 

•

establishing policies and procedures for the receipt and retention of accounting-related complaints and concerns;

 

•

recommending, based upon the audit committee’s review and discussions with management and the independent registered public accounting firm, whether our audited financial statements shall be included in our Annual Report on Form 10-K;

 

•

monitoring the integrity of our financial statements and our compliance with legal and regulatory requirements as they relate to our financial statements and accounting matters;

 

•

preparing the audit committee report required by SEC rules to be included in our annual proxy statement;

 

•

reviewing all related party transactions for potential conflict of interest situations and approving all such transactions; and

 

•

reviewing quarterly earnings releases.

Compensation Committee

            ,             and             currently serve on the compensation committee, which is chaired by             . Our board of directors has determined that each member of the compensation committee is “independent” as that term is defined in the applicable NASDAQ Stock Market rules. The compensation committee’s responsibilities include:

 

•

annually reviewing and approving corporate goals and objectives relevant to the compensation of our Chief Executive Officer;

 

•

evaluating the performance of our Chief Executive Officer in light of such corporate goals and objectives and determining the compensation of our Chief Executive Officer;

 

•

reviewing and approving the compensation of our other executive officers;

 

•

reviewing and establishing our overall management compensation, philosophy and policy;

 

•

overseeing and administering our compensation and similar plans;

 

•

evaluating and assessing potential and current compensation advisors in accordance with the independence standards identified in the applicable NASDAQ Stock Market rules;

 

•

retaining and approving the compensation of any compensation advisors;

 

•

reviewing and approving our policies and procedures for the grant of equity-based awards;

 

•

reviewing and making recommendations to our board of directors with respect to director compensation;

 

•

preparing the compensation committee report required by SEC rules to be included in our annual proxy statement;

 

•

reviewing and discussing with management the compensation discussion and analysis to be included in our annual proxy statement or Annual Report on Form 10-K; and

 

•

reviewing and discussing with our board of directors corporate succession plans for the Chief Executive Officer and other key officers.

 

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Nominating and Corporate Governance Committee

            ,              and             currently serve on the nominating and corporate governance committee, which is chaired by                     . Our board of directors has determined that each member of the nominating and corporate governance committee is “independent” as that term is defined in the applicable NASDAQ Stock Market rules. The nominating and corporate governance committee’s responsibilities include:

 

•

developing and recommending to our board of directors criteria for board and committee membership;

 

•

establishing procedures for identifying and evaluating board of director candidates, including nominees recommended by stockholders;

 

•

identifying individuals qualified to become members of our board of directors;

 

•

recommending to our board of directors the persons to be nominated for election as directors and to each of our board’s committees;

 

•

developing and recommending to our board of directors a set of corporate governance guidelines; and

 

•

overseeing the evaluation of our board of directors and management.

Our board of directors may establish other committees from time to time.

Compensation Committee Interlocks and Insider Participation

None of the members of our compensation committee has at any time during the prior three years been one of our officers or employees. None of our executive officers currently serves, or in the past fiscal year has served, as a member of our board of directors or compensation committee of any entity that has one or more executive officers serving on our board of directors or compensation committee.

Corporate Governance

Prior to the completion of this offering, we will adopt a written code of business conduct and ethics that applies to our directors, officers and employees, including our principal executive officer, principal financial officer, principal accounting officer or controller, or persons performing similar functions. Following the completion of this offering, a current copy of the code will be posted on the Corporate Governance section of our website, which is located at www.atyrpharma.com. If we make any substantive amendments to, or grant any waivers from, the code of business conduct and ethics for any officer or director, we will disclose the nature of such amendment or waiver on our website or in a current report on Form 8-K.

 

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EXECUTIVE AND DIRECTOR COMPENSATION

Summary Compensation Table

The following table presents information regarding the total compensation earned by each individual who served as our chief executive officer at any time during the fiscal year ended December 31, 2014 and our two other most highly compensated executive officers who were serving as executive officers as of December 31, 2014. We refer to these officers as our named executive officers.

 

Name and Principal Position		Year				Salary ($)				Stock Awards ($)(1)				Option Awards ($)(2)				Non-Equity Incentive Plan Compensation ($)(3)				All Other Compensation ($)(4)				Total ($)
John D. Mendlein, Ph.D			2014				410,000				*				*(5)				—				38,407				448,407
Chief Executive Officer and Executive Chairman			2013				400,000				—				408,959				160,000				—				968,959
Frederic Chereau			2014				319,731	(6)			—				1,503,835				—				149,511				1,973,077
President & Chief Operating Officer
David M. Weiner, M.D.			2014				265,208	(7)			—				1,470,231				—				75,207				1,810,646
Chief Medical Officer

 

(1)

In accordance with SEC rules, this column reflects the incremental grant date fair value, computed as of the modification date in accordance with Financial Accounting Standard Board ASC Topic 718 for stock-based compensation transactions, or ASC 718, associated with the amendment in December 2014 of a restricted stock grant to provide for the lapsing of the Company’s right of repurchase with respect to 192,870 shares of common stock underlying the grant. Assumptions used in the calculation of this amount are included in Note 7 to our consolidated financial statements included elsewhere in this prospectus. This amount was not paid to or realized by the officer in the year indicated. For 2014, the amount is not calculable through the latest practicable date; such amount is expected to be determined in February 2015 and will then be disclosed in accordance with SEC rules.

(2)

In accordance with SEC rules, this column reflects the aggregate grant date fair value of the option awards granted during the years indicated, computed in accordance with ASC 718. Assumptions used in the calculation of these amounts are included in Note 7 to our consolidated financial statements included elsewhere in this prospectus. These amounts do not reflect the actual economic value that will be realized by the named executive officer upon the vesting of the stock options, the exercise of the stock options or the sale of the common stock underlying such stock options.

(3)

The amount reported for 2013 reflects the discretionary cash bonus determined by our board of directors upon recommendation of our compensation committee based on achievement of certain performance goals and metrics as specified by our board of directors upon recommendation of our compensation committee. For 2014, the amounts of the discretionary cash bonus is not calculable through the latest practicable date; such amounts are expected to be determined in February 2015 and will then be disclosed in accordance with SEC rules.

(4)

The amounts reported in this column include (i) supplemental compensation paid to Dr. Mendlein and Mr. Chereau in the amounts of $28,407 and $21,067, respectively, (ii) reimbursements to Dr. Mendlein pursuant to his employment agreement for medical expenses in the amount of $10,000, (iii) contributions made by the Company to a health savings account for Mr. Chereau in the amount of $2,275, (iv) relocation expenses for Mr. Chereau and Dr. Weiner, in the amounts of $81,000 and $50,000, respectively and (v) related tax gross-ups for the relocation expenses of Mr. Chereau and Dr. Weiner, of $45,169 and $25,207, respectively.

(5)	The amount reported also reflects the incremental grant date fair value of $            , computed as of the modification date in accordance with ASC 718, associated with the amendment in December 2014 of the

 

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vesting schedule for a previously granted stock option. Assumptions used in the calculation of this amount are included in Note 7 to our consolidated financial statements included elsewhere in this prospectus. This amount was not paid to or realized by the officer in the year indicated. For 2014, the amount is not calculable through the latest practicable date; such amount is expected to be determined in February 2015 and will then be disclosed in accordance with SEC rules.

(6)	Mr. Chereau began his employment with us on January 9, 2014.

(7)	Dr. Weiner began his employment with us on March 17, 2014.

Employment Arrangements with Our Named Executive Officers

John D. Mendlein, Ph.D.

Dr. Mendlein entered into an at-will employment agreement with us as of January 1, 2010, which provided for an initial annual base salary of $150,000, subject to periodic review and increases as determined by our board of directors. Pursuant to the terms of his employment agreement, Dr. Mendlein is considered annually for a bonus target, currently in an amount of up to 50% of his then-current base salary, as determined by our board of directors and compensation committee. Dr. Mendlein may elect to receive a grant of fully-vested shares of our common stock in lieu of a cash bonus. In connection with commencement of his employment, we granted Dr. Mendlein a signing bonus of $31,250. In addition, Dr. Mendlein is entitled to reimbursement in an amount up to $10,000 per calendar year of certain healthcare fees and expenses.

Payments in Connection with a Change of Control

Upon the completion of this offering, Dr. Mendlein will be entitled to request an agreement with us regarding a change in control that would provide for a “gross-up” payment in the event certain excise taxes and penalties are imposed as a result of Sections 280G and/or 4999 of the Code. In the event that Dr. Mendlein’s employment ends within 12 months of any change of control as defined in the agreement, other than as a result of termination for cause, we have agreed to enter into a consulting or advisory relationship with Dr. Mendlein following such change of control such that any options or restricted shares that were unvested as of the consummation of such change of control become fully vested, subject to Dr. Mendlein continuing to provide bona fide services to the Company.

Payments Provided upon Termination for Good Reason or Without Cause

Dr. Mendlein’s employment is at-will. In the event of termination by Dr. Mendlein for good reason or by us without cause, Dr. Mendlein will be entitled to receive (i) the amount of his accrued but unpaid salary, earned but unpaid bonus, and any accrued but unused vacation as of the date of termination, (ii) reimbursement of any expenses properly incurred on behalf of the Company prior to any such termination and not yet reimbursed, (iii) continuation of his base salary for a period of six months after the effective date of termination and one half of the full bonus that Dr. Mendlein would have received had the Company met all of the targets in the annual bonus plan that was approved by our board for the calendar year in which the termination occurred, and (iv) continuation of group health plan benefits for a period of six months, in the case of each of (iii) and (iv), subject to the execution and non-revocation of a release agreement and written acknowledgement of Dr. Mendlein’s continuing confidentiality obligations.

Under Dr. Mendlein’s employment agreement, the terms below are generally defined as follows:

“cause” means (i) conduct constituting an uncured material act of willful misconduct in connection with the performance of his duties; (ii) conviction of, or entry of a pleading of guilty or nolo contendere to, any crime involving fraud or embezzlement that results in material damage to the Company or any felony; (iii) willful and repeated failure to substantially perform the duties, functions and responsibilities of the position that results in material damage to the Company that continues uncured for 30 days after prior written notice; (iv) a material breach of any of the material provisions of his employment agreement that is uncured for 30 days

 

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after prior written notice; or termination in connection with the bankruptcy, dissolution, liquidation, winding up, assignment for the benefit of creditors, or other cessation of the business of the Company as a going concern, other than to effectuate a change of control; and

“good reason” means (i) a substantial diminution or other substantive adverse change, not consented to by Dr. Mendlein, in the nature of scope of his responsibilities, authorities, powers, function or duties; (ii) an involuntary reduction in his base salary except for a decrease as part of reductions by the Company of the annual base salary of its executive employees generally; (iii) a breach by the Company of any of its material obligations under any agreement between the Company and Dr. Mendlein that remains uncured for 30 days after prior written notice; or (iv) the relocation of the Company’s headquarters more than 25 miles away from San Diego, California.

Frederic Chereau

Mr. Chereau entered into an at-will employment agreement with us on December 20, 2013, which provided for an initial base salary of $360,000, subject to periodic review and adjustments as determined by the Company in its sole discretion. Pursuant to the terms of his employment agreement, Mr. Chereau is considered annually for a bonus target of up to 50% of his then-current base salary, as determined by our board of directors based on corporate achievements of goals and achievement of Mr. Chereau’s individual goals. Pursuant to the terms of his employment agreement, Mr. Chereau was issued an option to purchase 1,987,795 shares of the Company’s common stock on March 5, 2014. In connection with commencement of his employment, we granted Mr. Chereau a relocation assistance payment of $45,000 and reimbursed Mr. Chereau $36,000 for temporary housing.

David M. Weiner, M.D.

Dr. Weiner entered into an at-will employment agreement with us on February 20, 2014, which provided for an initial base salary of $335,000, subject to periodic review and adjustments as determined by the Company in its sole discretion. Pursuant to the terms of his employment agreement, Dr. Weiner is considered annually for a bonus target of up to 40% of his then-current base salary, as determined by our board of directors based on corporate achievements of goals and achievement of Dr. Weiner’s individual goals. Pursuant to the terms of his employment agreement, Dr. Weiner was issued an option to purchase 961,836 shares of the Company’s common stock on July 10, 2014. In connection with commencement of his employment, we granted Dr. Weiner a relocation assistance payment of $50,000.

Outstanding Equity Awards at Fiscal Year-End

The following table summarizes, for each of the named executive officers, the number of outstanding equity awards held by each of our named executive officers as of December 31, 2014.

 

		Option Awards																Stock Awards
		Number of Securities underlying Unexercised Options (#) Exercisable				Number of Securities underlying Unexercised Options (#) Unexercisable				Option Exercise Price ($)				Option Expiration Date				Number of Shares that Have Not Vested (#)				Market Value of Shares that Have Not Vested ($)(1)
John D. Mendlein, Ph.D			397,052				8,448	(2)			0.09				3/16/2021				—				—
			209,931				125,959	(3)			0.09				3/16/2021				—				—
			456,935				639,709	(4)			0.11				9/13/2022				—				—
			263,402				684,848	(5)			0.51				6/28/2023				—				—
			30,555				169,445	(6)			0.51				3/5/2024				—				—
			—				—				—				—				192,870(7)				*
Frederic Chereau.			—				1,987,795	(8)			0.51				3/5/2024				—				—
David M. Weiner, M.D			—				961,836	(9)			0.51				7/10/2024				—				—

 

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(1)

There was no public market for our common stock as of December 31, 2014. The fair value of our common stock as of December 31, 2014 is not calculable through the latest practicable date; such amounts are expected to be determined in February 2015, and will then be disclosed in accordance with SEC rules.

(2)	Option vests with respect to 2.08% of the shares on each monthly anniversary of January 1, 2011.

(3)	Option vests with respect to 1.39% of the shares on each monthly anniversary of March 16, 2011.

(4)	Option vests with respect to 1.39% of the shares on each monthly anniversary of June 1, 2012.

(5)	Option vests with respect to 1.39% of the shares on each monthly anniversary of April 19, 2013.

(6)	Option vests with respect to 1.39% of the shares on each monthly anniversary of January 1, 2014.

(7)	Represents shares subject to our repurchase right, which will lapse upon the completion of a firm commitment underwritten initial public offering of our securities in which our pre-money valuation exceeds $200 million.

(8)	Option vests with respect to 1.39% of the shares on each monthly anniversary of January 9, 2014.

(9)	Option vests with respect to 1.39% of the shares on each monthly anniversary of March 17, 2014

Director Compensation

The following table provides certain information concerning compensation earned by the directors who were not named executive officers during the year ended December 31, 2014.

 

Name		Fees Earned or Paid in Cash ($)				Option Awards ($)(1)(2)				Total ($)
James C. Blair, Ph.D.			13,750				150,397				164,147
John K. Clarke			11,250				150,397				161,647
Kathryn E. Falberg			22,500				150,397				172,897
Amir H. Nashat, Sc.D.			11,250				150,397				161,647
Edward Penhoet, Ph.D.			10,000				150,397				160,397
Paul Schimmel, Ph.D.			11,250				150,397				161,647

 

(1)	The amounts reported reflect the aggregate grant date fair value computed in accordance with ASC 718.

(2)

Represents an option to purchase 100,000 shares of common stock at an exercise price of $0.51 per share granted to each of our non-employee directors in July 2014. The shares of common stock underlying each such option vest in 36 equal monthly installments over three years from June 1, 2014 through June 1, 2017. In October 2014, each of the options was amended to allow for the early exercise of the options, subject to our right of repurchase with respect to any unvested shares.

Our Chief Executive Officer received no compensation for his services as a director. Pursuant to our board of directors compensation plan, effective as of June 1, 2014, each non-employee director is paid a retainer fee of $20,000 per year, and each committee member is paid $2,500 per year. Committee chairs are paid $7,500 per year, with the exception of the audit committee chair, who is paid $25,000 per year. In addition, each director receives an annual option grant of 35,000 shares.

Compensation Risk Assessment

We believe that although a portion of the compensation provided to our executive officers and other employees is performance-based, our executive compensation program does not encourage excessive or unnecessary risk taking. This is primarily due to the fact that our compensation programs are designed to encourage our executive officers and other employees to remain focused on both short-term and long-term strategic goals, in particular in connection with our pay-for-performance compensation philosophy. As a result, we do not believe that our compensation programs are reasonably likely to have a material adverse effect on our company.

 

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Equity Compensation Plans

2014 Stock Plan

Our 2014 Stock Plan, or the 2014 Plan, was originally adopted by our board of directors and our stockholders in 2007, and was subsequently amended and restated in 2014. We have reserved an aggregate of 16,219,000 shares of our common stock for the issuance of options and other equity awards under the 2014 Plan. This number is subject to adjustment in the event of a consolidation, stock split, stock dividend or other change in our capitalization. Effective upon the closing of this offering, our board of directors has determined not to grant any further awards under our 2014 Plan. The shares we issue under the 2014 Plan are authorized but unissued shares or shares we reacquire. The shares of common stock underlying any awards that are forfeited, canceled, reacquired by us prior to vesting, satisfied without the issuance of stock or otherwise terminated (other than by exercise) under the 2014 Plan are currently added back to the shares of common stock available for issuance under the 2014 Plan. Upon the closing of this offering, such shares will be added to the shares of common stock available for issuance under the 2015 Plan.

The 2014 Plan is administered by our compensation committee. Our board of directors and our compensation committee have the authority to select the individuals to whom awards will be granted, to make any combination of awards to participants, to accelerate the exercisability or vesting of any award, to provide substitute awards and to determine the specific terms and conditions of each award.

The 2014 Plan permits us to make grants of incentive stock options and non-qualified stock options, restricted stock awards and restricted stock unit awards to our employees, directors and consultants.

The 2014 Plan permits the granting of (1) options to purchase common stock intended to qualify as incentive stock options under Section 422 of the Internal Revenue Code, or the Code, and (2) options that do not so qualify. The option exercise price of each option is determined by our board or directors or our compensation committee but may not be less than 100% of the fair market value of our common stock on the date of grant. In the case of an incentive stock option granted to a participant who, at the time of grant of such option, owns stock representing more than 10% of the voting power of all classes of stock of the Company, then the exercise price may not be less than 110% of the fair market value of our common stock on the date of grant. The term of each option will be fixed by our board of directors or our compensation committee and may not exceed ten years from the date of grant.

The 2014 Plan provides that upon the occurrence of a change in control event, awards may be assumed, substituted for new awards of a successor entity, or otherwise continued or terminated at the effective time of such sale event. In the event any award is not assumed, substituted or otherwise continued in connection with a change in control event, such award will be subject to accelerated vesting. We may make or provide for cash payment to holders of options equal to the difference between the per share cash consideration in the sale event and the exercise price to the holders of vested and exercisable options. We may make or provide for cash payment to holders of restricted stock and restricted stock unit awards in an amount equal to the product of the per share cash consideration and the number of shares subject to each such award. In 2014, we amended certain outstanding option agreements under the 2014 Plan to provide for “double trigger” acceleration upon certain termination events which occur after a change in control event. Additionally, future stock options granted to our Chief Executive Officer and other executive officers as designated by our Chief Executive Officer will also be subject to “double trigger” acceleration unless otherwise determined by our board of directors.

Our board of directors may amend, suspend or terminate the 2014 Plan at any time, subject to stockholder approval where such approval is required by applicable law. Our board of directors may also amend, modify or terminate any outstanding award, provided that no amendment to an award may materially impair any of the rights of a participant under any awards previously granted without his or her written consent.

 

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2015 Stock Option and Incentive Plan

Prior to the effectiveness of this offering, our board of directors intends to adopt, and we expect our stockholders will approve, our 2015 Stock Option and Incentive Plan, or the 2015 Plan. Our 2015 Plan will be effective on the business day immediately prior to the effective date of the registration statement of which this prospectus forms a part and is not expected to be utilized until after the completion of this offering. Our 2015 Plan will provide for the grant of incentive stock options, within the meaning of Section 422 of the Code, to our employees and any of our parent and subsidiary corporations’ employees, and for the grant of nonstatutory stock options, restricted stock, restricted stock units, stock appreciation rights, performance units and performance shares to our employees, directors and consultants, and our parent and subsidiary corporations’ employees and consultants.

We have initially reserved             shares of our common stock, or the Initial Limit, for the issuance of awards under the 2015 Plan. The 2015 Plan provides that the number of shares reserved and available for issuance under the plan will automatically increase each January 1, beginning on January 1, 2016, by     % of the outstanding number of shares of our common stock on the immediately preceding December 31 or such lesser number of shares as determined by our compensation committee, or the Annual Increase. This number is subject to adjustment in the event of a stock split, stock dividend or other change in our capitalization.

The shares we issue under the 2015 Plan will be authorized but unissued shares or shares that we reacquire. The shares of common stock underlying any awards that are forfeited, cancelled, held back upon exercise or settlement of an award to satisfy the exercise price or tax withholding, reacquired by us prior to vesting, satisfied without any issuance of stock, expire or are otherwise terminated (other than by exercise) under the 2015 Plan and 2014 Plan will be added back to the shares of common stock available for issuance under the 2015 Plan.

Stock options and stock appreciation rights with respect to no more than             shares of stock may be granted to any one individual in any one calendar year and the maximum “performance-based award” payable to any one individual under the 2015 Plan is             shares of stock or $     in the case of cash-based awards. The maximum aggregate number of shares that may be issued in the form of incentive stock options shall not exceed the Initial Limit cumulatively increased on January 1, 2015 and on each January 1 thereafter by the lesser of the Annual Increase for such year or             shares of common stock.

The 2015 Plan will be administered by our compensation committee. Our compensation committee has full power to select, from among the individuals eligible for awards, the individuals to whom awards will be granted, to make any combination of awards to participants, and to determine the specific terms and conditions of each award, subject to the provisions of the 2015 Plan. Persons eligible to participate in the 2015 Plan will be those full or part-time officers, employees, non-employee directors and other key persons (including consultants) as selected from time to time by our compensation committee in its discretion.

The 2015 Plan permits the granting of both options to purchase common stock intended to qualify as incentive stock options under Section 422 of the Code and options that do not so qualify. The option exercise price of each option will be determined by our compensation committee but may not be less than 100% of the fair market value of our common stock on the date of grant. The term of each option will be fixed by our compensation committee and may not exceed ten years from the date of grant. Our compensation committee will determine at what time or times each option may be exercised.

Our compensation committee may award stock appreciation rights subject to such conditions and restrictions as we may determine. Stock appreciation rights entitle the recipient to shares of common stock, or cash, equal to the value of the appreciation in our stock price over the exercise price. The exercise price of each stock appreciation right may not be less than 100% of the fair market value of our common stock on the date of grant.

Our compensation committee may award shares of restricted common stock and restricted stock units to participants subject to such conditions and restrictions as it may determine. These conditions and restrictions may

 

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include the achievement of certain performance goals and continued employment with us through a specified vesting period. Our compensation committee may also grant shares of common stock that are free from any restrictions under the 2015 Plan. Unrestricted stock may be granted to participants in recognition of past services or other valid consideration and may be issued in lieu of cash compensation due to such participant.

Our compensation committee may grant performance share awards to participants that entitle the recipient to receive shares of common stock upon the achievement of certain performance goals and such other conditions as our compensation committee shall determine.

Our compensation committee may grant cash bonuses under the 2015 Plan to participants, subject to the achievement of certain performance goals.

Our compensation committee may grant awards of restricted stock, restricted stock units, performance shares or cash-based awards under the 2015 Plan that are intended to qualify as “performance-based compensation” under Section 162(m) of the Code. Those awards would only vest or become payable upon the attainment of performance goals that are established by our compensation committee and related to one or more performance criteria. The performance criteria that would be used with respect to any such awards include: earnings before interest, taxes, depreciation and amortization, net income (loss) (either before or after interest, taxes, depreciation and amortization), changes in the market price of our common stock, economic value-added, funds from operations or similar measure, sales or revenue, acquisitions or strategic transactions, operating income (loss), cash flow (including, but not limited to, operating cash flow and free cash flow), return on capital, assets, equity, or investment, stockholder returns, return on sales, gross or net profit levels, productivity, expense, margins, operating efficiency, customer satisfaction, working capital, earnings (loss) per share of stock, sales or market shares and number of customers, any of which may be measured either in absolute terms or as compared to any incremental increase or as compared to results of a peer group. From and after the time that we become subject to Section 162(m) of the Code, the maximum award that is intended to qualify as “performance-based compensation” under Section 162(m) of the Code that may be made to any one employee during any one calendar year period is shares of common stock with respect to a stock-based award and $     with respect to a cash-based award.

The 2015 Plan provides that in the case of, and subject to, the consummation of a “sale event” as defined in the 2015 Plan, all outstanding awards may be assumed, substituted or otherwise continued by the successor entity. To the extent that the successor entity does not assume, substitute or otherwise continue such awards, then upon the effectiveness of the sale event, all stock options and stock appreciation rights will automatically terminate. In the event of such termination, individuals holding options and stock appreciation rights will be permitted to exercise such options and stock appreciation rights prior to the sale event. In addition, in connection with a sale event, we may make or provide for a cash payment to participants holding options and stock appreciation rights equal to the difference between the per share cash consideration payable to stockholders in the sale event and the exercise price of the options or stock appreciation rights.

Our board of directors may amend or discontinue the 2015 Plan and our compensation committee may amend or cancel outstanding awards for purposes of satisfying changes in law or any other lawful purpose, but no such action may adversely affect rights under an award without the holder’s consent. Certain amendments to the 2015 Plan require the approval of our stockholders.

No awards may be granted under the 2015 Plan after the date that is ten years from the date of stockholder approval. No awards under the 2015 Plan have been made prior to the date hereof.

401(k) Plan and Other Benefits

We maintain a tax-qualified retirement plan, or the 401(k) Plan, that provides eligible U.S. employees with an opportunity to save for retirement on a tax advantaged basis. Eligible employees are able to defer eligible compensation subject to applicable annual Code limits. Employees’ pre-tax contributions are allocated to each

 

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participant’s individual account and are then invested in selected investment alternatives according to the participants’ directions. Employees are immediately and fully vested in their contributions. Our 401(k) Plan is intended to be qualified under Section 401(a) of the Code with our 401(k) Plan’s related trust intended to be tax exempt under Section 501(a) of the Code. As a tax-qualified retirement plan, contributions to our 401(k) Plan and earnings on those contributions are not taxable to the employees until distributed from our 401(k) Plan. We also pay, on behalf of our employees, the premiums for health, life and disability insurance.

Pension Benefits, Non-Qualified Contribution Plans and other Non-Qualified Defined Compensation Plans

We do not provide a pension plan or non-qualified defined contribution plans for any of our employees, and none of our named executive officers participated in a non-qualified defined compensation plan during the fiscal year ended December 31, 2013.

 

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CERTAIN RELATIONSHIPS AND RELATED PARTY TRANSACTIONS

Other than the compensation agreements and other arrangements described under “Executive and Director Compensation” in this prospectus and the transactions described below, since January 1, 2012, there has not been and there is not currently proposed, any transaction or series of similar transactions to which we were, or will be, a party in which the amount involved exceeded, or will exceed, $120,000 and in which any director, executive officer, holder of five percent or more of any class of our capital stock or any member of the immediate family of, or entities affiliated with, any of the foregoing persons, had, or will have, a direct or indirect material interest.

Private Placements of Securities

2013 Convertible Note Financing

In March 2013, we issued convertible promissory notes, or the 2013 Notes, in an aggregate principal amount of $10,000,000 to certain existing stockholders. A portion of the principal amount of the 2013 Notes converted into Series D redeemable convertible preferred stock in April 2013. The remainder of the principal amount of the 2013 Notes was repaid through cancellation of indebtedness pursuant to the Securities Purchase Agreements entered into with the Affiliates (as defined in “Management’s Discussion and Analysis of Financial Condition and Results of Operations—Financial Operations Overview”). The following table summarizes participation in our convertible note financing by related persons:

 

Stockholder		Principal Amount of Notes Purchased				Amount of Notes Converted into Series D Redeemable Convertible Preferred Stock
Paul Schimmel, Ph.D.		$	697,574.30			$	665,266.10
John D. Mendlein, Ph.D.		$	31,888.71			$	30,413.76
CHP II, L.P.		$	2,331,981.85			$	2,223,969.73
Entities affiliated with Polaris Venture Management Co. V, LLC		$	2,300,891.40			$	2,194,322.28
Entities affiliated with Alta Partners Management VIII, LLC		$	2,300,891.40			$	2,194,319.73
Entities affiliated with Domain Partners VIII, L.P.		$	2,291,930.35			$	2,185,774.25

Series D Redeemable Convertible Preferred Stock Financing

In April 2013 and May 2013 we sold an aggregate of 18,275,830 shares of our Series D redeemable convertible preferred stock at a purchase price of $2.529 per share for an aggregate purchase price of $46,219,574.22, $9,536,813.24 of which was paid in cancellation of indebtedness under the 2013 Notes. The Affiliates also sold an aggregate of 19,364,416 of their Series D redeemable convertible preferred stock at an average purchase price of $0.022, for an aggregate purchase price of $2,575,467.33. We and the Affiliates entered into an Amended and Restated Affiliate Agreement under which each of our stockholders was entitled to receive stock in each Affiliate in proportion to the amount of our stock held by such stockholder, subject to certain adjustments. Under the Series D redeemable convertible preferred stock Securities Purchase Agreement, each investor in the our Series D redeemable convertible preferred stock was required to enter into a Securities Purchase Agreement with each of the Affiliates for the sale and issuance of Series D Preferred Stock of such Affiliates. The following table summarizes purchases of our Series D redeemable convertible preferred stock by related persons:

 

Stockholder		Shares of our Series D Redeemable Convertible Preferred Stock				Total Purchase Price (1)
Paul Schimmel, Ph.D.			263,055			$	700,252.41
John D. Mendlein, Ph.D.			21,122			$	56,226.71
CHP II, L.P.			1,536,787			$	4,090,926.99
Entities affiliated with Polaris Venture Management Co. V, LLC			1,524,018			$	4,056,935.92
Entities affiliated with Alta Partners Management VIII, LLC			1,126,866			$	2,999,717.29
Entities affiliated with Domain Partners VIII, L.P.			1,518,083			$	4,041,136.95
Entities affiliated with FMR LLC			12,002,254			$	31,950,000.15

 

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(1)	The table reflects the total purchase price of $2.662 per share. The Company received $2.529 per share, with the Affiliates receiving the remaining $0.133 per share.

Loan to Chief Executive Officer and Executive Chairman

In July 2010, we loaned $69,432.30 in principal amount to John D. Mendlein, Ph.D., our Chief Executive Officer and Executive Chairman, in connection with Dr. Mendlein’s purchase of restricted shares of our common stock. The loan was evidenced by a Secured Promissory Note and Pledge Agreement and bore interest at an annual rate of 5%. The loan was secured by 771,470 shares of our common stock. In January 2015, Dr. Mendlein repaid the full outstanding principal and accrued interest under the loan, totaling $85,021.27 in the aggregate.

Payments to The Scripps Research Institute

We provide funding to The Scripps Research Institute, or TSRI, under an amended and restated research funding and option agreement. See “Business” for more information about this agreement. Since January 1, 2012, we have paid $2,058,203.50 to TSRI under the agreement. Paul Schimmel, Ph.D., one of our directors, is a faculty member at TSRI and such payments fund a portion of his research activities conducted at TSRI.

Charitable Donations to National Foundation for Cancer Research

Since January 1, 2012, we have provided charitable donations to the National Foundation for Cancer Research, or NFCR, in the aggregate amount of $1,080,000. We have requested that the donations be restricted to a laboratory that performs basic research on the role of aminoacyl tRNA synthetase fragments and splice variants in cancer biology and therapeutics. The NFCR in its discretion selected Dr. Schimmel’s laboratory at TSRI as the laboratory to receive these funds.

 

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Executive Officer and Director Compensation

Employment Agreements

We have entered into offer letters or employment related agreements with each of John D. Mendlein, Ph.D., Frederic Chereau, David M. Weiner, M.D. and certain of our executive officers. For more information regarding these arrangements, see “Executive and Director Compensation—Employment Arrangements with Our Named Executive Officers.”

Consulting Agreement

In January 2012, we entered into a Consulting Agreement with Holly D. Chrzanowski, our current Vice President, Enterprise Talent and Organization. Under this agreement, we paid Ms. Chrzanowski an aggregate total of $151,322.50 in the fiscal year ending December 31, 2012 and an aggregate total of $101,197.50 in the fiscal year ending December 31, 2013. We hired Ms. Chrzanowski as our Vice President, Enterprise Talent and Organization in April 2013.

Restricted Stock and Stock Option Awards

For information regarding restricted stock and stock option awards granted to our named executive officers and directors, see “Executive and Director Compensation.”

Indemnification Agreements

We have entered into agreements to indemnify our directors and executive officers. These agreements will, among other things, require us to indemnify these individuals for certain expenses (including attorneys’ fees), judgments, fines and settlement amounts reasonably incurred by such person in any action or proceeding, including any action by or in our right, on account of any services undertaken by such person on behalf of our company or that person’s status as a member of our board of directors to the maximum extent allowed under Delaware law.

Registration Rights

We and certain holders of our capital stock have entered into a registration rights agreement pursuant to which these stockholders will have, among other things, registration rights under the Securities Act of 1933, or the Securities Act, with respect to common stock that they will hold following this offering. See “Description of Capital Stock—Registration Rights” for a further description of the terms of these agreements.

Policies for Approval of Related Party Transactions

Our board of directors reviews and approves transactions with directors, officers and holders of five percent or more of our voting securities and their affiliates, each a related party. Prior to this offering, the material facts as to the related party’s relationship or interest in the transaction are disclosed to our board of directors prior to their consideration of such transaction, and the transaction is not considered approved by our board of directors unless a majority of the directors who are not interested in the transaction approve the transaction. Further, when stockholders are entitled to vote on a transaction with a related party, the material facts of the related party’s relationship or interest in the transaction are disclosed to the stockholders, who must approve the transaction in good faith.

In connection with this offering, we intend to adopt a written related party transactions policy that such transactions must be approved by our audit committee or another independent body of our board of directors.

 

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PRINCIPAL STOCKHOLDERS

The following table sets forth certain information known to us regarding beneficial ownership of our capital stock as of December 31, 2014, as adjusted to reflect the sale of common stock offered by us in this offering, for:

 

•

each person or group of affiliated persons known by us to be the beneficial owner of more than five percent of our capital stock;

 

•

our named executive officers;

 

•

each of our other directors; and

 

•

all executive officers and directors as a group.

To the extent that the underwriters sell more than             shares in this offering, the underwriters have the option to purchase up to an additional             shares at the initial public offering price less the underwriting discount.

Beneficial ownership is determined in accordance with the rules of the Securities and Exchange Commission and generally includes voting or investment power with respect to securities. Except as noted by footnote, and subject to community property laws where applicable, we believe based on the information provided to us that the persons and entities named in the table below have sole voting and investment power with respect to all common stock shown as beneficially owned by them.

The percentage of beneficial ownership prior to this offering in the table below is based on 80,724,986 shares of common stock deemed to be outstanding as of December 31, 2014, and the percentage of beneficial ownership after this offering in the table below is based on             shares of common stock assumed to be outstanding after the closing of the offering. The information in the table below assumes no exercise of the underwriters’ option to purchase additional shares. Options to purchase shares of common stock that are exercisable within 60 days of December 31, 2014 are deemed to be beneficially owned by the persons holding these options for the purpose of computing percentage ownership of that person, but are not treated as outstanding for the purpose of computing any other person’s ownership percentage.

 

Name and Address of Beneficial Owner (1)		Number of Shares Beneficially Owned before Offering				Percentage of Shares Beneficially Owned before Offering				Number of Shares Beneficially Owned after Offering		Percentage of Shares Beneficially Owned after Offering
5% Stockholders:
Paul Schimmel, Ph.D. (2)			5,120,621				6.34	%
CHP II, L.P. (3)			13,984,620				17.32	%
Entities affiliated with Polaris Venture Management Co. V, LLC (4)			13,805,894				17.10	%
Entities affiliated with Alta Partners Management VIII, LLC (5)			13,408,742				16.61	%
Entities affiliated with Domain Partners VIII, L.P. (6)			13,752,126				17.04	%
Entities affiliated with FMR LLC (7)			12,002,254				14.87	%
Executive Officers and Directors:
John D. Mendlein, Ph.D. (8)			3,412,522				4.15	%
Frederic Chereau (9)			358,907				*
David M. Weiner, M.D.			—				—
James C. Blair, Ph.D. (6)(10)			13,852,126				17.14	%
John K. Clarke (3)(11)			14,084,620				17.43	%
Kathryn E. Falberg (12)			100,000				*
Amir H. Nashat, Sc.D. (4)(13)			13,905,894				17.20	%
Edward Penhoet, Ph.D. (5)(14)			13,508,742				16.71	%
Paul Schimmel, Ph.D. (2)			5,120,621				6.34	%
All executive officers and directors as a group (15 persons)(15)			65,572,367				78.02	%

 

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*	Represents beneficial ownership of less than one percent.

(1)	Unless otherwise indicated, the address for each beneficial owner is c/o aTyr Pharma, Inc., 3545 John Hopkins Court, Suite #250, San Diego, CA 92121.

(2)

Consists of: (i) 248,024 shares of Series D redeemable convertible preferred stock held by the Paul R. Schimmel Prototype PSP, (ii) 1,034,000 shares of common stock, 525,000 shares of Series A redeemable convertible preferred stock, 1,200,000 shares of Series B redeemable convertible preferred stock, 1,440,058 shares of Series B-2 redeemable convertible preferred stock, 558,508 shares of Series C redeemable convertible preferred stock and 15,031 shares of Series D redeemable convertible preferred stock, all held by the Schimmel Revocable Trust U/A Dtd 9/6/2000 and (iii) options to purchase an additional 100,000 shares of common stock that are exercisable within 60 days of December 31, 2014, 75,000 shares of which would be subject to our right of repurchase, held by Dr. Schimmel.

(3)

Consists of: 2,400,000 shares of Series A redeemable convertible preferred stock, 3,600,000 shares of Series B redeemable convertible preferred stock, 4,320,173 shares of Series B-2 redeemable convertible preferred stock, 2,127,660 shares of Series C redeemable convertible preferred stock and 1,536,787 shares of Series D redeemable convertible preferred stock, all held by CHP II, L.P. (“CHP”). The general partner of CHP is CHP II Management, LLC (“CHP Management”), which may be deemed to beneficially own certain of the shares held by CHP. CHP Management disclaims beneficial ownership of all shares held by CHP in which it does not have an actual pecuniary interest. One of our directors, John Clarke, Brandon Hull and John Park are managing members of CHP Management and as members of the general partner, they may be deemed to beneficially own certain of the shares held by CHP Management. The managing members disclaim beneficial ownership of all shares held by CHP Management in which they do not have an actual pecuniary interest. The mailing address of the beneficial owner is c/o Cardinal Partners, 230 Nassau Street, Princeton, NJ 08542.

(4)

Consists of: (i) 3,473,763 shares of Series B redeemable convertible preferred stock, 4,168,683 shares of Series B-2 redeemable convertible preferred stock, 4,208,756 shares of Series C redeemable convertible preferred stock and 1,470,577 shares of Series D redeemable convertible preferred stock, all held by Polaris Venture Partners V, L.P. (“Polaris Ventures”), (ii) 67,704 shares of Series B redeemable convertible preferred stock, 81,248 shares of Series B-2 redeemable convertible preferred stock, 82,029 shares of Series C redeemable convertible preferred stock and 28,661 shares of Series D redeemable convertible preferred stock, all held by Polaris Venture Partners Entrepreneurs’ Fund V, L.P. (“Polaris Entrepreneurs’ Fund”), (iii) 23,796 shares of Series B redeemable convertible preferred stock, 28,556 shares of Series B-2 redeemable convertible preferred stock, 28,831 shares of Series C redeemable convertible preferred stock and 10,074 shares of Series D redeemable convertible preferred stock, all held by Polaris Venture Partners Founders’ Fund V, L.P. (“Polaris Founders’ Fund”) and (iv) 34,737 shares of Series B redeemable convertible preferred stock, 41,686 shares of Series B-2 redeemable convertible preferred stock, 42,087 shares of Series C redeemable convertible preferred stock and 14,706 shares of Series D redeemable convertible preferred stock, all held by Polaris Venture Partners Special Founders’ Fund V, L.P. (“Polaris Special Founders’ Fund”). Each of the funds has sole voting and investment power with respect to the shares held by such funds. The general partner of Polaris Ventures, Polaris Entrepreneurs’ Fund, Polaris Founders’ Fund and Polaris Special Founders’ Fund is Polaris Venture Management Co. V, LLC (“Polaris Management”), and Polaris Management may be deemed to have sole voting and investment power over such shares. Director Amir H. Nashat is one of six members of Polaris Management. He has shared voting and investment power over such shares and may be deemed the indirect beneficial owner of such shares. The members of North Star Venture Management 2010 LLC are also members of Polaris Management, and as members of the general partner, they may be deemed to share voting and investment power over such shares. The mailing address of the beneficial owner is 1000 Winter Street, Suite 3350, Waltham, MA 02451.

(5)

Consists of 3,600,000 shares of Series B redeemable convertible preferred stock, 4,320,173 shares of Series B-2 redeemable convertible preferred stock, 4,361,703 shares of Series C redeemable convertible preferred stock and 1,126,866 shares of Series D redeemable convertible preferred stock, all held by Alta Partners VIII, L.P. (“Alta Partners”). Alta Partners Management VIII, LLC (“Alta Management”) is the general partner of Alta Partners and as the general partner may be deemed to have beneficial ownership of the shares held by Alta Partners. Alta

 

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Managers disclaims beneficial ownership of all such shares in which they do not have an actual pecuniary interest. The managing directors of Alta Management are Daniel Janney, Farah Champsi and Guy Nohra, and as managing directors of the general partner, they may be deemed to share voting and investment power over such shares. The managing directors disclaim beneficial ownership of all shares held by Alta Management in which they do not have an actual pecuniary interest. The mailing address of the beneficial owner is One Embarcadero Center, 37th Floor, San Francisco, CA 94111.

(6)

Consists of: (i) 12,143,933 shares of Series C redeemable convertible preferred stock and 1,506,901 shares of Series D redeemable convertible preferred stock, all held by Domain Partners VIII, L.P. (“Domain Partners”) and (ii) 90,110 shares of Series C redeemable convertible preferred stock and 11,182 shares of Series D redeemable convertible preferred stock, all held by DP VIII Associates, L.P. (“Domain Associates”). One Palmer Square Associates VIII, L.L.C. (“One Palmer”) is the general partner of Domain Partners and Domain Associates and may be deemed to have sole voting and investment power over such shares. One Palmer disclaims beneficial ownership of all shares held by Domain Partners and Domain Associates in which it does not have an actual pecuniary interest. One of our directors, Dr. Blair, is a managing member of One Palmer. Dr. Blair disclaims beneficial ownership of all shares held by One Palmer in which he does not have an actual pecuniary interest. The mailing address of the beneficial owner is One Palmer Square, Suite 515, Princeton, New Jersey 08542.

(7)

Consists of: (i) 3,455,296 shares of Series D redeemable convertible preferred stock held by Fidelity Select Portfolios: Biotechnology Portfolio (“Fidelity Select”), (ii) 282,494 shares of Series D redeemable convertible preferred stock held by Fidelity Advisor Series VII: Fidelity Advisor Biotechnology Fund (“Fidelity Advisor Biotechnology”), (iii) 7,513,149 shares of Series D redeemable convertible preferred stock held by Fidelity Mt. Vernon Street Trust: Fidelity Growth Company Fund (“Fidelity Mt. Vernon Street”), (iv) 112,697 shares of Series D redeemable convertible preferred stock held by Variable Insurance Products Fund III: Growth Opportunities Portfolio (“Fidelity Variable Insurance”) and (v) 638,618 shares of Series D redeemable convertible preferred stock held by Fidelity Advisor Series I: Fidelity Advisor Growth Opportunities Fund (“Fidelity Advisor Growth”). Fidelity Select, Fidelity Advisor Biotechnology, Fidelity Mt. Vernon Street, Fidelity Variable Insurance and Fidelity Advisor Growth are managed by direct or indirect subsidiaries of FMR LLC. Edward C. Johnson 3d is a Director and the Chairman of FMR LLC and Abigail P. Johnson is a Director, the Vice Chairman and the President of FMR LLC. Members of the family of Edward C. Johnson 3d, including Abigail P. Johnson, are the predominant owners, directly or through trusts, of Series B voting common shares of FMR LLC, representing 49% of the voting power of FMR LLC. The Johnson family group and all other Series B shareholders have entered into a shareholders’ voting agreement under which all Series B voting common shares will be voted in accordance with the majority vote of Series B voting common shares. Accordingly, through their ownership of voting common shares and the execution of the shareholders’ voting agreement, members of the Johnson family may be deemed, under the Investment Company Act of 1940, to form a controlling group with respect to FMR LLC. Neither FMR LLC nor Edward C. Johnson 3d nor Abigail P. Johnson has the sole power to vote or direct the voting of the shares owned directly by the various investment companies registered under the Investment Company Act (Fidelity Funds) advised by Fidelity Management & Research Company (FMR Co), a wholly owned subsidiary of FMR LLC, which power resides with the Fidelity Funds’ Boards of Trustees. Fidelity Management & Research Company carries out the voting of the shares under written guidelines established by the Fidelity Funds’ Boards of Trustees.

(8)

Consists of: (i) 1,765,162 shares of common stock, 192,870 of which are subject to our right of repurchase, which will lapse upon the completion of a firm commitment underwritten initial public offering of our securities in which our pre-money valuation exceeds $200 million, (ii) 170,218 shares of Series C redeemable convertible preferred stock, (iii) 21,122 shares of Series D redeemable convertible preferred stock and (iv) options to purchase an additional 1,456,020 shares of common stock that are exercisable within 60 days of December 31, 2014, held by Dr. Mendlein.

(9)	Consists of options to purchase 358,907 shares of common stock that are exercisable within 60 days of December 31, 2014, held by Mr. Chereau.

(10)	Consists of options to purchase 100,000 shares of common stock that are exercisable within 60 days of December 31, 2014, 75,000 shares of which would be subject to our right of repurchase, held by Dr. Blair.

 

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(11)	Consists of options to purchase 100,000 shares of common stock that are exercisable within 60 days of December 31, 2014, 75,000 shares of which would be subject to our right of repurchase, held by Mr. Clarke.

(12)	Consists of options to purchase 100,000 shares of common stock that are exercisable within 60 days of December 31, 2014, 75,000 shares of which would be subject to our right of repurchase, held by Ms. Falberg.

(13)	Consists of options to purchase 100,000 shares of common stock that are exercisable within 60 days of December 31, 2014, 75,000 shares of which would be subject to our right of repurchase, held by Dr. Nashat.

(14)	Consists of options to purchase 100,000 shares of common stock that are exercisable within 60 days of December 31, 2014, 75,000 shares of which would be subject to our right of repurchase, held by Dr. Penhoet.

(15)

Includes the number of shares beneficially owned by the named executive officers and directors listed in the above table, as well as (i) 323,366 shares of common stock and options to purchase 196,454 shares of common stock that are exercisable within 60 days of December 31, 2014, held by Dr. Ashlock, (ii) options to purchase 30,822 shares of common stock that are exercisable within 60 days of December 31, 2014, held by Dr. Ramsdell, (iii) 2,222 shares of common stock and options to purchase 121,402 shares of common stock that are exercisable within 60 days of December 31, 2014, held by Ms. Blackburn, (iv) options to purchase 394,549 shares of common stock that are exercisable within 60 days of December 31, 2014, held by Dr. Cubitt, and (v) options to purchase 160,120 shares of common stock that are exercisable within 60 days of December 31, 2014, held by Ms. Chrzanowski.

 

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DESCRIPTION OF CAPITAL STOCK

The following descriptions are summaries of the material terms of our amended and restated certificate of incorporation and amended and restated bylaws, which will be effective upon completion of this offering. The descriptions of the common stock and preferred stock give effect to changes to our capital structure that will occur immediately prior to the completion of this offering. We refer in this section to our amended and restated certificate of incorporation as our certificate of incorporation, and we refer to our amended and restated bylaws as our bylaws.

General

Upon completion of this offering, our authorized capital stock will consist of             shares of common stock, par value $0.001 per share, and             shares of preferred stock, par value $0.001 per share, all of which shares of preferred stock will be undesignated.

As of September 30, 2014, 80,724,986 shares of our common stock were outstanding and held by 73 stockholders of record. This amount assumes the conversion of all outstanding shares of our redeemable convertible preferred stock into common stock, which will occur immediately prior to the closing of this offering. In addition, as of September 30, 2014, we had outstanding options to purchase 10,679,777 shares of our common stock under our 2014 Plan, at a weighted average exercise price of $0.36 per share, 2,618,238 of which were exercisable.

Common Stock

The holders of our common stock are entitled to one vote for each share held on all matters submitted to a vote of the stockholders. The holders of our common stock do not have any cumulative voting rights. Holders of our common stock are entitled to receive ratably any dividends declared by our board of directors out of funds legally available for that purpose, subject to any preferential dividend rights of any outstanding preferred stock. Our common stock has no preemptive rights, conversion rights or other subscription rights or redemption or sinking fund provisions.

In the event of our liquidation, dissolution or winding up, holders of our common stock will be entitled to share ratably in all assets remaining after payment of all debts and other liabilities and any liquidation preference of any outstanding preferred stock. The shares to be issued by us in this offering will be, when issued and paid for, validly issued, fully paid and non-assessable.

Preferred Stock

Immediately prior to the completion of this offering, all outstanding shares of our redeemable convertible preferred stock will be converted into shares of our common stock. Immediately prior to the completion of this offering, our amended and restated certificate of incorporation will be amended and restated to delete all references to such shares of redeemable convertible preferred stock. Upon the consummation of this offering, our board of directors will have the authority, without further action by our stockholders, to issue up to             shares of preferred stock in one or more series and to fix the rights, preferences, privileges and restrictions thereof. These rights, preferences and privileges could include dividend rights, conversion rights, voting rights, terms of redemption, liquidation preferences, sinking fund terms and the number of shares constituting, or the designation of, such series, any or all of which may be greater than the rights of common stock. The issuance of our preferred stock could adversely affect the voting power of holders of common stock and the likelihood that such holders will receive dividend payments and payments upon our liquidation. In addition, the issuance of preferred stock could have the effect of delaying, deferring or preventing a change in control of our company or other corporate action. Immediately after consummation of this offering, no shares of preferred stock will be outstanding, and we have no present plan to issue any shares of preferred stock.

 

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Warrants

As of September 30, 2014, we had outstanding warrants to purchase 72,000 shares of Series B redeemable convertible preferred stock, 15,597 shares of Series C redeemable convertible preferred stock and 118,624 shares of Series D redeemable convertible preferred stock.

In September 2007, in connection with a loan and security agreement entered into with Comerica Bank, or Comerica, we issued to Comerica a warrant to purchase 72,000 shares of our Series B redeemable convertible preferred stock. The warrant contains provisions for the adjustment of the exercise price and the number of shares issuable upon the exercise of the warrant in the event of certain stock dividends, stock splits, recapitalizations, reclassifications, exchanges, substitutions, consolidations, combinations and other similar events. In addition, the number of shares of common stock issuable upon conversion of the shares of Series B redeemable convertible preferred stock underlying the warrant are subject to adjustment for certain dilutive issuances pursuant to our certificate of incorporation as in effect prior to the completion of this offering. The provision for adjustment upon dilutive issuances is an element of the preferred stock into which the warrant is currently exercisable. Upon completion of this offering, the warrants will become exercisable for common stock and will no longer be subject to adjustment for dilutive issuances because our common stock is not subject to any provision for adjustment for dilutive issuances. The warrant expires on September 18, 2017, unless the Company is acquired prior to that time in a transaction in which the consideration paid by the acquirer is comprised solely of cash, promissory notes, or assumption of indebtedness.

In March 2011, in connection with a loan and security agreement entered into with Comerica, we issued to Comerica a warrant to purchase 15,957 shares of our Series C redeemable convertible preferred stock. The warrant contains provisions for the adjustment of the exercise price and the number of shares issuable upon the exercise of the warrant in the event of certain stock dividends, stock splits, recapitalizations, reclassifications, exchanges, substitutions, consolidations, combinations and other similar events. In addition, the number of shares of common stock issuable upon conversion of the shares of Series C redeemable convertible preferred stock underlying the warrant are subject to adjustment for certain dilutive issuances pursuant to our certificate of incorporation as in effect prior to the completion of this offering. The provision for adjustment upon dilutive issuances is an element of the preferred stock into which the warrant is currently exercisable. Upon completion of this offering, the warrant will become exercisable for common stock and will no longer be subject to adjustment for dilutive issuances because our common stock is not subject to any provision for adjustment for dilutive issuances. The warrant expires on March 18, 2021, unless the Company is acquired prior to that time in a transaction in which the consideration paid by the acquirer is comprised solely of cash, promissory notes, or assumption of indebtedness. Both of our loan and security agreements with Comerica terminated upon our full repayment of all outstanding obligations under the agreements.

In July 2013, in connection with an amendment to a loan and security agreement entered into with Silicon Valley Bank, or SVB, we issued to SVB a warrant to purchase 59,312 shares of our Series D redeemable convertible preferred stock. Upon the funding of an additional tranche of financing, the number of shares exercisable under the warrant increased to 118,624. The warrant has a net exercise provision and contains provisions for the adjustment of the exercise price and the number of shares issuable upon the exercise of the warrant in the event of certain stock dividends, stock splits, reclassifications, exchanges, combinations, substitutions, replacements or other similar events. In addition, the number of shares of common stock issuable upon conversion of the shares of Series D redeemable convertible preferred stock underlying the warrant are subject to adjustment for certain dilutive issuances pursuant to our certificate of incorporation as in effect prior to the completion of this offering. The provision for adjustment upon dilutive issuances is an element of the preferred stock into which the warrant is currently exercisable. Upon the completion of this offering, the warrant

 

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will become exercisable for common stock and will no longer be subject to adjustment for dilutive issuances because our common stock is not subject to any provision for adjustment for dilutive issuances. The warrant expires on July 24, 2023. If the warrant has not been exercised prior to July 24, 2023, upon the expiration date the warrant will be deemed to automatically be exercised on a net exercise basis.

Registration Rights

Upon the completion of this offering, the holders of             shares of our common stock, including those issuable upon the conversion of our redeemable convertible preferred stock, are entitled to rights with respect to the registration of these securities under the Securities Act. These rights are provided under the terms of a registration rights agreement between us and certain holders our common stock, Series A redeemable convertible preferred stock, Series B redeemable convertible preferred stock, Series B-2 redeemable convertible preferred stock, Series C redeemable convertible preferred stock and Series D redeemable convertible preferred stock. The registration rights agreement includes demand registration rights, short-form registration rights and piggyback registration rights. All fees, costs and expenses of underwritten registrations under these agreements will be borne by us and all selling expenses, including underwriting discounts and selling commissions, will be borne by the holders of the shares being registered.

Demand Registration Rights

Beginning 180 days after the completion of this offering, the holders of             shares of our common stock are entitled to demand registration rights. Under the terms of the registration rights agreement, we will be required, upon the written request of holders of a majority of these securities, to use our best efforts to file a registration statement and use reasonable, diligent efforts to effect the registration of all or a portion of these shares for public resale. We are required to effect only two registrations pursuant to this provision of the registration rights agreement.

Short-Form Registration Rights

Upon the completion of this offering, the holders of             shares of our common stock, including those issuable upon the conversion of our redeemable convertible preferred stock are also entitled to short form registration rights. Pursuant to the registration rights agreement, if we are eligible to file a registration statement on Form S-3, upon the written request of 10% in interest of these holders to sell registrable securities at an aggregate price of at least $1.0 million, we will be required to use our best efforts to effect a registration of such shares. We are required to effect only two registrations in any twelve month period pursuant to this provision of the registration rights agreement.

Piggyback Registration Rights

Upon the completion of this offering, the holders of             shares of our common stock, including those issuable upon the conversion of our redeemable convertible preferred stock, are entitled to piggyback registration rights. If we register any of our securities either for our own account or for the account of other security holders, the holders of these shares are entitled to include their shares in the registration. Subject to certain exceptions contained in the registration rights agreement, we and the underwriters may limit the number of shares included in the underwritten offering if the underwriters determine in good faith that marketing factors require a limitation of the number of shares to be underwritten.

Indemnification

Our registration rights agreement contains customary cross-indemnification provisions, under which we are obligated to indemnify holders of registrable securities in the event of material misstatements or omissions in the registration statement attributable to us, and they are obligated to indemnify us for material misstatements or

 

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omissions attributable to them.

Expiration of Registration Rights

The demand registration rights and short form registration rights granted under the registration rights agreement will terminate on the seventh anniversary of the completion of this offering.

Anti-Takeover Effects of our Certificate of Incorporation and Bylaws and Delaware Law

Our certificate of incorporation and bylaws include a number of provisions that may have the effect of delaying, deferring or preventing another party from acquiring control of us and encouraging persons considering unsolicited tender offers or other unilateral takeover proposals to negotiate with our board of directors rather than pursue non-negotiated takeover attempts. These provisions include the items described below.

Board Composition and Filling Vacancies

Our certificate of incorporation provides for the division of our board of directors into three classes serving staggered three-year terms, with one class being elected each year. Our certificate of incorporation also provides that directors may be removed only for cause and then only by the affirmative vote of the holders of     % or more of the shares then entitled to vote at an election of directors. Furthermore, any vacancy on our board of directors, however occurring, including a vacancy resulting from an increase in the size of our board, may only be filled by the affirmative vote of a majority of our directors then in office even if less than a quorum. The classification of directors, together with the limitations on removal of directors and treatment of vacancies, has the effect of making it more difficult for stockholders to change the composition of our board of directors.

No Written Consent of Stockholders

Our certificate of incorporation provides that all stockholder actions are required to be taken by a vote of the stockholders at an annual or special meeting, and that stockholders may not take any action by written consent in lieu of a meeting. This limit may lengthen the amount of time required to take stockholder actions and would prevent the amendment of our bylaws or removal of directors by our stockholders without holding a meeting of stockholders.

Meetings of Stockholders

Our certificate of incorporation and bylaws provide that only a majority of the members of our board of directors then in office may call special meetings of stockholders and only those matters set forth in the notice of the special meeting may be considered or acted upon at a special meeting of stockholders. Our bylaws limit the business that may be conducted at an annual meeting of stockholders to those matters properly brought before the meeting.

Advance Notice Requirements

Our bylaws establish advance notice procedures with regard to stockholder proposals relating to the nomination of candidates for election as directors or new business to be brought before meetings of our stockholders. These procedures provide that notice of stockholder proposals must be timely given in writing to our corporate secretary prior to the meeting at which the action is to be taken. Generally, to be timely, notice must be received at our principal executive offices not less than 90 days nor more than 120 days prior to the first anniversary date of the annual meeting for the preceding year. Our bylaws specify the requirements as to form and content of all stockholders’ notices. These requirements may preclude stockholders from bringing matters before the stockholders at an annual or special meeting.

 

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Amendment to Certificate of Incorporation and Bylaws

Any amendment of our certificate of incorporation must first be approved by a majority of our board of directors, and if required by law or our certificate of incorporation, must thereafter be approved by a majority of the outstanding shares entitled to vote on the amendment and a majority of the outstanding shares of each class entitled to vote thereon as a class, except that the amendment of the provisions relating to stockholder action, board composition, limitation of liability and the amendment of our bylaws and certificate of incorporation must be approved by not less than 75% of the outstanding shares entitled to vote on the amendment, and not less than 75% of the outstanding shares of each class entitled to vote thereon as a class. Our bylaws may be amended by the affirmative vote of a majority of the directors then in office, subject to any limitations set forth in the bylaws; and may also be amended by the affirmative vote of at least 75% of the outstanding shares entitled to vote on the amendment, or, if our board of directors recommends that the stockholders approve the amendment, by the affirmative vote of the majority of the outstanding shares entitled to vote on the amendment, in each case voting together as a single class.

Undesignated Preferred Stock

Our certificate of incorporation provides for             authorized shares of preferred stock. The existence of authorized but unissued shares of preferred stock may enable our board of directors to discourage an attempt to obtain control of us by means of a merger, tender offer, proxy contest or otherwise. For example, if in the due exercise of its fiduciary obligations, our board of directors were to determine that a takeover proposal is not in the best interests of our stockholders, our board of directors could cause shares of preferred stock to be issued without stockholder approval in one or more private offerings or other transactions that might dilute the voting or other rights of the proposed acquirer or insurgent stockholder or stockholder group. In this regard, our certificate of incorporation grants our board of directors broad power to establish the rights and preferences of authorized and unissued shares of preferred stock. The issuance of shares of preferred stock could decrease the amount of earnings and assets available for distribution to holders of shares of common stock. The issuance may also adversely affect the rights and powers, including voting rights, of these holders and may have the effect of delaying, deterring or preventing a change in control of us.

Section 203 of the Delaware General Corporation Law

Upon completion of this offering, we will be subject to the provisions of Section 203 of the Delaware General Corporation Law. In general, Section 203 prohibits a publicly held Delaware corporation from engaging in a “business combination” with an “interested stockholder” for a three-year period following the time that this stockholder becomes an interested stockholder, unless the business combination is approved in a prescribed manner. Under Section 203, a business combination between a corporation and an interested stockholder is prohibited unless it satisfies one of the following conditions:

 

•

before the stockholder became interested, our board of directors approved either the business combination or the transaction which resulted in the stockholder becoming an interested stockholder;

 

•

upon consummation of the transaction which resulted in the stockholder becoming an interested stockholder, the interested stockholder owned at least 85% of the voting stock of the corporation outstanding at the time the transaction commenced, excluding for purposes of determining the voting stock outstanding, shares owned by persons who are directors and also officers, and employee stock plans, in some instances, but not the outstanding voting stock owned by the interested stockholder; or

 

•

at or after the time the stockholder became interested, the business combination was approved by our board of directors and authorized at an annual or special meeting of the stockholders by the affirmative vote of at least two-thirds of the outstanding voting stock which is not owned by the interested stockholder.

 

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Section 203 defines a business combination to include:

 

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any merger or consolidation involving the corporation and the interested stockholder;

 

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any sale, transfer, lease, pledge or other disposition involving the interested stockholder of 10% or more of the assets of the corporation;

 

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subject to exceptions, any transaction that results in the issuance or transfer by the corporation of any stock of the corporation to the interested stockholder;

 

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subject to exceptions, any transaction involving the corporation that has the effect of increasing the proportionate share of the stock of any class or series of the corporation beneficially owned by the interested stockholder; and

 

•

the receipt by the interested stockholder of the benefit of any loans, advances, guarantees, pledges or other financial benefits provided by or through the corporation.

In general, Section 203 defines an interested stockholder as any entity or person beneficially owning 15% or more of the outstanding voting stock of the corporation and any entity or person affiliated with or controlling or controlled by the entity or person.

Exchange Listing

We intend to apply to list our common stock on The NASDAQ Global Market under the trading symbol “LIFE.”

Transfer Agent and Registrar

The transfer agent and registrar for our common stock will be             . The transfer agent and registrar’s address is                             .

 

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SHARES ELIGIBLE FOR FUTURE SALE

Prior to this offering, there has been no public market for our shares. Future sales of our common stock in the public market, or the availability of such shares for sale in the public market, could adversely affect market prices prevailing from time to time. As described below, only a limited number of shares will be available for sale shortly after this offering due to contractual and legal restrictions on resale. Nevertheless, sales of our common stock in the public market after such restrictions lapse, or the perception that those sales may occur, could adversely affect the prevailing market price at such time and our ability to raise equity capital in the future.

Based on the number of shares outstanding as of December 31, 2014, upon the completion of this offering,             shares of our common stock will be outstanding, assuming no exercise of the underwriters’ option to purchase additional shares and no exercise of outstanding options or warrants. Of the outstanding shares, all of the shares sold in this offering will be freely tradable, except that any shares held by our affiliates, as that term is defined in Rule 144 under the Securities Act, may only be sold in compliance with the limitations described below.

As a result of the lock-up agreements described below and the provisions of Rule 144 and Rule 701 under the Securities Act, the shares of our common stock (excluding the shares sold in this offering) that will be available for sale in the public market are as follows:

 

Date of Availability of Sale		Approximate Number of Shares
As of the date of this prospectus
90 days after the date of this prospectus
180 days after the date of this prospectus, although a portion of such shares held by our affiliates will be subject to volume limitations pursuant to Rule 144

Rule 144

In general, a person who has beneficially owned restricted stock for at least six months would be entitled to sell their securities provided that (i) such person is not deemed to have been one of our affiliates at the time of, or at any time during the 90 days preceding, a sale and (ii) we are subject to the Exchange Act periodic reporting requirements for at least 90 days before the sale. Persons who have beneficially owned restricted shares for at least six months but who are our affiliates at the time of, or any time during the 90 days preceding, a sale, would be subject to additional restrictions, by which such person would be entitled to sell within any three-month period only a number of securities that does not exceed the greater of either of the following:

 

•

1% of the number of shares then outstanding, which will equal approximately             shares immediately after this offering assuming no exercise of the underwriters’ option to purchase additional shares, based on the number of shares outstanding as of September 30, 2014; or

 

•

the average weekly trading volume of our common stock on The NASDAQ Global Market during the four calendar weeks preceding the filing of a notice on Form 144 with respect to the sale;

provided, in each case, that we are subject to the Exchange Act periodic reporting requirements for at least 90 days before the sale. Such sales both by affiliates and by non-affiliates must also comply with the manner of sale, current public information and notice provisions of Rule 144.

Rule 701

Rule 701 under the Securities Act, as in effect on the date of this prospectus, permits resales of shares in reliance upon Rule 144 but without compliance with certain restrictions of Rule 144, including the holding period requirement. Most of our employees, executive officers or directors who purchased shares under a written

 

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compensatory plan or contract may be entitled to rely on the resale provisions of Rule 701, but all holders of Rule 701 shares are required to wait until 90 days after the date of this prospectus before selling their shares. However, substantially all Rule 701 shares are subject to lock-up agreements as described below and under “Underwriting” included elsewhere in this prospectus and will become eligible for sale upon the expiration of the restrictions set forth in those agreements.

Lock-Up Agreements

All of our directors and executive officers and certain holders of our shares, who collectively hold                                 shares of common stock (including shares of common stock issuable upon the conversion of shares of our redeemable convertible preferred stock), have signed a lock-up agreement which prevents them from selling any of our common stock or any securities convertible into or exercisable or exchangeable for common stock for a period of not less than 180 days from the date of this prospectus without the prior written consent of the representatives, subject to certain exceptions. See “Underwriting.”

Registration Rights

Upon completion of this offering, certain holders of our securities will be entitled to various rights with respect to registration of their shares under the Securities Act. Registration of these shares under the Securities Act would result in these shares becoming fully tradable without restriction under the Securities Act immediately upon the effectiveness of the registration. See “Description of Capital Stock—Registration Rights” for additional information.

Equity Incentive Plans

We intend to file one or more registration statements on Form S-8 under the Securities Act to register our shares issued or reserved for issuance under our equity incentive plans. The first such registration statement is expected to be filed soon after the date of this prospectus and will automatically become effective upon filing with the Securities and Exchange Commission. Accordingly, shares registered under such registration statement will be available for sale in the open market, unless such shares are subject to vesting restrictions with us or the lock-up restrictions described above. As of                     , 2015, we estimate that such registration statement on Form S-8 will cover approximately             shares.

 

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CERTAIN MATERIAL UNITED STATES FEDERAL INCOME TAX

CONSIDERATIONS FOR NON-U.S. HOLDERS

The following is a summary of certain material U.S. federal income tax considerations of the ownership and disposition of our common stock to non-U.S. holders (as defined below). It is not intended to be a complete analysis of all the U.S. federal income tax considerations that may be relevant to non-U.S. holders. This summary is based upon the provisions of the Internal Revenue Code, or the Code, Treasury regulations promulgated thereunder, administrative rulings and judicial decisions, all as of the date hereof. These authorities may be changed, possibly with retroactive effect, which may result in U.S. federal income tax consequences different from those set forth below. We have not sought any ruling from the Internal Revenue Service, or IRS, with respect to the statements made and the conclusions reached in the following summary. There can be no assurance that the IRS will agree with such statements and conclusions or that any contrary position taken by the IRS would not be sustained by a court.

This summary also does not address alternative minimum tax consequences, estate or gift tax consequences, or the tax considerations arising under the laws of any foreign, state or local jurisdiction. In addition, this discussion does not address tax considerations applicable to an investor’s particular circumstances or to investors that may be subject to special tax rules, including, without limitation:

 

•

banks, insurance companies or other financial institutions;

 

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tax-exempt organizations;

 

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an integral part or controlled entity of a foreign sovereign;

 

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dealers in securities or currencies;

 

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traders in securities that elect to use a mark-to-market method of accounting for their securities holdings;

 

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persons that own, or are deemed to own, more than five percent of our capital stock (except to the extent specifically set forth below);

 

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controlled foreign corporations or passive foreign investment companies

 

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certain former citizens or long-term residents of the United States;

 

•

persons who hold our common stock as a position in a hedging transaction, “straddle,” “conversion transaction” or other risk reduction transaction;

 

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persons deemed to sell our common stock under the constructive sale provisions of the Code;

 

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an entity that is treated as a partnership for U.S. federal income tax purposes; or

 

•

persons who hold our common stock other than as a capital asset (generally, an asset held for investment purposes).

If a partnership holds our common stock, the tax treatment of a partner generally will depend on the status of the partner and upon the activities of the partnership. Accordingly, partnerships that hold our common stock, and partners in such partnerships, should consult their tax advisors.

YOU ARE URGED TO CONSULT YOUR TAX ADVISOR WITH RESPECT TO THE APPLICATION OF THE UNITED STATES FEDERAL INCOME TAX LAWS TO YOUR PARTICULAR SITUATION, AS WELL AS ANY TAX CONSEQUENCES OF THE PURCHASE, OWNERSHIP AND DISPOSITION OF OUR COMMON STOCK ARISING UNDER THE UNITED STATES FEDERAL ESTATE OR GIFT TAX RULES OR UNDER THE LAWS OF ANY STATE, LOCAL, FOREIGN OR OTHER TAXING JURISDICTION OR UNDER ANY APPLICABLE TAX TREATY.

 

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Non-U.S. Holder Defined

For purposes of this discussion, a “non-U.S. holder” is a beneficial owner of a share of common stock received that is (i) a foreign corporation, (ii) a nonresident alien individual, or (iii) a foreign trust or a foreign estate that is not subject to United States federal income tax on a net income basis.

Distributions

We have not made any distributions on our common stock and do not plan to make any distributions for the foreseeable future. However, if we do make distributions on our common stock, those payments will constitute dividends for U.S. tax purposes to the extent paid from our current or accumulated earnings and profits, as determined under U.S. federal income tax principles. To the extent those distributions exceed both our current and our accumulated earnings and profits, they will constitute a return of capital and will first reduce your basis in our common stock, but not below zero, and then will be treated as gain from the sale of stock, which will be subject to tax as described in “Gain on Disposition of Common Stock”, below.

Any dividend paid to you generally will be subject to U.S. withholding tax either at a rate of 30% of the gross amount of the dividend or such lower rate as may be specified by an applicable income tax treaty. In order to receive a reduced treaty rate, you must provide us with an IRS Form W-8BEN, IRS Form W-8BEN-E, or other appropriate version of IRS Form W-8 or successor form certifying qualification for the reduced rate.

Dividends received by you that are effectively connected with your conduct of a U.S. trade or business and, if required by an applicable income tax treaty, are attributable to a U.S. permanent establishment, are exempt from such withholding tax. In order to obtain this exemption, you must provide us with an IRS Form W-8ECI or successor form properly certifying such exemption. Such effectively connected dividends, although not subject to withholding tax, are taxed at the same graduated rates applicable to U.S. persons, net of certain deductions and credits. In addition, if you are a corporate non-U.S. holder, dividends you receive that are effectively connected with your conduct of a U.S. trade or business may also be subject to a branch profits tax at a rate of 30% or such lower rate as may be specified by an applicable income tax treaty. Non-U.S. holders are urged to consult their tax advisers regarding their entitlement to benefits under an applicable income tax treaty.

If you are eligible for a reduced rate of withholding tax pursuant to a tax treaty, you may obtain a refund of any excess amounts withheld if you file an appropriate claim for refund with the IRS.

Gain on Disposition of Common Stock

Subject to the discussions below regarding backup withholding and FATCA (as defined below), you generally will not be subject to U.S. federal income tax on any gain realized upon the sale or other disposition of our common stock unless:

 

•

the gain is effectively connected with your conduct of a U.S. trade or business and, if required by an applicable income tax treaty, is attributable to a U.S. permanent establishment;

 

•

you are an individual non-U.S. holder who holds our common stock as a capital asset, you are present in the United States for a period or periods aggregating 183 days or more during the calendar year in which the sale or disposition occurs and certain other conditions are met; or

 

•

our common stock constitutes a U.S. real property interest by reason of our status as a “United States real property holding corporation” for U.S. federal income tax purposes, or USRPHC, at any time within the shorter of the five-year period preceding the disposition or your holding period for our common stock.

If you are a non-U.S. holder described in the first bullet above, you will be required to pay tax on the net gain derived from the sale under regular graduated U.S. federal income tax rates. Corporate non-U.S. holders described in the first bullet above may be subject to the branch profits tax at a 30% rate or such lower rate as may be specified by an applicable income tax treaty. If you are an individual non-U.S. holder described in the second

 

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bullet above, you will be required to pay a flat 30% tax on the gain derived from the sale, which may be offset by U.S.-source capital losses (even though you are not considered a resident of the United States) provided that you have timely filed a federal income tax return with respect to such losses. You should consult any applicable income tax or other treaties, which may provide different rules.

We believe that we are not currently and will not become a USRPHC. However, because the determination of whether we are a USRPHC depends on the fair market value of our U.S. real property relative to the fair market value of our other business assets, there can be no assurance that we will not become a USRPHC in the future. Even if we become a USRPHC, however, as long as our common stock is regularly traded on an established securities market, such common stock will be treated as U.S. real property interests only if you actually or constructively hold more than five percent of such regularly traded common stock at any time during the shorter of the five-year period preceding the disposition or your holding period for our common stock.

Backup Withholding and Information Reporting

Generally, we must report annually to the IRS the amount of dividends paid to you, your name and address, and the amount of tax withheld, if any. A similar report will be sent to you. Pursuant to applicable income tax treaties or other agreements, the IRS may make these reports available to tax authorities in your country of residence.

Payments of dividends or of proceeds on the disposition of stock made to you may be subject to additional information reporting and backup withholding (currently at a rate of 28%) unless you establish an exemption, for example by properly certifying your non-U.S. status on a Form W-8BEN, Form W-8BEN-E, or another appropriate version of IRS Form W-8 or successor form. Notwithstanding the foregoing, backup withholding and information reporting may apply if the applicable withholding agent has actual knowledge, or reason to know, that you are a U.S. person.

Backup withholding is not an additional tax; rather, the U.S. income tax liability of persons subject to backup withholding will be reduced by the amount of tax withheld. If withholding results in an overpayment of taxes, a refund or credit may be obtained, provided that the required information is furnished to the IRS in a timely manner.

FATCA

Legislation known as the Foreign Account Tax Compliance Act and guidance issued thereunder (together, FATCA) imposes withholding taxes on certain types of payments made to “foreign financial institutions” and certain other non-U.S. entities (including financial intermediaries). FATCA imposes a 30% withholding tax on certain payments of dividends, and, for dispositions that occur on or after January 1, 2014, the gross proceeds from such dispositions of our common stock paid to a foreign financial institution or to certain non-financial foreign entities unless certain certification, information reporting and other specified requirements are met or an exemption applies. Prospective investors should consult their tax advisors regarding FATCA.

 

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UNDERWRITING

We are offering the shares of common stock described in this prospectus through a number of underwriters. J.P. Morgan Securities LLC and Deutsche Bank Securities Inc. are acting as joint book-running managers of the offering and as representatives of the underwriters. We have entered into an underwriting agreement with the underwriters. Subject to the terms and conditions of the underwriting agreement, we have agreed to sell to the underwriters, and each underwriter has severally agreed to purchase, at the public offering price less the underwriting discounts and commissions set forth on the cover page of this prospectus, the number of shares of common stock listed next to its name in the following table:

 

Name		Number of Shares
J.P. Morgan Securities LLC
Deutsche Bank Securities Inc.
BMO Capital Markets Corp.
William Blair & Company, L.L.C.
Total

The underwriters are committed to purchase all the common shares offered by us if they purchase any shares. The underwriting agreement also provides that if an underwriter defaults, the purchase commitments of non-defaulting underwriters may also be increased or the offering may be terminated.

The underwriters propose to offer the common shares directly to the public at the initial public offering price set forth on the cover page of this prospectus and to certain dealers at that price less a concession not in excess of $         per share. Any such dealers may resell shares of certain brokers or dealers at a discount of up to $         per share from the initial offering price. After the initial public offering of the shares, the offering price and other selling terms may be changed by the underwriters. Sales of shares made outside of the United States may be made by affiliates of the underwriters.

The underwriters have an option to buy up to             additional shares of common stock from us to cover sales by the underwriters which exceed the number of shares specified in the table above. The underwriters have 30 days from the date of this prospectus to exercise this over-allotment option. If any shares are purchased with this over-allotment option, the underwriters will purchase shares in approximately the same proportion as shown in the table above. If any additional shares of common stock are purchased, the underwriters will offer the additional shares on the same terms as those on which the shares are being offered.

The underwriting fee is equal to the public offering price per share of common stock less the amount paid by the underwriters to us per share of common stock. The underwriting fee is $         per share. The following table shows the per share and total underwriting discounts and commissions to be paid to the underwriters assuming both no exercise and full exercise of the underwriters’ option to purchase additional shares.

 

		Without over-allotment exercise				With full over-allotment exercise
Per share		$				$
Total		$				$

We estimate that the total expenses of this offering, including registration, filing and listing fees, printing fees and legal and accounting expenses, but excluding the underwriting discounts and commissions, will be approximately $         million. We have agreed to reimburse the underwriters for expenses of $         relating to the clearance of this offering with the Financial Industry Regulatory Authority.

A prospectus in electronic format may be made available on the web sites maintained by one or more underwriters or selling group members, if any, participating in the offering. The underwriters may agree to

 

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allocate a number of shares to underwriters and selling group members for sale to their online brokerage account holders. Internet distributions will be allocated by the representatives to underwriters and selling group members that may make Internet distributions on the same basis as other allocations.

We have agreed that we will not (i) offer, pledge, announce the intention to sell, sell, contract to sell, sell any option or contract to purchase, purchase any option or contract to sell, grant any option, right or warrant to purchase or otherwise dispose of, directly or indirectly, or file with the Securities and Exchange Commission, or SEC, a registration statement under the Securities Act of 1933, or Securities Act, relating to, any shares of our common stock or securities convertible into or exchangeable or exercisable for any shares of our common stock, or publicly disclose the intention to make any offer, sale, pledge, disposition or filing, or (ii) enter into any swap or other arrangement that transfers all or a portion of the economic consequences associated with the ownership of any shares of common stock or any such other securities (regardless of whether any of these transactions are to be settled by the delivery of shares of common stock or such other securities, in cash or otherwise), in each case without the prior written consent of J.P. Morgan Securities LLC and Deutsche Bank Securities Inc. for a period of 180 days after the date of this prospectus, other than the shares of our common stock to be sold hereunder and any shares of our common stock issued upon the exercise of options granted under our existing stock-based compensation plans.

Our directors, executive officers and substantially all of our equity holders have entered into lock-up agreements with the underwriters prior to the commencement of this offering pursuant to which each of these persons or entities, with limited exceptions, for a period of 180 days after the date of this prospectus, may not, without the prior written consent of J.P. Morgan Securities LLC and Deutsche Bank Securities Inc., (1) offer, pledge, announce the intention to sell, sell, contract to sell, sell any option or contract to purchase, purchase any option or contract to sell, grant any option, right or warrant to purchase, or otherwise transfer or dispose of, directly or indirectly, any shares of our common stock or any securities convertible into or exercisable or exchangeable for our common stock (including, without limitation, common stock or such other securities which may be deemed to be beneficially owned by such directors, executive officers, managers and members in accordance with the rules and regulations of the SEC and securities which may be issued upon exercise of a stock option or warrant) or (2) enter into any swap or other agreement that transfers, in whole or in part, any of the economic consequences of ownership of the common stock or such other securities, whether any such transaction described in clause (1) or (2) above is to be settled by delivery of common stock or such other securities, in cash or otherwise, or (3) make any demand for or exercise any right with respect to the registration of any shares of our common stock or any security convertible into or exercisable or exchangeable for our common stock.

We have agreed to indemnify the underwriters against certain liabilities, including liabilities under the Securities Act.

We intend to apply to have our common stock approved for listing/quotation on The NASDAQ Global Market under the symbol “LIFE.”

In connection with this offering, the underwriters may engage in stabilizing transactions, which involves making bids for, purchasing and selling shares of common stock in the open market for the purpose of preventing or retarding a decline in the market price of the common stock while this offering is in progress. These stabilizing transactions may include making short sales of the common stock, which involves the sale by the underwriters of a greater number of shares of common stock than they are required to purchase in this offering, and purchasing shares of common stock on the open market to cover positions created by short sales. Short sales may be “covered” shorts, which are short positions in an amount not greater than the underwriters’ over-allotment option referred to above, or may be “naked” shorts, which are short positions in excess of that amount. The underwriters may close out any covered short position either by exercising their over-allotment option, in whole or in part, or by purchasing shares in the open market. In making this determination, the underwriters will consider, among other things, the price of shares available for purchase in the open market compared to the price at which the underwriters may purchase shares through the over-allotment option. A naked short position is more likely to be created if the underwriters are concerned that there may be downward pressure on the price of the common stock

 

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in the open market that could adversely affect investors who purchase in this offering. To the extent that the underwriters create a naked short position, they will purchase shares in the open market to cover the position.

The underwriters have advised us that, pursuant to Regulation M of the Securities Act of 1933, they may also engage in other activities that stabilize, maintain or otherwise affect the price of the common stock, including the imposition of penalty bids. This means that if the representatives of the underwriters purchase common stock in the open market in stabilizing transactions or to cover short sales, the representatives can require the underwriters that sold those shares as part of this offering to repay the underwriting discount received by them.

These activities may have the effect of raising or maintaining the market price of the common stock or preventing or retarding a decline in the market price of the common stock, and, as a result, the price of the common stock may be higher than the price that otherwise might exist in the open market. If the underwriters commence these activities, they may discontinue them at any time. The underwriters may carry out these transactions on The NASDAQ Global Market, in the over-the-counter market or otherwise.

Prior to this offering, there has been no public market for our common stock. The initial public offering price will be determined by negotiations between us and the representatives of the underwriters. In determining the initial public offering price, we and the representatives of the underwriters expect to consider a number of factors including:

 

•

the information set forth in this prospectus and otherwise available to the representatives;

 

•

our prospects and the history and prospects for the industry in which we compete;

 

•

an assessment of our management;

 

•

our prospects for future earnings;

 

•

the general condition of the securities markets at the time of this offering;

 

•

the recent market prices of, and demand for, publicly traded common stock of generally comparable companies; and

 

•

other factors deemed relevant by the underwriters and us.

Neither we nor the underwriters can assure investors that an active trading market will develop for our common shares, or that the shares will trade in the public market at or above the initial public offering price.

Certain of the underwriters and their affiliates have provided in the past to us and our affiliates and may provide from time to time in the future certain commercial banking, financial advisory, investment banking and other services for us and such affiliates in the ordinary course of their business, for which they have received and may continue to receive customary fees and commissions. In addition, from time to time, certain of the underwriters and their affiliates may effect transactions for their own account or the account of customers, and hold on behalf of themselves or their customers, long or short positions in our debt or equity securities or loans, and may do so in the future.

Selling Restrictions

General

Other than in the United States, no action has been taken by us or the underwriters that would permit a public offering of the securities offered by this prospectus in any jurisdiction where action for that purpose is required. The securities offered by this prospectus may not be offered or sold, directly or indirectly, nor may this prospectus or any other offering material or advertisements in connection with the offer and sale of any such securities be distributed or published in any jurisdiction, except under circumstances that will result in compliance with the applicable rules and regulations of that jurisdiction. Persons into whose possession this prospectus comes are advised to inform themselves about and to observe any restrictions relating to the offering

 

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and the distribution of this prospectus. This prospectus does not constitute an offer to sell or a solicitation of an offer to buy any securities offered by this prospectus in any jurisdiction in which such an offer or a solicitation is unlawful.

United Kingdom

This document is only being distributed to and is only directed at (i) persons who are outside the United Kingdom or (ii) to investment professionals falling within Article 19(5) of the Financial Services and Markets Act 2000 (Financial Promotion) Order 2005 (the “Order”) or (iii) high net worth entities, and other persons to whom it may lawfully be communicated, falling with Article 49(2)(a) to (d) of the Order (all such persons together being referred to as “relevant persons”). The securities are only available to, and any invitation, offer or agreement to subscribe, purchase or otherwise acquire such securities will be engaged in only with, relevant persons. Any person who is not a relevant person should not act or rely on this document or any of its contents.

European Economic Area

In relation to each Member State of the European Economic Area which has implemented the Prospectus Directive (each, a “Relevant Member State”), from and including the date on which the E.U. Prospectus Directive (as defined below) was implemented in that Relevant Member State (the “Relevant Implementation Date”) an offer of securities described in this prospectus may not be made to the public in that Relevant Member State prior to the publication of a prospectus in relation to the shares which has been approved by the competent authority in that Relevant Member State or, where appropriate, approved in another Relevant Member State and notified to the competent authority in that Relevant Member State, all in accordance with the E.U. Prospectus Directive, except that, with effect from and including the Relevant Implementation Date, an offer of securities described in this prospectus may be made to the public in that Relevant Member State at any time:

 

•

to any legal entity which is a qualified investor as defined under the E.U. Prospectus Directive;

 

•

to fewer than 100 or, if the Relevant Member State has implemented the relevant provision of the 2010 PD Amending Directive, 150 natural or legal persons (other than qualified investors as defined in the E.U. Prospectus Directive); or

 

•

in any other circumstances falling within Article 3(2) of the E.U. Prospectus Directive, provided that no such offer of securities described in this prospectus shall result in a requirement for the publication by us of a prospectus pursuant to Article 3 of the E.U. Prospectus Directive.

For the purposes of this provision, the expression an “offer of securities to the public” in relation to any securities in any Relevant Member State means the communication in any form and by any means of sufficient information on the terms of the offer and the securities to be offered so as to enable an investor to decide to purchase or subscribe for the securities, as the same may be varied in that Member State by any measure implementing the E.U. Prospectus Directive in that Member State. The expression “E.U. Prospectus Directive” means Directive 2003/71/EC (and any amendments thereto, including the 2010 PD Amending Directive, to the extent implemented in the Relevant Member State) and includes any relevant implementing measure in each Relevant Member State, and the expression “2010 PD Amending Directive” means Directive 2010/73/EU.

Switzerland

The shares may not be publicly offered in Switzerland and will not be listed on the SIX Swiss Exchange, or the SIX, or on any other stock exchange or regulated trading facility in Switzerland. This document has been prepared without regard to the disclosure standards for issuance prospectuses under art. 652a or art. 1156 of the Swiss Code of Obligations or the disclosure standards for listing prospectuses under art. 27 ff. of the SIX Listing Rules or the listing rules of any other stock exchange or regulated trading facility in Switzerland. Neither this prospectus nor any other offering or marketing material relating to the shares or the offering may be publicly distributed or otherwise made publicly available in Switzerland.

 

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Neither this prospectus nor any other offering or marketing material relating to the offering, the Company, or the shares have been or will be filed with or approved by any Swiss regulatory authority. In particular, this document will not be filed with, and the offer of shares will not be supervised by, the Swiss Financial Market Supervisory Authority FINMA, and the offer of shares has not been and will not be authorized under the Swiss Federal Act on Collective Investment Schemes, or the CISA. The investor protection afforded to acquirers of interests in collective investment schemes under the CISA does not extend to acquirers of shares.

Hong Kong

The shares have not been offered or sold and will not be offered or sold in Hong Kong, by means of any document, other than (a) to “professional investors” as defined in the Securities and Futures Ordinance (Cap. 571) of Hong Kong and any rules made under that Ordinance; or (b) in other circumstances which do not result in the document being a “prospectus” as defined in the Companies Ordinance (Cap. 32) of Hong Kong or which do not constitute an offer to the public within the meaning of that Ordinance. No advertisement, invitation or document relating to the shares has been or may be issued or has been or may be in the possession of any person for the purposes of issue, whether in Hong Kong or elsewhere, which is directed at, or the contents of which are likely to be accessed or read by, the public of Hong Kong (except if permitted to do so under the securities laws of Hong Kong) other than with respect to shares which are or are intended to be disposed of only to persons outside Hong Kong or only to “professional investors” as defined in the Securities and Futures Ordinance and any rules made thereunder.

Singapore

This prospectus has not been registered as a prospectus with the Monetary Authority of Singapore. Accordingly, this prospectus and any other document or material in connection with the offer or sale or invitation for subscription or purchase, of shares may not be circulated or distributed, nor may the shares be offered or sold or be made the subject of an invitation for subscription or purchase, whether directly or indirectly, to persons in Singapore other than (i) to an institutional investor under Section 274 of the Securities and Futures Act, Chapter 289 of Singapore, or SFA, (ii) to a relevant person pursuant to Section 275(1), or any person pursuant to Section 275(1A), and in accordance with the conditions specified in Section 275, of the SFA, or (iii) otherwise pursuant to, and in accordance with the conditions of, any other applicable provision of the SFA.

Where the shares are subscribed or purchased under Section 275 of the SFA by a relevant person which is: (a) a corporation (which is not an accredited investor (as defined in Section 4A of the SFA)) the sole business of which is to hold investments and the entire share capital of which is owned by one or more individuals, each of whom is an accredited investor; or (b) a trust (where the trustee is not an accredited investor) whose sole purpose is to hold investments and each beneficiary of the trust is an individual who is an accredited investor, securities (as defined in Section 239(1) of the SFA) of that corporation or the beneficiaries’ rights and interest (howsoever described) in that trust shall not be transferred within six months after that corporation or that trust has acquired the shares pursuant to an offer made under Section 275 of the SFA except: (1) to an institutional investor or to a relevant person defined in Section 275(2) of the SFA, or to any person arising from an offer referred to in Section 275(1A) or Section 276(4)(i)(B) of the SFA; (2) where no consideration is or will be given for the transfer; (3) where the transfer is by operation of law; (4) as specified in Section 276(7) of the SFA; or (5) as specified in Regulation 32 of the Securities and Futures (Offers of Investments) (Shares and Debentures) Regulations 2005 of Singapore.

Japan

The shares have not been and will not be registered under the Financial Instruments and Exchange Law of Japan (Law No. 25 of 1948, as amended) and, accordingly, will not be offered or sold, directly or indirectly, in Japan, or for the benefit of any Japanese Person or to others for re-offering or resale, directly or indirectly, in Japan or to any Japanese Person, except in compliance with all applicable laws, regulations and ministerial

 

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guidelines promulgated by relevant Japanese governmental or regulatory authorities in effect at the relevant time. For the purposes of this paragraph, “Japanese Person” shall mean any person resident in Japan, including any corporation or other entity organized under the laws of Japan.

Notice to Prospective Investors in Qatar

The shares described in this prospectus have not been, and will not be, offered, sold or delivered, at any time, directly or indirectly in the State of Qatar in a manner that would constitute a public offering. This prospectus has not been, and will not be, registered with or approved by the Qatar Financial Markets Authority or Qatar Central Bank and may not be publicly distributed. This prospectus is intended for the original recipient only and must not be provided to any other person. It is not for general circulation in the State of Qatar and may not be reproduced or used for any other purpose.

Notice to Prospective Investors in Saudi Arabia

No offering, whether directly or indirectly, will be made to an investor in the Kingdom of Saudi Arabia unless such offering is in accordance with the applicable laws of the Kingdom of Saudi Arabia and the rules and regulations of the Capital Market Authority, including the Capital Market Law of the Kingdom of Saudi Arabia. The shares will not be marketed or sold in the Kingdom of Saudi Arabia by us or the underwriters.

This prospectus may not be distributed in the Kingdom of Saudi Arabia except to such persons as are permitted under the Office of Securities Regulation issued by the Capital Market Authority. The Saudi Arabian Capital Market Authority does not make any representation as to the accuracy or completeness of this prospectus and expressly disclaims any liability whatsoever for any loss arising from, or incurred in reliance upon, any part of this prospectus. Prospective purchasers of the shares offered hereby should conduct their own due diligence on the accuracy of the information relating to the shares. If you do not understand the contents of this prospectus, you should consult an authorized financial advisor.

Notice to Prospective Investors in the United Arab Emirates

This offering has not been approved or licensed by the Central Bank of the United Arab Emirates (UAE), Securities and Commodities Authority of the UAE or any other relevant licensing authority in the UAE including any licensing authority incorporated under the laws and regulations of any of the free zones established and operating in the territory of the UAE, in particular the Dubai Financial Services Authority (DFSA), a regulatory authority of the Dubai International Financial Centre (DIFC). The offering does not constitute a public offer of securities in the UAE, DIFC or any other free zone in accordance with the Commercial Companies Law, Federal Law No. 8 of 1984 (as amended), DFSA Offered Securities Rules and NASDAQ Dubai Listing Rules, accordingly, or otherwise. The shares may not be offered to the public in the UAE or any of the free zones.

The shares may be offered and issued only to a limited number of investors in the UAE or any of its free zones who qualify as sophisticated investors under the relevant laws and regulations of the UAE or the free zone concerned.

 

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LEGAL MATTERS

The validity of the shares of common stock offered by this prospectus will be passed upon for us by Goodwin Procter LLP, San Francisco, California. Certain legal matters will be passed upon for the underwriters by Davis Polk & Wardwell LLP, Menlo Park, California.

EXPERTS

Ernst & Young LLP, independent registered public accounting firm, has audited our consolidated financial statements at December 31, 2012 and 2013 and for each of the two years in the period ended December 31, 2013, as set forth in their report. We have included our financial statements in the prospectus and elsewhere in the registration statement in reliance on Ernst & Young LLP’s report, given on their authority as experts in accounting and auditing.

WHERE YOU CAN FIND MORE INFORMATION

We have filed with the Securities and Exchange Commission, or SEC, a registration statement on Form S-1 (File Number 333-             ) under the Securities Act of 1933, or the Securities Act, with respect to the common stock we are offering by this prospectus. This prospectus does not contain all of the information included in the registration statement. For further information pertaining to us and our common stock, you should refer to the registration statement and to its exhibits. Whenever we make reference in this prospectus to any of our contracts, agreements or other documents, the references are not necessarily complete, and you should refer to the exhibits attached to the registration statement for copies of the actual contract, agreement or other document.

Upon the completion of the offering, we will be subject to the informational requirements of the Securities Exchange Act of 1934, or the Exchange Act, and will file annual, quarterly and current reports, proxy statements and other information with the SEC. You can read our SEC filings, including the registration statement, over the Internet at the SEC’s website at www.sec.gov. You may also read and copy any document we file with the SEC at its public reference facility at 100 F Street, N.E., Room 1580, Washington, D.C. 20549. We also maintain a website at www.atyrpharma.com. Upon completion of the offering, you may access, free of charge, our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendment to those reported filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after such material is electronically filed with, or furnished to, the SEC.

You may also obtain copies of the documents at prescribed rates by writing to the Public Reference Section of the SEC at 100 F Street, N.E., Washington, D.C. 20549. Please call the SEC at 1-800-SEC-0330 for further information on the operation of the public reference facilities.

 

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aTyr Pharma, Inc.

Index to Consolidated Financial Statements

 

		Page
Report of Independent Registered Public Accounting Firm			F-2
Consolidated Balance Sheets			F-3
Consolidated Statements of Operations			F-4
Consolidated Statements of  Redeemable Convertible Preferred Stock and Stockholders’ Equity (Deficit)			F-5
Consolidated Statements of Cash Flows			F-6
Notes to Consolidated Financial Statements			F-7

 

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Report of Independent Registered Public Accounting Firm

The Board of Directors and Stockholders of

aTyr Pharma, Inc.

We have audited the accompanying consolidated balance sheets of aTyr Pharma, Inc. as of December 31, 2012 and 2013, and the related consolidated statements of operations, redeemable convertible preferred stock and stockholders’ equity (deficit), and cash flows for the years then ended. These financial statements are the responsibility of the Company’s management. Our responsibility is to express an opinion on these financial statements based on our audits.

We conducted our audits in accordance with the standards of the Public Company Accounting Oversight Board (United States). Those standards require that we plan and perform the audit to obtain reasonable assurance about whether the financial statements are free of material misstatement. We were not engaged to perform an audit of the Company’s internal control over financial reporting. Our audits included consideration of internal control over financial reporting as a basis for designing audit procedures that are appropriate in the circumstances, but not for the purpose of expressing an opinion on the effectiveness of the Company’s internal control over financial reporting. Accordingly, we express no such opinion. An audit also includes examining, on a test basis, evidence supporting the amounts and disclosures in the financial statements, assessing the accounting principles used and significant estimates made by management, and evaluating the overall financial statement presentation. We believe that our audits provide a reasonable basis for our opinion.

In our opinion, the financial statements referred to above present fairly, in all material respects, the consolidated financial position of aTyr Pharma, Inc. at December 31, 2012 and 2013, and the consolidated results of its operations and its cash flows for the years then ended, in conformity with U.S. generally accepted accounting principles.

/s/ Ernst & Young LLP

San Diego, California

December 18, 2014

 

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aTyr Pharma, Inc.

Consolidated Balance Sheets

(in thousands, except share and per share data)

 

														Pro Forma September 30, 2014
		December 31,								September  30, 2014
		2012				2013
Assets											(unaudited)				(unaudited)
Current assets:
Cash and cash equivalents		$	3,675			$	36,457			$	18,735
Investment securities			-				-				4,718
Prepaid expenses and other assets			816				564				571
Total current assets			4,491				37,021				24,024
Property and equipment, net			2,575				2,505				2,134
Other assets			331				260				597
Total assets		$	7,397			$	39,786			$	26,755
Liabilities, Redeemable Convertible Preferred Stock and Stockholders’ Equity (Deficit)
Current liabilities:
Accounts payable		$	593			$	1,055			$	1,230
Accrued expenses			1,808				2,941				3,182
Current portion of deferred rent			255				276				290
Current portion of commercial bank debt			833				728				3,080
Current portion of convertible promissory note			-				-				2,000
Preferred stock warrant liabilities			42				207				568			$	-
Total current liabilities			3,531				5,207				10,350
Deferred rent, net of current portion			1,016				741				521
Commercial bank debt, net of current portion			1,667				4,158				5,947
Convertible promissory note			2,000				2,000				-
Other long-term liabilities			512				597				306
Commitments and contingencies (Note 6)
Redeemable convertible preferred stock, $0.001 par value; authorized shares - 57,983,583 at December 31, 2012 and 75,772,871 at December 31, 2013 and September 30, 2014 (unaudited); issued and outstanding shares - 55,211,585 at December 31, 2012 and 73,487,415 at December 31, 2013 and September 30, 2014 (unaudited); liquidation preference of $95,619 at December 31, 2013 and September 30, 2014 (unaudited); no shares issued and outstanding, pro forma (unaudited)			63,225				93,165				93,581				-
Stockholders’ equity (deficit):
Common stock, $0.001 par value; authorized shares - 73,258,133 at December 31, 2012 and 94,000,000 at December 31, 2013 and September 30, 2014 (unaudited); issued and outstanding - 6,275,574 shares, 6,813,699 shares and 7,237,571 shares at December 31, 2012 and 2013 and September 30, 2014 (unaudited), respectively; 80,724,986 shares issued and outstanding, pro forma (unaudited)			6				7				7				81
Additional paid-in capital			-				17,367				17,782				111,857
Stockholder note receivable			(69)				(69)				(69)				(69)
Accumulated deficit			(64,516)				(85,801)				(104,113)				(104,113)
Total stockholders’ equity (deficit) of aTyr Pharma, Inc.			(64,579)				(68,496)				(86,393)				7,756
Noncontrolling interest			25				2,414				2,443				2,443
Total stockholders’ equity (deficit)			(64,554)				(66,082)				(83,950)			$	10,199
Total liabilities, redeemable convertible preferred stock and stockholders’ equity (deficit)		$	7,397			$	39,786			$	26,755

See accompanying notes.

 

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aTyr Pharma, Inc.

Consolidated Statements of Operations

(in thousands, except share and per share data)

 

		Years Ended December 31,								Nine Months Ended September 30,
		2012				2013				2013				2014
										(unaudited)
Operating expenses:
Research and development		$	7,745			$	13,832			$	9,723			$	12,436
General and administrative			4,854				5,710				4,512				5,088
Total operating expenses			12,599				19,542				14,235				17,524
Loss from operations			(12,599)				(19,542)				(14,235)				(17,524)
Other income (expense):
Interest expense, net			(272)				(444)				(317)				(575)
Change in fair value of warrant liabilities			11				(28)				(27)				(213)
Total other income (expense)			(261)				(472)				(344)				(788)
Net loss			(12,860)				(20,014)				(14,579)				(18,312)
Accretion to redemption value of redeemable convertible preferred stock			(4,748)				(1,637)				(1,499)				(416)
Net loss attributable to common stockholders		$	(17,608)			$	(21,651)			$	(16,078)			$	(18,728)
Net loss per share attributable to common stockholders, basic and diluted		$	(3.19)			$	(3.57)			$	(2.68)			$	(2.86)
Weighted average shares outstanding, basic and diluted			5,518,629				6,067,342				6,004,837				6,554,969
Pro forma net loss per share attributable to common stockholders, basic and diluted (unaudited)						$	(0.27)							$	(0.23)
Pro forma weighted average shares outstanding, basic and diluted (unaudited)							74,382,326								80,042,384

See accompanying notes.

 

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aTyr Pharma, Inc.

Consolidated Statements of Redeemable Convertible Preferred Stock and Stockholders’ Equity (Deficit)

(in thousands, except share data)

 

		Redeemable Convertible Preferred Stock								Common Stock								Additional Paid-in Capital				Stockholder Note Receivable				Accumulated Deficit				Non- Controlling Interest				Total Stockholders’ Equity (Deficit)
		Shares				Amount				Shares				Amount
Balance at December 31, 2011			55,211,585			$	58,477				6,243,559			$	6			$	-			$	(69)			$	(47,067)			$	-			$	(47,130)
Exercise of common stock options			-				-				32,015				-				3				-				-				1				4
Equity activity of Affiliates			-				-				-				-				-				-				-				24				24
Vested shares related to repurchase liability			-				-				-				-				14				-				-				-				14
Stock-based compensation			-				-				-				-				142				-				-				-				142
Accretion to redemption value of redeemable convertible preferred stock			-				4,748				-				-				(159)				-				(4,589)				-				(4,748)
Net loss			-				-				-				-				-								(12,860)				-				(12,860)
Balance at December 31, 2012			55,211,585				63,225				6,275,574				6				-				(69)				(64,516)				25				(64,554)
Issuance of Series D redeemable convertible preferred stock for cash			14,504,841				36,683				-				-				-				-				-				2,431				2,431
Issuance of Series D redeemable convertible preferred stock for conversion of debt and accrued interest			3,770,989				9,537				-				-				-				-				-				-				-
Series D redeemable convertible preferred stock issuance costs			-				(389)				-				-				-				-				-				(65)				(65)
Exercise of common stock options			-				-				538,125				1				53				-				-				23				77
Vested shares related to repurchase liability, net			-				-				-				-				(3)				-				-				-				(3)
Stock-based compensation			-				-				-				-				155				-				-				-				155
Accretion to redemption value of redeemable convertible preferred stock			-				1,637				-				-				(366)				-				(1,271)				-				(1,637)
Capital contribution related to reversal of historical accretion of redeemable convertible preferred stock			-				(17,528)				-				-				17,528				-				-				-				17,528
Net loss			-				-				-				-				-				-				(20,014)				-				(20,014)
Balance at December 31, 2013			73,487,415				93,165				6,813,699				7				17,367				(69)				(85,801)				2,414				(66,082)
Exercise of common stock options (unaudited)			-				-				423,872				-				43				-				-				29				72
Vested shares related to repurchase liability (unaudited)			-				-				-				-				3				-				-				-				3
Stock-based compensation (unaudited)			-				-				-				-				785				-				-				-				785
Accretion to redemption value of redeemable convertible preferred stock (unaudited)			-				416				-				-				(416)				-				-				-				(416)
Net loss (unaudited)			-				-				-				-				-				-				(18,312)				-				(18,312)
Balance at September 30, 2014 (unaudited)			73,487,415			$	93,581				7,237,571			$	7			$	17,782			$	(69)			$	(104,113)			$	2,443			$	(83,950)

See accompanying notes.

 

F-5

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Table of Contents

aTyr Pharma, Inc.

Consolidated Statements of Cash Flows

(in thousands)

 

		Years Ended December 31,								Nine Months Ended September 30,
		2012				2013				2013				2014
Cash flows from operating activities											(unaudited)
Net loss		$	(12,860)			$	(20,014)			$	(14,579)			$	(18,312)
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation and amortization			540				714				521				620
Stock-based compensation			166				155				85				785
Amortization of debt discount			10				211				143				295
Change in fair value of preferred stock warrant liability			(11)				28				27				213
Amortization of investment premium (discount)			-				-				-				29
Deferred rent			(10)				(254)				(189)				(206)
Changes in assets and liabilities:
Prepaid expenses and other assets			37				323				441				(348)
Accounts payable and accrued expenses			750				1,526				551				(99)
Net cash used in operating activities			(11,378)				(17,311)				(13,000)				(17,023)
Cash flows from investing activities
Purchase of property and equipment			(598)				(644)				(348)				(249)
Purchases of investment securities			-				-				-				(5,397)
Maturities of investment securities			-				-				-				650
Net cash used in investing activities			(598)				(644)				(348)				(4,996)
Cash flows from financing activities
Issuance of preferred stock for cash, net of issuance costs			-				38,660				38,660				-
Proceeds from stock option exercises			4				77				73				72
Proceeds from commercial bank debt			2,500				5,000				5,000				5,000
Repayment of commercial bank debt			(846)				(2,500)				(2,500)				(779)
Proceeds from convertible debt			-				10,000				10,000				-
Repayment of convertible debt			-				(500)				(500)				-
Costs paid in connection with initial public offering			-				-				-				4
Net cash provided by financing activities			1,658				50,737				50,733				4,297
Net (decrease) increase in cash and cash equivalents			(10,318)				32,782				37,385				(17,722)
Cash at beginning of period			13,993				3,675				3,675				36,457
Cash at end of period		$	3,675			$	36,457			$	41,060			$	18,735
Supplemental disclosure of cash flow information
Interest paid		$	69			$	254			$	184			$	289
Supplemental schedule of noncash investing and financing activities
Issuance of warrants in connection with long-term debt		$	-			$	137			$	137			$	148
Capitalized tenant improvements paid directly by landlord		$	1,668			$	-			$	-			$	-
Change in unvested share liability		$	14			$	(3)			$	(4)			$	3
Capital contribution related to reversal of historical accretion of redeemable convertible preferred stock		$	-			$	17,528			$	17,528			$	-
Conversion of convertible debt and accrued interest		$	-			$	9,537			$	9,537			$	-

See accompanying notes.

 

F-6

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

1. Organization, Business and Basis of Presentation

Organization and Business

aTyr Pharma, Inc. (the Company) was incorporated in the state of Delaware on September 8, 2005. The Company is focused on the discovery and clinical development of innovative medicines for patients suffering from severe rare diseases.

Principles of Consolidation

The consolidated financial statements include the accounts of aTyr Pharma, Inc., its 98% majority-owned subsidiary in Hong Kong, Pangu BioPharma Limited (Pangu BioPharma), and six variable interest entities (Affiliates), in which aTyr Pharma, Inc. is considered to be the primary beneficiary (see Note 3). All intercompany transactions and balances are eliminated in consolidation.

Liquidity

The Company has a limited operating history and the revenue and income potential of the Company’s business and market are unproven. The Company has experienced net losses and negative cash flows from operating activities since its inception. The Company expects to continue to incur net losses and negative cash flows from operating activities into the foreseeable future. Successful transition to attaining profitable operations is dependent upon achieving a level of revenues adequate to support the Company’s cost structure.

The Company plans to continue to fund its losses from operations and capital funding needs through public or private equity or debt financings or other sources. If the Company is not able to secure adequate additional funding, the Company may be forced to make reductions in spending, extend payment terms with suppliers, liquidate assets where possible, or suspend or curtail planned programs. Any of these actions could materially harm the Company’s business, results of operations and future prospects.

The Company believes that its existing cash, cash equivalents and investments as of September 30, 2014 will be sufficient to meet its anticipated cash requirements through approximately September 2015.

Use of Estimates

The Company’s consolidated financial statements are prepared in accordance with accounting principles generally accepted in the United States (GAAP). The preparation of the Company’s consolidated financial statements requires it to make estimates and assumptions that impact the reported amounts of assets, liabilities and expenses and the disclosure of contingent assets and liabilities in the Company’s consolidated financial statements and accompanying notes. The most significant estimates in the Company’s consolidated financial statements relate to the fair value of equity awards and research and development expense accruals. Although these estimates are based on the Company’s knowledge of current events and actions it may undertake in the future, actual results may ultimately materially differ from these estimates and assumptions.

Unaudited Interim Financial Information

The accompanying interim consolidated balance sheet as of September 30, 2014 and the consolidated statements of operations and consolidated cash flows for the nine months ended September 30, 2013 and 2014 and the statements of redeemable convertible preferred stock and stockholders’ equity (deficit) for the nine months ended September 30, 2014 and the related consolidated footnote disclosures are unaudited. These

 

F-7

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

unaudited interim consolidated financial statements have been prepared in accordance with GAAP. In management’s opinion, the unaudited interim consolidated financial statements have been prepared on the same basis as the audited consolidated financial statements and include all adjustments, which include only normal recurring adjustments, necessary for the fair presentation of the Company’s consolidated financial position as of September 30, 2014 and its consolidated results of operations and its consolidated cash flows for the nine months ended September 30, 2013 and 2014. The results for the nine months ended September 30, 2014 are not necessarily indicative of the results expected for the full fiscal year or any other interim period.

Unaudited Pro Forma Balance Sheet Information

The unaudited pro forma balance sheet information as of September 30, 2014 assumes the conversion of all outstanding shares of redeemable convertible preferred stock into 73,487,415 shares of the Company’s common stock and the related reclassification of the carrying value of the redeemable convertible preferred stock and warrant liabilities to additional paid-in capital upon completion of the Company’s initial public offering (IPO). Shares of common stock issued in such IPO and any related net proceeds are excluded from the pro forma information.

Segment Reporting

Operating segments are identified as components of an enterprise about which separate discrete financial information is available for evaluation by the chief operating decision-maker in making decisions regarding resource allocation and assessing performance. The Company views its operations and manages its business in one operating segment.

2. Summary of Significant Accounting Policies

Cash and Cash Equivalents

Cash and cash equivalents consists primarily of readily available checking, money market accounts and money market funds. The Company considers all highly liquid investments that have maturities of three months or less when purchased to be cash equivalents.

Investment Securities

Investment securities primarily consist of investment grade corporate debt securities and commercial paper. The Company classifies all investment securities as available-for-sale and as current assets, as the sale of such securities may be required prior to maturity to execute management strategies. Investment securities are carried at fair value, with the unrealized gains and losses, if any, reported as a component of other comprehensive income (loss) in stockholders’ equity (deficit) until realized. Realized gains and losses from the sale of investment securities, if any, are determined on a specific identification basis. A decline in the market value of any investment security below cost that is determined to be other than temporary will result in an impairment charge to earnings and a new cost basis for the security is established. No such impairment charges were recorded for any period presented. Premiums and discounts are amortized or accreted over the life of the related security as an adjustment to yield using the straight-line method and are included in interest income. Interest income is recognized when earned. As of December 31, 2013 the Company had no investment securities. As of September 30, 2014, the Company held $2.6 million of corporate debt securities and $2.1 million of commercial paper, all of which mature in less than six months, and there was no difference between the amortized cost and fair value of these investment securities.

 

F-8

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

Concentration of Credit Risk

Financial instruments that potentially subject the Company to significant concentration of credit risk consist primarily of cash, cash equivalents and investment securities. The Company has established guidelines regarding diversification of investments and their maturities, which are designed to maintain principal and maximize liquidity. The Company maintains deposits in federally insured financial institutions in excess of federally insured limits. The Company has not experienced any losses in such accounts and management believes that the Company is not exposed to significant credit risk due to the financial position of the depository institutions in which those deposits are held.

Property and Equipment

Property and equipment are stated at cost and depreciated on a straight-line basis over the estimated useful life of the related assets (generally three to seven years). Leasehold improvements are stated at cost and amortized on a straight-line basis over the lesser of the remaining term of the related lease or the estimated useful life of the leasehold improvements. Repairs and maintenance costs are charged to expense as incurred.

Impairment of Long-Lived Assets

Long-lived assets consist primarily of property and equipment. An impairment loss is recorded if and when events and circumstances indicate that assets might be impaired and the undiscounted cash flows estimated to be generated by those assets are less than the carrying amount of those assets. While the Company’s current and historical operating losses and negative cash flows from operations are indicators of impairment, management believes that future cash flows to be received support the carrying value of its long-lived assets and, accordingly, has not recognized any impairment losses since inception.

Accrued Expenses

As part of the process of preparing its consolidated financial statements, the Company is required to estimate its accrued expenses, including accrued research and development expenses for fees paid to investigative sites and CROs in connection with clinical trials; service providers in connection with preclinical development activities; service providers related to product manufacturing; and other professional services. The accrual process involves reviewing open contracts and purchase orders, communicating with its personnel to identify services that have been performed on its behalf and estimating the level of service performed and the associated cost incurred for the service when the Company has not yet been invoiced or otherwise notified of the actual cost. The Company makes estimates of its accrued expenses as of each balance sheet date in its consolidated financial statements based on facts and circumstances known to it at that time. Although the Company does not expect its estimates to be materially different from amounts actually incurred, if its estimates of the status and timing of services performed differs from the actual status and timing of services performed, it may report amounts that are too high or too low in any particular period.

Deferred Rent

Rent expense, including the value of tenant improvement allowances received, is recorded on a straight-line basis over the term of the lease. The difference between rent expense and amounts paid under the lease agreements is recorded as deferred rent in in the accompanying consolidated balance sheets.

 

F-9

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

Preferred Stock Warrant Liabilities

The Company has issued freestanding warrants to purchase shares of its Series B, Series C and Series D redeemable convertible preferred stock. Since the underlying redeemable convertible preferred stock is classified outside of permanent equity, these warrants are classified as liabilities in the accompanying consolidated balance sheets. The Company adjusts the carrying value of such warrants to their estimated fair value at each reporting date, with any related increase or decrease in the fair value recorded as an increase or decrease to other income (expense) in the consolidated statements of operations. The warrant liabilities will continue to be adjusted to fair value until such time as the warrants are no longer outstanding or the underlying securities are no longer redeemable outside the control of the Company, including at the completion of the IPO.

Research and Development Costs

Research and development costs are expensed as incurred. Research and development costs include: salaries and employee-related expenses, including stock-based compensation and benefits for personnel in research and product development functions; costs associated with conducting our preclinical, development and regulatory activities, including fees paid to third-party professional consultants, service providers and our scientific, therapeutic and clinical advisory board; costs to acquire, develop and manufacture preclinical study and clinical trial materials; costs incurred under clinical trial agreements with clinical research organizations and investigative sites; costs for laboratory supplies; payments related to licensed products and technologies; allocated facilities and information technology costs; and depreciation.

Patent Costs

Costs related to filing and pursuing patent applications are recorded as general and administrative expense and expensed as incurred since recoverability of such expenditures is uncertain.

Stock-Based Compensation

Stock-based compensation expense represents the cost of the grant date fair value of employee stock option grants recognized over the requisite service period of the awards (usually the vesting period) on a straight-line basis, net of estimated forfeitures. For stock option grants with performance-based milestones, the expense is recorded over the service period after the achievement of the milestone is probable or the performance condition is achieved. The Company accounts for stock options granted to non-employees using the fair value approach. These option grants are subject to periodic revaluation over their vesting terms. The Company estimates the fair value of employee and non-employee stock option grants using the Black-Scholes option pricing model.

Income Taxes

The Company accounts for income taxes under the asset and liability method, which requires the recognition of deferred tax assets and liabilities for the expected future tax consequences of events that have been included in the financial statements. Under this method, deferred tax assets and liabilities are determined on the basis of the differences between the financial statements and tax basis of assets and liabilities using enacted tax rates in effect for the year in which the differences are expected to reverse. The effect of a change in tax rates on deferred tax assets and liabilities is recognized as income in the period that includes the enactment date.

The Company recognizes net deferred tax assets to the extent that the Company believes these assets are more likely than not to be realized. In making such a determination, management considers all available positive

 

F-10

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

and negative evidence, including future reversals of existing taxable temporary differences, projected future taxable income, tax-planning strategies and results of recent operations. If management determines that the Company would be able to realize its deferred tax assets in the future in excess of their net recorded amount, management would make an adjustment to the deferred tax asset valuation allowance, which would reduce the provision for income taxes.

The Company records uncertain tax positions on the basis of a two-step process whereby (1) management determines whether it is more likely than not that the tax positions will be sustained on the basis of the technical merits of the position and (2) for those tax positions that meet the more-likely-than-not recognition threshold, management recognizes the largest amount of tax benefit that is more than 50% likely to be realized upon ultimate settlement with the related tax authority. The Company recognizes interest and penalties related to unrecognized tax benefits within income tax expense. Any accrued interest and penalties are included within the related tax liability.

In July 2013, the Financial Accounting Standards Board (FASB) issued guidance that requires an unrecognized tax benefit, or a portion of an unrecognized tax benefit, to be presented in the financial statements as a reduction to a deferred tax asset for a net operating loss carryforward, a similar tax loss, or a tax credit carryforward, unless an exception applies. The guidance is effective for fiscal years, and interim periods within those fiscal years, beginning after December 15, 2013. The Company early adopted this guidance for the year ended December 31, 2013, which is reflected in the financial statements as of and for the year ended December 31, 2013. There was no material impact on the financial statements upon adoption.

Comprehensive Loss

Comprehensive loss is defined as a change in equity during a period from transactions and other events and circumstances from non-owner sources. Net loss and comprehensive loss were the same for all periods presented.

Net Loss Per Share

Basic net loss per share is calculated by dividing the net loss attributable to common stockholders by the weighted average number of common shares outstanding for the period, without consideration for common stock equivalents and adjusted for the weighted average number of common shares outstanding that are subject to repurchase. The Company has excluded weighted average shares subject to repurchase of 747,351 shares, 609,185 shares, 625,463 shares and 531,574 shares from the weighted average number of common shares outstanding for the years ended December 31, 2012 and 2013 and the nine months ended September 30, 2013 and 2014, respectively. Diluted net loss per share attributable to common stockholders is calculated by dividing the net loss attributable to common stockholders by the weighted average number of common stock equivalents outstanding for the period determined using the treasury-stock method. Dilutive common stock equivalents are comprised of redeemable convertible preferred stock, warrants for the purchase of redeemable convertible preferred stock and options outstanding under the Company’s stock option plan. For all periods presented, there is no difference in the number of shares used to calculate basic and diluted shares outstanding due to the Company’s net loss position.

 

F-11

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

Potentially dilutive securities not included in the calculation of diluted net loss per share because to do so would be anti-dilutive are as follows:

 

		December 31,								September 30,
		2012				2013				2013				2014
Redeemable convertible preferred stock outstanding			55,211,585				73,487,415				73,487,415				73,487,415
Redeemable convertible preferred stock issuable upon conversion of convertible promissory note			751,314				751,314				751,314				751,314
Warrants for redeemable convertible preferred stock			87,957				147,269				147,269				206,581
Common stock options			5,613,487				6,531,417				6,477,258				10,679,777
			61,664,343				80,917,415				80,863,256				85,125,087

Unaudited Pro Forma Net Loss Per Share

The following table summarizes the Company’s unaudited pro forma net loss per share (in thousands, except share and per share data):

 

		Year Ended December  31, 2013				Nine Months Ended September 30, 2014
		(unaudited)
Numerator:
Net loss attributable to common stockholders		$	(21,651)			$	(18,728)
Change in fair value of warrant liabilities			28				213
Accretion to redemption value of redeemable convertible preferred stock			1,637				416
Pro forma net loss attributable to common stockholders		$	(19,986)			$	(18,099)
Denominator:
Weighted average shares outstanding, basic and diluted			6,067,342				6,554,969
Pro forma adjustments to reflect assumed weighted average effect of conversion of redeemable convertible preferred stock			68,314,984				73,487,415
Pro forma weighted average shares outstanding, basic and diluted			74,382,326				80,042,384
Pro forma net loss per share attributable to common stockholders, basic and diluted		$	(0.27)			$	(0.23)

 

F-12

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

Recent Accounting Pronouncements

In June 2014, the FASB issued ASU No. 2014-10, Development Stage Entities (Topic 915) Elimination of Certain Financial Reporting Requirements, Including an Amendment to Variable Interest Entities Guidance in Topic 810, Consolidation. This ASU does the following, among other things: (1) eliminates the requirement to present inception-to-date information on the statements of income, cash flows, and stockholders’ equity; (2) eliminates the need to label the financial statements as those of a development stage entity; (3) eliminates the need to disclose a description of the development stage activities in which the entity is engaged; and (4) amends FASB ASC 275, Risks and Uncertainties, to clarify that information on risks and uncertainties for entities that have not commenced planned principal operations is required. The amendments in ASU No. 2014-10 related to the elimination of Topic 915 disclosures and the additional disclosure for Topic 275 are effective for public companies for annual and interim reporting periods beginning after December 15, 2014. Early adoption is permitted. The Company has early adopted this new guidance in its consolidated financial statements for the year ended December 31, 2013, and therefore has not labeled its consolidated financial statements as those of a development stage entity or included the previously required inception-to-date information.

In August 2014, the FASB issued ASU 2014-15, Disclosure of Uncertainties about an Entity’s Ability to Continue as a Going Concern. ASU 2014-15 requires management to evaluate relevant conditions, events and certain management plans that are known or reasonably knowable that when, considered in the aggregate, raise substantial doubt about the entity’s ability to continue as a going concern within one year after the date that the consolidated financial statements are issued, for both annual and interim periods. ASU 2014-15 also requires certain disclosures around management’s plans and evaluation, as well as the plans, if any, that are intended to mitigate those conditions or events that will alleviate the substantial doubt. ASU 2014-15 is effective for fiscal years ending after December 15, 2016. The Company is currently evaluating the impact that the adoption of ASU 2014-15 will have on its consolidated financial statements and related disclosures.

3. Affiliates

In October and November 2011, the Company established the Affiliates to perform research and development for specified programs. In April 2012, the Company purchased preferred and common stock of each Affiliate and subsequently issued those shares to each of the Company shareholders in the form of dividends, in proportion to their relative holdings of aTyr Pharma, Inc., in order to effectuate the spin-out of the Affiliates into stand-alone entities. The Company and each Affiliate entered into nonexclusive license agreements allowing each of the six Affiliates to utilize certain intellectual property owned by the Company. The Company and each Affiliate also entered into research and development services agreements in the Company’s therapeutic program area of interest covered by the respective nonexclusive license agreement. The working capital of the Affiliates was primarily provided by amounts borrowed from aTyr Pharma, Inc. under convertible promissory note agreements. The Affiliates were not capitalized with sufficient equity to finance their operations and were therefore each considered a variable interest entity, or VIE. In May 2012, the Affiliates commenced operations. The Affiliates have no employees and substantially all of their expenses relate to the services provided to them by aTyr Pharma, Inc. The expenses related to services provided by aTyr Pharma, Inc. are eliminated in consolidation. The liquidation preference structure underlying the preferred stock issued by the Affiliates and the convertible promissory notes issued by the Affiliates to aTyr Pharma, Inc. in exchange for cash effectively protected the Affiliate stockholders from absorbing the losses of the Affiliates and, as a result, no losses were allocated to these noncontrolling interests and such losses were included in the consolidated net loss of the Company. None of the related parties to the Affiliates individually had the power and benefits to control the Affiliates. aTyr Pharma, Inc. is the related party that is most closely associated with the Affiliates and therefore is considered to be the primary beneficiary, and has consolidated the six Affiliates for financial reporting purposes. In the fourth quarter of 2014, the board of directors

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

and shareholders of each of the Affiliates approved the dissolution of each applicable Affiliate in accordance with the laws of its respective jurisdiction of organization (see Note 10).

From May 2012 through December 2014, the Company provided research and development and management services to the six Affiliates through utilization of its employees, equipment, and facilities. In addition, the Company provided financial support through loans to the Affiliates.

The aggregate carrying amount and classification of the Affiliates’ assets and liabilities were as follows (in thousands):

 

		December 31,								September  30, 2014
		2012				2013
Cash and cash equivalents		$	340			$	1,914			$	427
Total assets of Affiliates		$	340			$	1,914			$	427
Amounts due to aTyr Pharma, Inc.		$	4,817			$	12,864			$	19,265
Total liabilities of Affiliates		$	4,817			$	12,864			$	19,265

The aggregate statements of operations and statements of cash flows of the Affiliates are as follows (in thousands):

 

		Years Ended December 31,								Nine Months Ended September 30,
		2012				2013				2013				2014
Operating expenses		$	(4,487)			$	(8,856)			$	(6,348)			$	(7,886)
Other expense			(3)				(18)				(11)				(31)
Net loss of Affiliates		$	(4,490)			$	(8,874)			$	(6,359)			$	(7,917)
Cash used in operating activities		$	(4,477)			$	(8,861)			$	(6,348)			$	(7,915)
Cash provided by financing activities – aTyr Pharma, Inc.			4,817				8,047				5,367				6,399
Cash provided by financing activities – issuance of common and preferred stock of Affiliates			-				2,388				2,386				29
Increase (decrease) in cash and cash equivalents of Affiliates		$	340			$	1,574			$	1,405			$	(1,487)

 

F-14

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

4. Balance Sheet Details

Property and equipment consist of the following (in thousands):

 

		December 31,								September  30, 2014
		2012				2013
Computer and office equipment		$	308			$	364			$	369
Scientific and laboratory equipment			2,087				2,607				2,848
Tenant improvements			1,668				1,668				1,668
			4,063				4,639				4,885
Less accumulated depreciation and amortization			(1,488)				(2,134)				(2,751)
		$	2,575			$	2,505			$	2,134

Accrued expenses consist of the following (in thousands):

 

		December 31,								September  30, 2014
		2012				2013
Compensation and benefits		$	1,364			$	1,533			$	1,775
Other accrued expenses			444				1,408				1,407
		$	1,808			$	2,941			$	3,182

5. Fair Value Measurements

The carrying amounts of cash equivalents, prepaid and other assets, accounts payable and accrued liabilities are considered to be representative of their respective fair values because of the short-term nature of those instruments. Based on the borrowing rates currently available to the Company for loans with similar terms, which is considered a Level 2 input, the Company believes that the fair value of its commercial bank debt and convertible promissory notes approximate their carrying values. Investment securities and preferred stock warrant liabilities are recorded at fair value.

The accounting guidance defines fair value, establishes a consistent framework for measuring fair value and expands disclosure for each major asset and liability category measured at fair value on either a recurring or nonrecurring basis. Fair value is defined as an exit price, representing the amount that would be received to sell an asset or paid to transfer a liability in an orderly transaction between market participants. As such, fair value is a market-based measurement that should be determined based on assumptions that market participants would use in pricing an asset or liability. As a basis for considering such assumptions, the accounting guidance establishes a three-tier fair value hierarchy, which prioritizes the inputs used in measuring fair value as follows:

Level 1: Observable inputs such as quoted prices in active markets.

Level 2: Inputs, other than the quoted prices in active markets that are observable either directly or indirectly.

Level 3: Unobservable inputs in which there is little or no market data, which require the reporting entity to develop its own assumptions.

Financial assets measured at fair value on a recurring basis consist of investment securities. Investment securities are recorded at fair value, defined as the exit price in the principal market in which the Company would

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

transact, representing the amount that would be received to sell an asset or paid to transfer a liability in an orderly transaction between market participants. Level 2 securities are valued using quoted market prices for similar instruments, non-binding market prices that are corroborated by observable market data, or discounted cash flow techniques and include the Company’s investments in corporate debt securities and commercial paper. Financial liabilities measured at fair value on a recurring basis include the Company’s preferred stock warrant liabilities. None of the Company’s non-financial assets and liabilities are recorded at fair value on a non-recurring basis. No transfers between levels have occurred during the periods presented.

Assets and liabilities measured at fair value on a recurring basis are as follows (in thousands):

 

						Fair Value Measurements as of September 30, 2014 Using
						Quoted Prices in Active Markets for Identical Assets (Level 1)				Significant Other Observable Inputs (Level 2)				Significant Unobservable Inputs (Level 3)
As of September 30, 2014:
Assets:
Commercial paper		$	2,099			$	-			$	2,099			$	-
Corporate debt securities			2,619				-				2,619				-
		$	4,718			$	-			$	4,718			$	-
Liabilities:
Preferred stock warrant liabilities		$	568			$	-			$	-			$	568
As of December 31, 2013:
Liabilities:
Preferred stock warrant liabilities		$	207			$	-			$	-			$	207
As of December 31, 2012:
Liabilities:
Preferred stock warrant liabilities		$	42			$	-			$	-			$	42

All warrant liabilities are recorded at fair value utilizing the Black-Scholes option pricing model using significant unobservable inputs consistent with the inputs used for the Company’s stock-based compensation expense adjusted for the warrants’ expected life.

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

The following table provides a reconciliation of all liabilities measured at fair value using Level 3 significant unobservable inputs (in thousands):

 

		Warrant Liabilities
Balance at December 31, 2011		$	53
Decrease in fair value of warrant liabilities			(11)
Balance at December 31, 2012			42
Issuance of preferred stock warrants			137
Increase in fair value of warrant liabilities			28
Balance at December 31, 2013			207
Issuance of preferred stock warrants			148
Increase in fair value of warrant liabilities			213
Balance at September 30, 2014		$	568

6. Debt, Commitments and Contingencies

Commercial Bank Debt

Commercial bank debt and unamortized discount balances are as follows (in thousands):

 

		December 31,								September  30, 2014
		2012				2013
Commercial bank debt		$	2,500			$	5,000			$	9,221
Less debt discount, net of current portion			-				(61)				(81)
Commercial bank debt, net of debt discount			2,500				4,939				9,140
Less current portion of commercial bank debt			(833)				(781)				(3,193)
Commercial bank debt, net of current portion		$	1,667			$	4,158			$	5,947
Current portion of commercial bank debt		$	833			$	781			$	3,193
Current portion of debt discount			-				(53)				(113)
Current portion of commercial bank debt		$	833			$	728			$	3,080

In each of April 2012 and August 2012, the Company borrowed $1.25 million under a loan and security agreement with Silicon Valley Bank (SVB Loan), at fixed interest rates of 4.89% and 4.85%, respectively. The Company was obligated to make interest-only payments through December 2012 and, beginning in December 2013, equal monthly payments of principal and interest through the maturity date in December 2015. The SVB Loan was amended in July 2013 to increase the available credit under the agreement to $10.0 million. In July 2013, the Company borrowed $5.0 million under the SVB Loan at a fixed interest rate of 5.0% and received $2.9 million of cash proceeds after repayment of the existing principal balance and related accrued interest and fees. In June 2014, the Company borrowed the remaining $5.0 million of available credit at a fixed interest rate of 5.88% and, subsequent to June 2014, had no available credit under the SVB Loan. The Company was obligated to make interest-only payments on each $5.0 million borrowing through June 2014 and, beginning in July 2014, equal monthly payments of principal and interest through the maturity date in June 2017. The final payment due in June 2017 includes an additional fee of $0.5 million, which is being accreted over the term of the debt using the effective interest method and is included in interest expense.

 

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aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

The loan is collateralized by all assets of the Company, other than intellectual property, and contains customary affirmative and negative covenants, reporting requirements and events of default.

In July 2013, in connection with the SVB Loan, the Company issued a warrant to purchase 59,312 shares of Series D redeemable convertible preferred stock at an exercise price of $2.529 per share. In June 2014, the warrant became exercisable for a total of 118,624 shares of Series D redeemable convertible preferred stock when the Company borrowed the remaining $5.0 million of available credit under the SVB Loan. The warrant is fully exercisable and expires on July 24, 2023.

The initial fair value of the warrant in July 2013 was estimated to be $0.1 million and the initial fair value of the additional 59,312 additional warrant shares earned in June 2014 was estimated to be $0.1 million, based on the application of the Black-Scholes option pricing model, and this discount is amortized to interest expense using the effective interest method over the term of the debt.

Future minimum principal and interest payments under the SVB Loan, including the final payment, are as follows (in thousands):

 

		As of December 31, 2013				As of September 30, 2014
2014		$	1,027			$	905
2015			1,800				3,622
2016			1,800				3,622
2017			1,050				2,311
			5,677				10,460
Less interest and final payment			(677)				(1,239)
Commercial bank debt		$	5,000			$	9,221

Facility Lease

In December 2011, the Company entered into a noncancelable operating lease that included certain tenant improvement allowances and is subject to base lease payments, which escalate over the term of the lease, additional charges for common area maintenance and other costs. The lease expires in May 2017 and the Company has an option to extend the lease for a period of five years. Rent expense for the years ended December 31, 2012 and 2013 and the nine months ended September 30, 2013 and 2014 was $0.4 million, $0.2 million, $0.2 million and $0.2 million, respectively.

In conjunction with this lease, the Company borrowed $2.0 million under a subordinated unsecured convertible promissory note issued to the venture arm of its landlord. The convertible promissory note carries an annual interest rate of 8.0% and matures at the earlier of (i) May 2015, (ii) a liquidation event, and (iii) the closing of an initial firm commitment underwritten public offering of the Company’s common stock pursuant to a registration statement under the Act, at which time all outstanding principal and accrued interest amounts would be due, unless previously converted. At any time prior to maturity, the holder may elect to convert the promissory note into shares of the Company’s Series D redeemable convertible preferred stock at the price of $2.662 per share. Upon conversion, all then accrued interest will be forgiven. As of December 31, 2012 and 2013 and September 30, 2014, the outstanding principal balance of the convertible promissory note was $2.0 million. As of December 31, 2012 and 2013 and September 30, 2014, the accrued interest on the convertible promissory note was $0.2 million, $0.3 million and $0.4 million, respectively.

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

Future minimum payments under the non-cancelable operating lease as of December 31, 2013 were as follows (in thousands):

 

		Operating Lease
2014		$	571
2015			590
2016			610
2017			231
		$	2,002

Research Agreements and Funding Obligations

In October 2007, the Company entered into a research funding and option agreement for certain technologies from The Scripps Research Institute (TSRI). Under the agreement (as amended), the Company provides funding to TSRI to conduct certain research activities. The agreement renews automatically for successive 12 month periods starting on May 31st of each year unless the Company provides 30 days’ prior written notice to terminate the agreement. TSRI has the right to terminate the agreement if the Company fails to make any payment under the agreement or for breach or insolvency. Under the research funding and option agreement, TSRI has granted the Company options to enter into license agreements to acquire rights and exclusive licenses to develop, make, have made, use, have used, import, have imported, offer to sell, sell, and have sold certain licensed products, processes and services based on certain technology arising from the sponsored research activities. Pursuant to the terms of these license agreements, TSRI is entitled to receive tiered royalties as a percentage of net sales and a percentage of nonroyalty revenue the Company may receive from its sublicensees or partners, with the amount owed decreasing if it enters into the applicable sublicense or partnering agreement after meeting a specified clinical milestone. In addition, the Company is obligated to pay TSRI up to an aggregate of $2.75 million under each license agreement upon the achievement of specific clinical and regulatory milestone events. A member of the Company’s board of directors is a faculty member at TSRI and such payments fund a portion of his research activities conducted at TSRI. For the years ended December 31, 2012 and 2013 and the nine months ended September 30, 2013 and 2014, the Company recognized expense under the agreement in the amount of $0.7 million, $0.6 million, $0.4 million and $0.5 million, respectively.

During the years ended December 31, 2012 and 2013 and the nine months ended September 30, 2013 and 2014, the Company provided charitable donations to the National Foundation for Cancer Research of $0.4 million, $0.4 million, $0.3 million and $0.3 million, respectively. The Company has requested that the donations be restricted to certain basic research in cancer biology and therapeutics, a portion of which fund research activities conducted at TSRI in the laboratory of a member of the Company’s board of directors.

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

7. Redeemable Convertible Preferred Stock and Stockholders’ Equity (Deficit)

Redeemable Convertible Preferred Stock

The authorized, issued and outstanding shares of redeemable convertible preferred stock by series were as follows (in thousands, except share and per share amounts):

 

		Shares Authorized				Shares Outstanding				Liquidation Preference Per Share		Liquidation Preference and Redemption Value				Carrying Value as of December 31, 2013				Carrying Value as of September 30, 2014
Series A			2,925,000				2,925,000			$0.2500		$	731			$	731			$	731
Series B			12,672,000				12,600,000			0.8333			10,500				10,500				10,500
Series B-2			14,686,583				14,686,583			0.8333			12,238				12,238				12,238
Series C			25,015,959				25,000,002			0.9400			23,500				23,500				23,500
Series D			20,473,329				18,275,830			2.6620			48,650				46,196				46,612
			75,772,871				73,487,415					$	95,619			$	93,165			$	93,581

During 2005, the Company sold 2,925,000 shares of Series A redeemable convertible preferred stock at $0.25 per share for gross proceeds of $0.7 million in cash.

During 2006, the Company sold 12,600,000 shares of Series B redeemable convertible redeemable preferred stock at $0.8333 per share for gross proceeds of $10.5 million in cash. The Company incurred $44,000 of offering costs in connection with this stock issuance.

During 2009, the Company sold 14,686,583 shares of Series B-2 redeemable convertible preferred stock at $0.8333 per share for gross proceeds of $12.2 million in cash. The Company incurred $0.1 million of offering costs in connection with this stock issuance.

During 2010 and 2011, the Company sold an aggregate of 25,000,002 shares of Series C redeemable convertible preferred stock at $0.94 per share for gross proceeds of $23.5 million in cash. The Company incurred $0.1 million of offering costs in connection with this stock issuance.

In March 2013, the Company issued convertible notes to investors totaling $10.0 million. The notes carried a 7.0% interest rate. In April and May 2013, the Company sold an aggregate of 18,275,830 shares of Series D redeemable convertible preferred stock for aggregate gross proceeds of $48.7 million, inclusive of the conversion of the convertible notes and related accrued interest and shares of Series D redeemable convertible preferred stock sold by the Affiliates. The Company incurred $0.5 million of offering costs in connection with this stock issuance.

Conversion

The shares of Series A, Series B, Series B-2, Series C, and the Series D redeemable convertible preferred stock (together, the Series Preferred) are convertible into an equal number of shares of common stock, at the option of the holder. Each share of the Series Preferred is automatically converted into common stock upon either (i) the Company’s sale of its common stock in an underwritten public offering pursuant to a registration statement under the Securities Act of 1933, as amended, in which the per share price is at least $5.324 (as adjusted), the net cash proceeds are at least $25,000,000, and the result of offering is listing on a national securities exchange or (ii) upon the majority vote of the holders of Series B-2, Series C and Series D redeemable convertible preferred stock, voting together as a single class, including at least a majority of the Series D stockholders.

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

Liquidation

The Series D redeemable preferred stock has a liquidation preference of $2.662 per share, plus any declared but unpaid dividends, in priority to the Series A, Series B, Series B-2, and Series C redeemable convertible preferred stock, in which the Series D holders shall receive their full liquidation preference in advance of the other classes of preferred stock. Upon payment of the full liquidation preference of Series D holders, the holders of Series C and Series B-2 redeemable convertible preferred stock are entitled to receive their liquidation preference of $0.94 and $0.8333 per share, respectively, plus any declared but unpaid dividends. Upon payment of the full liquidation preference of Series C and Series B-2 holders, the holders of Series B and Series A redeemable convertible preferred stock are entitled to receive their liquidation preference of $0.8333 and $0.25 per share, respectively, plus any declared but unpaid dividends, prior to and in preference to any distribution of the assets of the Company to common stockholders. The remaining assets of the Company are to be distributed to the common stockholders based on the number of shares of common stock held by each stockholder.

Dividends

The holders of Series Preferred Stock are entitled to non-cumulative dividends at a rate of 8.0% of the purchase price for the applicable series of redeemable convertible preferred stock per share per annum and are payable only if and when declared by the Company’s board of directors. The Series Preferred Stock participates in any dividends paid to the holders of common stock on an as-converted to common stock basis. As of December 31, 2013 and September 30, 2014, the board of directors had not declared any dividends.

Redemption

The Series Preferred Stock may be redeemed, in whole or in part, at the option of the holders any time after April 2018, upon the majority vote of the holders of Series B-2, Series C and Series D, voting together as a single class, including at least a majority of the Series D stockholders. The redemption amount is equal to the then current liquidation preference of each share of redeemable convertible preferred stock and is payable in three equal annual installments.

Prior to closing of the Series D redeemable convertible preferred stock financing in April 2013, the redemption amount of the Series Preferred Stock was based on the original liquidation preference of each series of redeemable convertible preferred stock and increased each period at a rate of 10% per annum. The Company recorded the accretion of such amounts as increases to the carrying value of the Series Preferred Stock. In connection with the Series D redeemable convertible preferred stock financing in April 2013, the cumulative increase over the original liquidation preference of the Series Preferred Stock of the Company was eliminated. The Company deemed this change to represent a modification to the Series Preferred Stock which was accounted for as a capital contribution from stockholders who are considered related parties of the Company as they owned approximately 90% of the outstanding capital stock at that date. Accordingly, the resulting adjustment to the carrying value of the redeemable convertible preferred stock was reclassified from mezzanine equity to additional paid-in capital in April 2013.

Voting

The holders of each share of Series Preferred Stock are entitled to one vote for each share of common stock into which the Series Preferred would convert.

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

Stock Options

The Company adopted a stock option plan in 2007 (the 2007 Plan), which was subsequently amended, restated and renamed in July 2014 (the 2014 Plan) to provide for the grant of incentive stock options, nonstatutory stock options, stock, and rights to purchase restricted stock to eligible recipients. Recipients of incentive stock options are eligible to purchase shares of the Company’s common stock at an exercise price equal to no less than the estimated fair market value of such stock on the date of grant. The maximum term of options granted under the 2014 Plan is ten years. Options granted prior to September 2012 generally vest over four years and options granted thereafter generally vest over six years. As of December 31, 2013 and September 30, 2014, the Company had 13,470,812 shares and 16,219,000 shares, respectively, authorized for issuance to employees, nonemployee directors, and consultants of the Company under the 2014 Plan.

Stock option activity under the 2014 Plan is summarized as follows:

 

		Number of Options				Weighted- Average Exercise Price
Outstanding at December 31, 2012			5,613,487			$	0.10
Granted			2,300,787			$	0.51
Exercised			(538,125)			$	0.10
Forfeited			(844,732)			$	0.10
Outstanding at December 31, 2013			6,531,417			$	0.24
Granted			4,611,597			$	0.51
Exercised			(423,872)			$	0.10
Forfeited			(39,365)			$	0.35
Outstanding at September 30, 2014			10,679,777			$	0.36

Information about the Company’s outstanding stock options is as follows (in thousands, except share and per share data):

 

		Number of Shares				Weighted- Average Exercise Price				Weighted- Average Remaining Contractual Term (in years)				Aggregate Intrinsic Value
September 30, 2014:
Options outstanding			10,679,777			$	0.36				8.52			$	19,926
Options vested and expected to vest			10,343,887			$	0.37				8.59			$	19,208
Options exercisable			2,618,238			$	0.20				7.23			$	5,325
December 31, 2013:
Options outstanding			6,531,417			$	0.24				8.43			$	1,735
Options vested and expected to vest			6,195,527			$	0.25				8.50			$	1,594
Options exercisable			2,035,803			$	0.13				7.56			$	768

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

Stock-Based Compensation Expense

The assumptions used in the Black-Scholes option pricing model to determine the fair value of the employee stock option grants were as follows:

 

		Years Ended December 31,				Nine Months  Ended September 30, 2014
		2012		2013
Expected term (in years)		6.02 – 6.52		6.52 – 6.56		5.77 – 6.56
Risk-free interest rate		0.9% – 1.2%		2.0% – 2.2%		1.7% – 2.2%
Expected volatility		102%		109%		111%
Expected dividend yield		-		-		-

Expected term. The expected term represents the period of time that options are expected to be outstanding. Because the Company does not have sufficient historical exercise behavior, it determines the expected life assumption using the simplified method, which is an average of the contractual term of the option and its vesting period.

Risk-free interest rate. The Company bases the risk-free interest rate assumption on the U.S. Treasury’s rates for U.S. Treasury zero-coupon bonds with maturities similar to those of the expected term of the award being valued.

Expected volatility. The expected volatility assumption is based on volatilities of a peer group of similar companies whose share prices are publicly available. The peer group was developed based on companies in the biotechnology industry.

Expected dividend yield. The Company bases the expected dividend yield assumption on the fact that it has never paid cash dividends and has no present intention to pay cash dividends.

The allocation of stock-based compensation is as follows (in thousands):

 

		Years Ended December 31,								Nine Months Ended September 30,
		2012				2013				2013				2014
Research and development		$	28			$	96			$	64			$	324
General and administrative			138				59				21				461
		$	166			$	155			$	85			$	785

The weighted-average grant date fair values of stock options granted by the Company during the years ended December 31, 2012 and 2013 and the nine months ended September 30, 2014, was $0.11 per share, $0.51 per share and $1.20 per share, respectively. The aggregate intrinsic value of stock options exercised during the years ended December 31, 2012 and 2013 and the nine months ended September 30, 2013 and 2014 was $1,000, $47,000, $42,000 and $0.4 million, respectively. As of September 30, 2014, total unrecognized share-based compensation costs related to unvested employee stock options of the Company were approximately $5.9 million. This unrecognized cost is expected to be recognized over a weighted-average period of approximately 4.7 years on a straight-line basis.

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

Warrants

Information about the Company’s outstanding and fully exercisable redeemable convertible preferred stock warrants is as follows:

 

		Outstanding Warrants								Exercise Price Per Share
		December 31, 2013				September 30, 2014						Expiration Date
Series B			72,000				72,000			$    0.8334		September 2017
Series C			15,957				15,957			0.9400		March 2021
Series D			59,312				118,624			2.5290		July 2023
			147,269				206,581

Common Stock Reserved for Future Issuance

Common stock reserved for future issuance is as follows:

 

		December 31, 2013				September 30, 2014
Conversion of redeemable convertible preferred stock			73,487,415				73,487,415
Conversion of redeemable convertible preferred stock issuable upon conversion of promissory note			751,314				751,314
Redeemable convertible preferred stock warrants			147,269				206,581
Common stock options granted and outstanding			6,531,417				10,679,777
Awards available under the 2014 Plan			4,623,636				2,799,592
			85,541,051				87,924,679

8. Income Taxes

A reconciliation of the expected statutory federal income tax provision to the actual income tax provision is summarized as follows (in thousands):

 

		Years Ended December  31,
		2012				2013
Expected income tax benefit at federal statutory rate		$	(4,372)			$	(6,804)
State income taxes, net of federal benefit			(356)				(634)
Permanent items and other			81				2
Research credits			(135)				(397)
Unrecognized tax benefits			267				159
Foreign rate differential			1,967				2,978
Other, net			23				(26)
Change in valuation allowance			2,525				4,722
Income tax (benefit) expense		$	-			$	-

Deferred income taxes are provided for temporary differences in recognizing certain income and expense items for financial and tax reporting purposes. The deferred tax assets consisted primarily of the income tax benefits from net operating loss (NOL) carryforwards, research and development credits and capitalized research and development

 

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Table of Contents

aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

expenses, along with other accruals and reserves. Valuation allowances of $16.6 million and $21.3 million as of December 31, 2012 and 2013, respectively, have been recorded to offset deferred tax assets as realization of such assets does not meet the more-likely-than-not threshold under ASC 740, Accounting for Income Taxes.

Significant components of the Company’s deferred tax assets are summarized as follows (in thousands):

 

		December 31,
		2012				2013
Net operating loss carryforwards		$	8,960			$	13,093
Capitalized research and development expenses			6,150				6,346
Research credits and other state credits			933				1,171
Depreciation and amortization			(416)				(333)
Reserve and accruals			944				1,016
Valuation allowance			(16,571)				(21,293)
Net deferred tax assets		$	-			$	-

At December 31, 2013, the Company had approximately $30.7 million, $31.9 million, and $5.0 million of net operating loss carryforwards for federal, state, and foreign purposes, respectively, available to offset future taxable income. The federal and state net operating loss carryforwards begin to expire in 2025 and 2016, respectively. The foreign net operating losses carry over indefinitely. At December 31, 2013, the Company had federal and state research and development credit carryforwards of approximately $1.2 million and $1.2 million, respectively, which begin to expire in 2026 for federal purposes and carry over indefinitely for state purposes.

Utilization of the domestic NOL and research and development credit carryforwards may be subject to a substantial annual limitation due to ownership change limitations that may have occurred or that could occur in the future, as required by Section 382 and 383 of the Internal Revenue Code of 1986, as amended (the Code), as well as similar state and foreign provisions. These ownership changes may limit the amount of NOL and research and development credit carryforwards that can be utilized annually to offset future taxable income and tax, respectively. In general, an “ownership change” as defined by Section 382 of the Code results from a transaction or series of transactions over a three-year period resulting in an ownership change of more than 50 percentage points of the outstanding stock of a company by certain stockholders. Since the Company’s formation, the Company has raised capital through the issuance of capital stock on several occasions which on its own or combined with the purchasing stockholders’ subsequent disposition of those shares, has resulted in such an ownership change, and could result in an ownership change in the future.

Upon the occurrence of an ownership change under Section 382 as outlined above, utilization of the NOL and research and development credit carryforwards become subject to an annual limitation under Section 382 of the Code, which is determined by first multiplying the value of the Company’s stock at the time of the ownership change by the applicable long-term, tax-exempt rate, which could be subject to additional adjustments. Any limitation may result in expiration of a portion of the NOL or research and development credit carryforwards before utilization. The Company completed an analysis through September 7, 2011, and has adjusted its NOL and research and development tax credit carryforwards accordingly. Ownership changes that may have occurred subsequent to September 7, 2011, and future ownership changes, including any ownership change resulting from this offering, may further limit the Company’s ability to utilize its remaining tax attributes.

The Company recognizes a tax benefit from an uncertain tax position when it is more likely than not that the position will be sustained upon examination, including resolutions of any related appeals or litigation processes, based on the technical merits. Income tax positions must meet a more-likely-than-not recognition threshold to be recognized.

 

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aTyr Pharma, Inc.

Notes to Consolidated Financial Statements—(Continued)

(Information as of September 30, 2014 and thereafter and for the nine months ended September 30, 2013 and 2014 is unaudited)

 

The Company’s practice is to recognize interest and penalties related to income tax matters in income tax expense. The Company had no accrual for interest and penalties on the Company’s balance sheet and has not recognized interest or penalties in the consolidated statements of operations for the years ended December 31, 2012 and 2013.

Due to the existence of the valuation allowance, future changes in unrecognized tax benefits will not impact the Company’s effective tax rate.

Uncertain tax positions are evaluated based upon the facts and circumstances that exist at each reporting period. Subsequent changes in judgment based upon new information may lead to changes in recognition, derecognition, and measurement. Adjustments may result, for example, upon resolution of an issue with the taxing authorities, or expiration of a statute of limitations barring an assessment for an issue.

The activity related to the Company’s unrecognized tax benefits is summarized as follows (in thousands):

 

Balance at December 31, 2011		$	432
Increase related to prior year tax positions			260
Increase related to current year tax positions			82
Balance at December 31, 2012			774
Increase related to prior year tax positions			79
Increase related to current year tax positions			94
Balance at December 31, 2013		$	947

The Company does not anticipate that the amount of unrecognized tax benefits as of December 31, 2013 will change within the next twelve months.

The Company is subject to taxation in the United States, Hong Kong and state jurisdictions. The Company’s tax years from inception are subject to examination by the United States, Hong Kong and California authorities due to the carry forward of unutilized NOLs and research and development credits.

9. 401(k) Plan

The Company maintains a defined contribution 401(k) plan available to eligible employees. Employee contributions are voluntary and are determined on an individual basis, limited to the maximum amount allowable under federal tax regulations. The Company, at its discretion, may make certain matching contributions to the 401(k) plan. As of September 30, 2014, the Company had not made any matching contributions.

10. Subsequent Events

The Company has completed an evaluation of all subsequent events through December 18, 2014 to ensure that this filing includes appropriate disclosure of events both recognized in the September 30, 2014 consolidated financial statements and events which occurred but were not recognized in the consolidated financial statements. Except as described below, the Company has concluded that no subsequent event has occurred that requires disclosure.

In the fourth quarter of 2014, the board of directors and stockholders of each of the Affiliates approved the dissolution of each applicable Affiliate in accordance with the laws of its respective jurisdiction of organization. In connection with the dissolution of the Affiliates, the license and operating agreements by and between aTyr Pharma, Inc. and each Affiliate were terminated. The Company’s consolidated financial statements for periods after the effectiveness of the dissolution of the Affiliates will no longer include a noncontrolling interest, and the operating activities that the Affiliates performed prior to dissolution will be continued by aTyr Pharma, Inc.

 

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                Shares

 

Common Stock

 

 

 

J.P. Morgan		Deutsche Bank Securities
BMO Capital Markets
William Blair

                    , 2015

 

 

 

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PART II

Information Not Required in Prospectus

Item 13. Other Expenses of Issuance and Distribution.

The following table sets forth the fees and expenses, other than underwriting discounts and commissions, payable in connection with the registration of the common stock hereunder. All amounts are estimates except the Securities and Exchange Commission, or SEC, registration fee.

 

		Amount to Be Paid
SEC registration fee
FINRA filing fee			*
The NASDAQ Global Market listing fee			*
Printing and mailing			*
Legal fees and expenses			*
Accounting fees and expenses			*
Transfer agent and registrar fees and expenses			*
Miscellaneous			*
Total		$

 

*	To be filed by amendment.

Item 14. Indemnification of Directors and Officers.

Section 145 of the Delaware General Corporation Law, or the DGCL, authorizes a corporation to indemnify its directors and officers against liabilities arising out of actions, suits and proceedings to which they are made or threatened to be made a party by reason of the fact that they have served or are currently serving as a director or officer to a corporation. The indemnity may cover expenses (including attorneys’ fees) judgments, fines and amounts paid in settlement actually and reasonably incurred by the director or officer in connection with any such action, suit or proceeding. Section 145 permits corporations to pay expenses (including attorneys’ fees) incurred by directors and officers in advance of the final disposition of such action, suit or proceeding. In addition, Section 145 provides that a corporation has the power to purchase and maintain insurance on behalf of its directors and officers against any liability asserted against them and incurred by them in their capacity as a director or officer, or arising out of their status as such, whether or not the corporation would have the power to indemnify the director or officer against such liability under Section 145.

We have adopted provisions in our certificate of incorporation and bylaws to be in effect at the completion of this offering that limit or eliminate the personal liability of our directors to the fullest extent permitted by the DGCL, as it now exists or may in the future be amended. Consequently, a director will not be personally liable to us or our stockholders for monetary damages or breach of fiduciary duty as a director, except for liability for:

 

•

any breach of the director’s duty of loyalty to us or our stockholders;

 

•

any act or omission not in good faith or that involves intentional misconduct or a knowing violation of law;

 

•

any unlawful payments related to dividends or unlawful stock purchases, redemptions or other distributions; or

 

•

any transaction from which the director derived an improper personal benefit.

These limitations of liability do not alter director liability under the federal securities laws and do not affect the availability of equitable remedies such as an injunction or rescission.

 

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In addition, our bylaws provide that:

 

•

we will indemnify our directors, officers and, in the discretion of our board of directors, certain employees to the fullest extent permitted by the DGCL, as it now exists or may in the future be amended; and

 

•

we will advance reasonable expenses, including attorneys’ fees, to our directors and, in the discretion of our board of directors, to our officers and certain employees, in connection with legal proceedings relating to their service for or on behalf of us, subject to limited exceptions.

We have entered into indemnification agreements with each of our directors and certain of our executive officers. These agreements provide that we will indemnify each of our directors, certain of our executive officers and, at times, their affiliates to the fullest extent permitted by Delaware law. We will advance expenses, including attorneys’ fees (but excluding judgments, fines and settlement amounts), to each indemnified director, executive officer or affiliate in connection with any proceeding in which indemnification is available and we will indemnify our directors and officers for any action or proceeding arising out of that person’s services as a director or officer brought on behalf of the Company or in furtherance of our rights. Additionally, certain of our directors may have certain rights to indemnification, advancement of expenses or insurance provided by their affiliates, which indemnification relates to and might apply to the same proceedings arising out of such director’s services as a director referenced herein. Nonetheless, we have agreed in the indemnification agreements that the Company’s obligations to those same directors are primary and any obligation of the affiliates of those directors to advance expenses or to provide indemnification for the expenses or liabilities incurred by those directors are secondary.

We also maintain general liability insurance which covers certain liabilities of our directors and officers arising out of claims based on acts or omissions in their capacities as directors or officers, including liabilities under the Securities Act of 1933, or the Securities Act.

The underwriting agreement filed as Exhibit 1.1 to this registration statement provides for indemnification of us and our directors and officers by the underwriters against certain liabilities under the Securities Act and the Securities Exchange Act of 1934, or the Exchange Act.

Item 15. Recent Sales of Unregistered Securities.

In the three years preceding the filing of this registration statement, we have issued the following securities that were not registered under the Securities Act:

(a) Issuances of Capital Stock

In March 2013, we issued convertible promissory notes to thirteen existing stockholders for aggregate consideration of $10.0 million.

In April 2013 and May 2013, we issued an aggregate of 18,275,830 shares of our Series D redeemable convertible preferred stock to twenty-three investors for aggregate consideration of approximately $46.2 million.

In July 2013, we issued a warrant to purchase 59,312 shares of our Series D redeemable convertible preferred stock to a lending institution at an exercise price per share of $2.529. Pursuant to the terms of the warrant, the number of shares underlying the warrant automatically increased to an aggregate of 118,624 upon the funding of a capital advance to us in June 2014.

No underwriters were involved in the foregoing sales of securities. Unless otherwise stated, the sales of securities described above were deemed to be exempt from registration pursuant to Section 4(2) of the Securities Act as transactions by an issuer not involving a public offering. All of the purchasers in these transactions represented to us in connection with their purchase that they were acquiring the securities for investment and not distribution, that they could bear the risks of the investment and could hold the securities for an indefinite period

 

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of time. Such purchasers received written disclosures that the securities had not been registered under the Securities Act and that any resale must be made pursuant to a registration or an available exemption from such registration. All of the foregoing securities are deemed restricted securities for the purposes of the Securities Act.

(b) Grants and Exercises of Stock Options

Since January 1, 2012, we have granted stock options to purchase an aggregate of 11,004,026 shares of our common stock, with exercise prices ranging from $0.11 to $2.23 per share, to employees, directors and consultants pursuant to the 2014 Plan. 354,244 shares of common stock have been issued upon the exercise of these options.

The issuances of the securities described above were deemed to be exempt from registration pursuant to Rule 701 promulgated under the Securities Act as transactions pursuant to compensatory benefit plans. The shares of common stock issued upon the exercise of options are deemed to be restricted securities for purposes of the Securities Act.

Item 16. Exhibits and Financial Statement Schedules.

(a) Exhibits:

The exhibits to the registration statement are listed in the Exhibit Index to this registration statement and are incorporated herein by reference.

 

(b)	Financial Statements Schedules:

Schedules have been omitted because the information required to be set forth therein is not applicable or is shown in the financial statements or notes thereto.

Item 17. Undertakings.

Insofar as indemnification for liabilities arising under the Securities Act of 1933, as amended, or the Act, may be permitted to directors, officers and controlling persons of the Registrant pursuant to the foregoing provisions, or otherwise, the Registrant has been advised that in the opinion of the Securities and Exchange Commission such indemnification is against public policy as expressed in the Act and is therefore unenforceable. In the event that a claim for indemnification against such liabilities (other than the payment by the Registrant of expenses incurred or paid by a director, officer or controlling person of the Registrant in the successful defense of any action, suit or proceeding) is asserted by such director, officer or controlling person in connection with the securities being registered, the Registrant will, unless in the opinion of its counsel the matter has been settled by controlling precedent, submit to a court of appropriate jurisdiction the question whether such indemnification by it is against public policy as expressed in the Act and will be governed by the final adjudication of such issue.

The Registrant hereby undertakes that:

 

(a)

The Registrant will provide to the underwriter at the closing as specified in the underwriting agreement, certificates in such denominations and registered in such names as required by the underwriter to permit prompt delivery to each purchaser.

 

(b)

For purposes of determining any liability under the Securities Act of 1933, as amended, the information omitted from a form of prospectus filed as part of this registration statement in reliance upon Rule 430A and contained in the form of prospectus filed by the Registrant pursuant to Rule 424(b)(1) or (4) or 497(h) under the Securities Act of 1933, as amended, shall be deemed to be part of this registration statement as of the time it was declared effective.

 

(c)

For the purpose of determining any liability under the Securities Act of 1933, as amended, each post-effective amendment that contains a form of prospectus shall be deemed to be a new registration statement relating to the securities offered therein, and the offering of such securities at that time shall be deemed to be the initial bona fide offering thereof.

 

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SIGNATURES

Pursuant to the requirements of the Securities Act of 1933, the registrant has duly caused this Registration Statement on Form S-1 to be signed on its behalf by the undersigned, thereunto duly authorized, in the City of San Diego, State of California, on the     day of                     , 2015.

 

POWER OF ATTORNEY AND SIGNATURES

Each individual whose signature appears below hereby constitutes and appoints each of John D. Mendlein, Ph.D. and Frederic Chereau as such person’s true and lawful attorney-in-fact and agent with full power of substitution and resubstitution, for such person in such person’s name, place and stead, in any and all capacities, to sign any and all amendments (including post-effective amendments) to this Registration Statement (or any Registration Statement for the same offering that is to be effective upon filing pursuant to Rule 462(b) under the Securities Act of 1933), and to file the same, with all exhibits thereto, and all documents in connection therewith, with the Securities and Exchange Commission granting unto each said attorney-in-fact and agent full power and authority to do and perform each and every act and thing requisite and necessary to be done in and about the premises, as fully to all intents and purposes as such person might or could do in person, hereby ratifying and confirming all that any said attorney-in-fact and agent, or any substitute or substitutes of any of them, may lawfully do or cause to be done by virtue hereof.

Pursuant to the requirements of the Securities Act of 1933, as amended, this Registration Statement and Power of Attorney has been signed by the following persons in the capacities and on the date indicated.

 

Name		Title		Date
John D. Mendlein, Ph.D.		Chief Executive Officer and Executive Chairman (Principal Executive Officer)		, 2015
Stan Blackburn		Principal Financial and Accounting Officer (Principal Financial and Accounting Officer)		, 2015
John K. Clarke		Chairman of the Board and Director		, 2015
James C. Blair, Ph.D.		Director		, 2015
Kathryn E. Falberg		Director		, 2015
Amir H. Nashat, Sc.D.		Director		, 2015
Edward Penhoet, Ph.D.		Director		, 2015
Paul Schimmel, Ph.D.		Director		, 2015

 

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EXHIBIT INDEX

 

Exhibit No.		Exhibit
1.1*		Form of Underwriting Agreement
3.1+		Amended and Restated Certificate of Incorporation of the Registrant, as currently in effect
3.2*		Form of Amended and Restated Certificate of Incorporation of the Registrant (to be effective upon completion of this offering)
3.3+		Bylaws of the Registrant, as currently in effect
3.4*		Form of Amended and Restated Bylaws of the Registrant (to be effective upon completion of this offering)
4.1*		Specimen Common Stock Certificate
4.2+		Warrant to Purchase Stock issued to Comerica Bank on September 18, 2007
4.3+		Warrant to Purchase Stock issued to Comerica Bank on March 18, 2011
4.4+		Warrant to Purchase Stock issued to Silicon Valley Bank on July 24, 2013
4.5+		Subordinated Convertible Unsecured Promissory Note issued to BMV Direct RE LP on December 22, 2011
5.1*		Opinion of Goodwin Procter LLP
10.1#+		2014 Stock Plan and forms of agreements thereunder
10.2#*		2015 Stock Option and Incentive Plan and forms of agreements thereunder
10.3#+		Employment Agreement by and between the Registrant and John D. Mendlein, Ph.D., dated as of January 1, 2010
10.4#		Offer Letter by and between the Registrant and Frederic Chereau, dated December 20, 2013
10.5#		Offer Letter by and between the Registrant and David M. Weiner, M.D., dated February 20, 2014
10.6#		Amended and Restated Restricted Stock Purchase Agreement by and between the Registrant and John D. Mendlein, Ph.D., dated as of December 18, 2014
10.7†		Amended and Restated Research Funding and Option Agreement by and between the Registrant and The Scripps Research Institute, dated January 19, 2015
10.8+		Master Services Agreement by and between the Registrant and Syngene International Limited, dated November 5, 2012
10.9+		Lease by and between the Registrant and BMR-John Hopkins Court LLC, dated December 22, 2011
10.10+		Loan and Security Agreement by and between the Registrant and Silicon Valley Bank, dated April 25, 2012, as amended by First Amendment to Loan and Security Agreement by and between the Registrant and Silicon Valley Bank, dated July 24, 2013
10.11*		Fourth Amended and Restated Registration Rights Agreement by and among the Registrant and the stockholders named therein, dated April 8, 2013
10.12*		Form of Amended and Restated Indemnification Agreement
21.1+		Subsidiaries of the Registrant

 

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Exhibit No.		Exhibit
23.1*		Consent of Independent Registered Public Accounting Firm
23.2*		Consent of Goodwin Procter LLP (included in Exhibit 5.1)
24.1*		Power of Attorney (included in page II-4)

 

+	Previously submitted.

*	To be included by amendment.

†	Application has been made to the Securities and Exchange Commission for confidential treatment of certain provisions. Omitted material for which confidential treatment has been requested has been filed separately with the Securities and Exchange Commission.

#	Indicates a management contract or any compensatory plan, contract or arrangement.

 

II-6

Exhibit 10.4

 

December 20, 2013

Mr. Frederic Chereau

160 Upland Road

Cambridge, MA 02140

Dear Fred,

This letter is a formal offer setting forth the principal terms for you to join aTyr Pharma, Inc. (the “Company”), a Delaware corporation, which is located in San Diego, California. This offer is contingent upon satisfactory completion of a background check.

 

Position:		President and Chief Operating Officer
Location:		San Diego, CA
Status:		Full-Time, Exempt. This means you are paid for the job and not by the hour. Accordingly, you will not receive overtime pay if you work more than 8 hours in a work day or 40 hours in a workweek.
Reporting to:		John Mendlein, Ph.D., Executive Chairman and Chief Executive Officer
Base Salary Rate:		$15,000.00 semi-monthly (which equals $360,000.00 per year) less applicable withholdings, paid in accordance with Company’s normal payroll practices. Future adjustments in compensation, if any, will be made by the Company in its sole and absolute discretion.
Target Bonus:		Your annual target bonus will be 40% of your base salary with a range of 0-50% based upon the achievement of your individual goals, the achievement of team goals and the achievement of corporate goals. Your annual target bonus is subject to review and approval by the aTyr Board of Directors. Any bonus would be prorated based upon service in the year.
Equity:		Shortly after commencement of your employment with the Company, and subject to approval by the board of directors, you will be granted an Option to purchase 1,987,795 shares of the Common Stock of the Company pursuant to the 2007 Stock Plan. The exercise price per share of the Option shall be the fair market value of the Common Stock, as determined by the board of directors at the time of the Option grant. The specific terms and conditions of your Option will be subject to the terms

 

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Mr. Frederic Chereau

December 20, 2013

Page two

 

		of the 2007 Stock Plan, as well as the terms set forth in a Stock Option Agreement between you and the Company. This Stock Option Agreement will be entered into and executed after you commence your employment with the Company. In addition to the foregoing, in connection with the Company option grant, we anticipate that you will also be granted options to purchase a corresponding type and number of shares in each of the entities which the Company has previously spun-out as stand-alone entities (the “Related Entities”). The specific terms and conditions of your options in the Related Entities will be subject to the terms of the 2012 Stock Plan for each Related Entity, as well as the terms set forth in a Stock Option Agreement between you and the Related Entity.
Relocation Assistance:		You will be offered a lump sum relocation assistance payment in the amount of $45,000.00 to be paid at the time of your first paycheck. This amount will be grossed up for tax purposes. This payment will be subject to repayment to the Company if you voluntarily resign within one year of commencing your employment. We will also reimburse you up to $6,000.00 per month for up to 6 months for temporary housing.
Benefits:		You will be entitled to receive standard medical, life and dental insurance benefits for yourself and your dependents in accordance with Company policy. Company reserves the right to change or eliminate these benefits on a prospective basis at any time.
401(k) Plan:		You will be eligible to participate in the aTyr Pharma, Inc. 401(k) Savings Plan immediately following the start of your employment.
Vacation & Sick Time:		You will be entitled to accrue 15 days of vacation per year. You will have 6 days of sick time available each year.
Holidays:		You will be eligible for aTyr’s paid holidays. The schedule is published prior to the beginning of each calendar year.

 

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Mr. Frederic Chereau

December 20, 2013

Page three

 

Employment at Will:		Your employment will be at-will, which means it may be terminated at any time by you or the Company with or without cause and that your employment is not for any specific period of time. Any change to the at-will employment relationship must be by a specific, written agreement signed by you and the Company’s Chief Executive Officer.
Start Date:		January 9, 2014 based on a mutually agreed prorated part-time basis through February 28, 2014 or other mutually agreed full time status start date.

As a condition of your employment, you will be required to sign and abide by our Employee Nondisclosure and Assignment Agreement when you begin your employment. A copy is attached for your reference. In addition, in order to comply with the Immigration Reform and Control Act of 1986, within three (3) days of your Start Date you will be required to provide sufficient documentation to verify your identity and legal authorization to work in the United States. Please bring with you on your Start Date, the original of one of the documents noted in List A or one document from List B and one document from List C as itemized in the enclosed “Lists of Acceptable Documents”. If you do not have the originals of any of these documents, please contact me immediately.

In the event of any dispute or claim relating to or arising out of your employment relationship with the Company, this agreement, or the termination of your employment with the Company for any reason (including, but not limited to, any claims of breach of contract, defamation, wrongful termination or age, sex, sexual orientation, race, color, national origin, ancestry, marital status, religious creed, physical or mental disability or medical condition or other discrimination, retaliation or harassment), you and the Company agree that all such disputes shall be fully resolved by confidential, binding arbitration conducted by a single arbitrator through the American Arbitration Association (“AAA”) under the AAA’s National Rules for the Resolution of Employment Disputes then in effect, which are available online at the AAA’s website at www.adr.org. The arbitrator shall permit adequate discovery and is empowered to award all remedies otherwise available in a court of competent jurisdiction and any judgment rendered by the arbitrator may be entered by any court of competent jurisdiction. By executing this letter, you and the Company are both waiving the right to a jury trial with respect to any such disputes. Company shall bear the costs of the arbitrator, forum and filing fees. Each party shall bear its own respective attorney fees and all other costs, unless otherwise provided by law and awarded by the arbitrator.

 

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Mr. Frederic Chereau

December 20, 2013

Page four

 

It is aTyr’s policy to respect fully the rights of your previous employers in their proprietary or confidential information. No employee is expected to disclose, or is allowed to use for aTyr’s purposes, any confidential or proprietary information he or she may have acquired as a result of previous employment.

I am pleased to extend this offer to you and look forward to your acceptance. Please sign and return the enclosed copy of this offer letter as soon as possible to indicate your agreement with the terms of this offer. This offer will lapse if not signed and returned by December 24, 2013.

Once signed by you, this letter will constitute the complete agreement between you and aTyr Pharma, Inc. regarding employment matters and will supersede all prior written or oral agreements or understandings on these matters.

Our mission is to discover life-changing therapies with relentless determination for people with grave maladies where others fall short. I believe you will be able to make an immediate contribution to this mission and I think you will enjoy the rewards of working for an innovative, fast-paced company. One of the keys to our success is top people. We hope you accept our offer to be one of those people.

Yours sincerely,

/s/ John Mendlein, Ph.D.

John Mendlein, Ph.D.

Executive Chairman and Chief Executive Officer

Enclosures

I accept the terms of employment as described in this offer letter dated December 20^th, 2013 and will start my employment on January 9^th, 2014. I confirm that by my start date at aTyr Pharma, Inc. I will be under no contract or agreement with any other entity which would in any way restrict my ability to work at aTyr Pharma, Inc. or perform the functions of my job for aTyr, including, but, not limited to, any employment agreement and/or non-compete agreement.

 

/s/ Frederic Chereau		Date 1/09/14
Frederic Chereau

 

Exhibit 10.5

 

February 20, 2014

David Weiner, M.D.

P.O. 51245

Boston, MA 02205

Dear Dave,

This letter is a formal offer setting forth the principal terms for you to join aTyr Pharma, Inc. (“aTyr” or the “Company”), a Delaware corporation, which is located in San Diego, California. This offer is contingent upon satisfactory completion of the Questionnaire for Directors and Executive Officers.

 

Position:		Chief Medical Officer
Location:		San Diego, CA
Status:		Full-Time, Exempt. This means you are paid for the job and not by the hour. Accordingly, you will not receive overtime pay if you work more than 8 hours in a work day or 40 hours in a workweek.
Reporting to:		John Mendlein, Ph.D., Executive Chairman and Chief Executive Officer
Base Salary Rate:		$13,958.34 semi-monthly (which equals $335,000.00 per year) less applicable withholdings, paid in accordance with Company’s normal payroll practices. Future adjustments in compensation, if any, will be made by the Company in its sole and absolute discretion.
Target Bonus:		Your annual target bonus will be 30% of your base salary with a range of 0-40% based upon the achievement of your individual goals, the achievement of team goals and the achievement of corporate goals. Your annual target bonus is subject to review and approval by the aTyr Board of Directors. Any bonus will be prorated based upon service in a year.
Equity:		Shortly after commencement of your employment with the Company, and subject to approval by the board of directors, you will be granted an option to purchase 916,035 shares of the Common Stock of the Company (the “Initial Option”) pursuant to the Company’s 2007 Stock Plan (the “aTyr Plan”). Subject to your continued full-time employment with the Company, the shares subject to the Initial Option shall vest over a six (6)

 

 

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David Weiner, M.D.

February 20, 2014

Page two

 

		year period, with a one (1) year cliff, such that one-sixth (1/6) of the shares subject to the Initial Option shall vest on the first year anniversary of your employment start date and the remainder of the shares shall thereafter vest in equal monthly installments over the subsequent five (5) years. In addition, after commencement of your employment with the Company, and subject to approval by the board of directors, you will be granted an additional option to purchase 45,801 shares of the Common Stock of the Company (the “Additional Option” and together with the Initial Option, the “Options”) pursuant to the 2007 Stock Plan. Subject to your continued full-time employment with the Company, the shares subject to the Additional Option shall vest over a six (6) year period, with a one (1) year cliff, such that one-sixth (1/6) of the shares subject to the Additional Option shall vest on the first year anniversary of your employment start date and the remainder of the shares shall thereafter vest in equal monthly installments over the subsequent five (5) years. The exercise price per share of each of these Options shall be the fair market value of the Common Stock, as determined by the board of directors at the time the Options are grant. The specific terms and conditions of your Options will be subject to the terms of the 2007 Stock Plan, as well as the terms set forth in a Stock Option Agreement between you and the Company. This Stock Option Agreement will be entered into and executed after you commence your employment with the Company. In-addition to the foregoing, we anticipate that you will also be granted options to purchase a corresponding type and number of shares in each of the entities which the Company has previously spun-out as stand-alone entities (the “Related Entities”). The specific terms and conditions of the options in the Related Entities (the “Related Entity Options”) will be subject to the terms of the 2012 Stock Plan for each Related Entity, as well as the terms set forth in a Stock Option Agreement between you and the Related Entity. The vesting of the shares subject to the Options and Related Entity Options will be subject to acceleration in full if your employment with the Company is terminated by the Company (or any successor thereto) without Cause (as defined in the aTyr Plan) within twelve (12) months following a Change in Control (as defined in the aTyr Plan).

 

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David Weiner, M.D.

February 20, 2014

Page three

 

Relocation Assistance:		You will be offered a lump sum relocation assistance payment in the amount of $50,000.00 to be paid at the time of your first paycheck. This amount will be grossed up for tax purposes. This payment will be subject to repayment to the Company if you voluntarily resign within one year following commencing your employment.
Benefits:		You will be entitled to receive standard medical, life and dental insurance benefits for yourself and your dependents in accordance with Company policy. Company reserves the right to change or eliminate these benefits on a prospective basis at any time.
401(k) Plan:		You will be eligible to participate in the aTyr Pharma, Inc. 401(k) Savings Plan immediately following the start of your employment.
Vacation & Sick Time:		You will be entitled to accrue 15 days of vacation per year. You will have 6 days of sick time available each year.
Holidays:		You will be eligible for aTyr’s paid holidays. The schedule is published prior to the beginning of each calendar year.
Employment at Will:		Your employment will be at-will, which means it may be terminated at any time by you or the Company for any reason, with or without cause, and that your employment is not for any specific period of time. Any change to the at-will employment relationship must be by a specific, written agreement signed by you and the Company’s Chief Executive Officer.
Start Date:		March 17, 2014 or a mutually agreed upon date.

As a condition of your employment, you will be required to sign and abide by our Employee Nondisclosure and Assignment Agreement (the “Employee NDA”) when you begin your employment. A copy is attached for your reference. As a condition of your employment, you will also be required to abide by the Company’s code of conduct and other policies applicable to

 

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David Weiner, M.D.

February 20, 2014

Page four

 

employees as set forth in the Company’s employee handbook in effect from time to time. A copy will be made available to you during your employment. In addition, in order to comply with the Immigration Reform and Control Act of 1986, within three (3) days of your Start Date you will be required to provide sufficient documentation to verify your identity and legal authorization to work in the United States. Please bring with you on your Start Date, the original of one of the documents noted in List A or one document from List B and one document from List C as itemized in the enclosed “Lists of Acceptable Documents”. If you do not have the originals of any of these documents, please contact me immediately.

In the event of any dispute or claim relating to or arising out of your employment relationship with the Company, this agreement, or the termination of your employment with the Company for any reason (including, but not limited to, any claims of breach of contract, defamation, wrongful termination or age, sex, sexual orientation, race, color, national origin, ancestry, marital status, religious creed, physical or mental disability or medical condition or other discrimination, retaliation or harassment), you and the Company agree that all such disputes shall be fully resolved by confidential, binding arbitration conducted by a single arbitrator through the American Arbitration Association (“AAA”) under the AAA’s National Rules for the Resolution of Employment Disputes then in effect, which are available online at the AAA’s website at www.adr.org. The arbitrator shall permit adequate discovery and is empowered to award all remedies otherwise available in a court of competent jurisdiction and any judgment rendered by the arbitrator may be entered by any court of competent jurisdiction. By executing this letter, you and the Company are both waiving the right to a jury trial with respect to any such disputes. Company shall bear the costs of the arbitrator, forum and filing fees. Each party shall bear its own respective attorney fees and all other costs, unless otherwise provided by law and awarded by the arbitrator.

It is aTyr’s policy to respect fully the rights of your previous employers in their proprietary or confidential information. No employee is expected to disclose, or is allowed to use for aTyr’s purposes, any confidential or proprietary information he or she may have acquired as a result of previous employment.

I am pleased to extend this offer to you and look forward to your acceptance. Please sign and return the enclosed copy of this offer letter as soon as possible to indicate your agreement with the terms of this offer. This offer will lapse if not signed and returned by February 22, 2014.

 

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David Weiner, M.D.

February 20, 2014

Page five

 

Once signed by you, this letter, together with the Employee NDA, will constitute the complete agreement between you and the Company regarding employment matters and will supersede all prior written or oral agreements or understandings on these matters.

Our mission is to discover life-changing therapies with relentless determination for people with grave maladies where others fall short. I believe you will be able to make an immediate contribution to this mission and I think you will enjoy the rewards of working for an innovative, fast-paced company. One of the keys to our success is top people. We hope you accept our offer to be one of those people.

Yours sincerely,

/s/ John Mendlein, Ph.D.

John Mendlein, Ph.D.

Executive Chairman and Chief Executive Officer

Enclosures

 

I accept the terms of employment as described in this offer letter dated 2-21-14             and will start my employment on _3-17-14            . I confirm that by my start date at aTyr Pharma, Inc. I will be under no contract or agreement with any other entity which would in any way restrict my ability to work at aTyr Pharma, Inc. or perform the functions of my job for aTyr, including, but not limited to, any employment agreement and/or non-compete agreement.

 

/s/ David Weiner, M.D.				Date 2-21-14
David Weiner, M.D.

 

Exhibit 10.6

AMENDED AND RESTATED RESTRICTED STOCK PURCHASE AGREEMENT

This Amended and Restated Restricted Stock Purchase Agreement (this “Agreement”) is made and entered into as of December 18, 2014, by and between aTyr Pharma, Inc., a Delaware corporation (the “Company”), and John D. Mendlein (the “Purchaser”). Capitalized terms used but not otherwise defined herein will have the meanings ascribed to them in the Employment Agreement (as defined below).

WHEREAS, the Purchaser and the Company are parties to (i) an Employment Agreement, dated July 14, 2010, by and between the Purchaser and the Company (the “Employment Agreement”) and (ii) a Restricted Stock Purchase Agreement, dated July 14, 2010, by and between the Purchaser and the Company, as amended by the First Amendment to Restricted Stock Purchase Agreement, dated April 18, 2012 (the “Prior Purchase Agreement”);

WHEREAS, in connection with Purchaser’s continued employment by the Company, the Purchaser and the Company desire to amend and restate the Prior Purchase Agreement on the terms set forth below.

NOW, THEREFORE, in consideration of the mutual covenants and agreements herein contained and other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, the parties agree as follows:

1.          Issuance of Shares; Purchase Price. Prior to the date hereof, the Purchaser purchased, and the Company sold to Purchaser: (a) 1,157,200 shares of the Company’s common stock, par value $0.001 (the “Time Vested Shares”) and (b) 385,740 shares of the Company’s common stock, par value $0.001 (the “Milestone Vested Shares” and collectively with the Time Vested Shares, the “Shares”), all at a purchase price of $0.09 per share (the “Purchase Price”).

2.          Right to Repurchase Shares.

2.1       Termination. If the Purchaser will cease to be an employee, director or consultant of the Company (an “Advisor”), the Company will, from such time (as determined by the Company in its discretion), have an irrevocable, exclusive option to repurchase (the “Repurchase Right”) any Shares which have not yet been released from the Repurchase Right (the “Unreleased Shares”), at a price per share equal to the Purchase Price (as adjusted for stock splits, combinations, recapitalizations and the like).

2.2       Lapse of Repurchase Right. As of the date hereof, all of the Time Vested Shares and 192,870 of the Milestone Vested Shares are fully vested and not subject to the Repurchase Right. Subject to Section 2.4 below, the remaining Shares will be released from the Repurchase Right as follows: So long as the Purchaser’s continuing status as an Advisor has not been terminated, (i) 192,870 Milestone Vested Shares will be released from the Repurchase Right upon the completion of a firm commitment underwritten initial public offering of the Company’s securities pursuant to an effective registration statement under the Securities Act of 1933, as amended (the “Act”) in which the Company’s pre-money valuation exceeds $200 million and (ii) all or any portion of the remaining Milestone Vested Shares will be released from the Repurchase Right at the discretion of the Company’s Board of Directors upon the achievement of any other milestone mutually agreed upon by the Purchaser and the Company.

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2.3       Exercise of Repurchase Right. The Company may exercise its Repurchase Right by written notice to the Purchaser or Purchaser’s legal representative within 90 days after the date on which the Purchaser ceases to be an Advisor. Such notice will specify the number of Unreleased Shares which the Company elects to purchase and a date for the closing under this Section 2.3, which date will not be more than 30 days from the date of such notice. If the Company exercises its Repurchase Right, the Purchaser will, if necessary, endorse and deliver to the Company the stock certificates representing the Shares being repurchased, and the Company will pay the Purchaser the total repurchase price in cash upon such delivery. For purposes of the foregoing, cancellation of any promissory note made by the Purchaser to the Company shall be treated as payment by the Company to the Purchaser in cash for the Unreleased Shares to the extent of the unpaid principal amount of such promissory note and any accrued and unpaid interest canceled with respect thereto. The Purchaser will cease to have any rights with respect to such repurchased Shares immediately upon receipt of such written notice, provided the repurchase price is paid timely.

2.4       Acceleration of Lapse of Repurchase Right Upon Certain Events. Notwithstanding the provisions of Section 2.2 regarding expiration of the Repurchase Right, the lapse of the Repurchase Right will be accelerated upon the occurrence of certain events as set forth below:

(a)       If the Purchaser is no longer employed by the Company as a result of his Disability (as provided in the Employment Agreement) or dies, the Repurchase Right will expire with respect to 50% of the then remaining Unreleased Shares.

(b)       Immediately prior to the closing of a firm commitment underwritten initial public offering of the Company’s securities pursuant to an effective registration statement under the Act (an “IPO”), the Repurchase Right will expire with respect to 25% of the then remaining Unreleased Shares.

(c)       Immediately prior to the completion of a Change of Control (as provided in the Employment Agreement), the Repurchase Right will expire with respect to 50% of the then remaining Unreleased Shares. In addition, in the event Purchaser resigns as an employee of the Company for Good Reason or is terminated as an employee by the Company without Cause, as provided in the Employment Agreement, at any time within 12 months after the completion of a Change of Control, the Repurchase Right will expire with respect to all of the then remaining Unreleased Shares upon Purchaser’s resignation or termination.

(d)       Upon the election of the Company’s Board of Directors at any time, the Company may release all or a portion of the then remaining Unreleased Shares from the Repurchase Right.

With respect to the acceleration provided for in this Section 2.4, the Unreleased Shares for which vesting is accelerated will be the applicable percentage of the Unreleased Shares that would vest on each of the future dates or events on which vesting is to occur under Section 2.2. The acceleration in this Section 2.4 may be waived by the Purchaser at any time.

3.          Other Restrictions on Resale of Shares.

 

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3.1       Transfer Restrictions. The Purchaser may not dispose of or transfer any Shares that are subject to the Company’s Repurchase Right under Section 2; provided that the Purchaser may transfer any or all of the Shares to: (i) any member of the Purchaser’s immediate family or any trust for the benefit of the Purchaser or any such family member; or (ii) by will or the laws of descent and distribution. Prior to and as a condition of any transfer described in the preceding sentence, the transferee will agree (in a written agreement which will be satisfactory in form and substance to the Company and its counsel) to be bound by all of the provisions of this Agreement in the same manner as the Purchaser, and, whether or not the transferee so agrees, the Shares will remain Subject to, and the transferee will be bound by, those provisions (including, without limitation, the vesting provisions hereof, which will continue to relate to the Purchaser’s status as an Advisor). Upon any permitted transfer and absent the Company’s prior written approval to the contrary, the number of Unreleased Shares and released Shares transferred to the transferee will be in the same proportion as the number of Unreleased Shares and released Shares held by the Purchaser immediately prior to the transfer, and all subsequent vesting of Unreleased Shares will be attributed in the same proportion between the Purchaser and the transferee. For purposes of this Agreement, “immediate family” will mean the Purchaser’s spouse and lineal descendants (including, without limitation, stepchildren and adopted children). In addition, any transfer of Shares will be subject to the restrictions set forth in this Section 3 and restrictions imposed by federal and state securities laws. Any person or entity receiving any Shares that are transferred in accordance with this Agreement will agree in writing to be bound by the applicable terms of this Agreement.

3.2       Legends. The Purchaser understands and acknowledges that the Shares are not registered under the Act, and that under the Act and other applicable laws the Purchaser may be required to hold such Shares for an indefinite period of time. Each stock certificate representing Shares will bear the following legends:

“THE SECURITIES REPRESENTED BY THIS CERTIFICATE HAVE NOT BEEN REGISTERED UNDER THE SECURITIES ACT OF 1933, AS AMENDED. THE SECURITIES HAVE BEEN ACQUIRED FOR INVESTMENT AND MAY NOT BE SOLD, TRANSFERRED OR OTHERWISE DISPOSED OF EXCEPT IN COMPLIANCE WITH SUCH ACT.

THE SECURITIES EVIDENCED BY THIS CERTIFICATE ARE SUBJECT TO AGREEMENTS, COVENANTS AND RESTRICTIONS PROVIDED IN THE FOURTH AMENDED AND RESTATED STOCKHOLDERS AGREEMENT DATED APRIL 8, 2013, AS AMENDED, RESTATED OR OTHERWISE MODIFIED FROM TIME TO TIME, BY AND AMONG THE COMPANY AND THE PERSONS NAMED THEREIN. A COPY OF SUCH AGREEMENT MAY BE OBTAINED BY ANY STOCKHOLDER OF THE COMPANY UPON REQUEST WITHOUT CHARGE FROM THE SECRETARY OF THE CORPORATION AT THE PRINCIPAL OFFICE OF THE COMPANY.”

3.3       Market Standoff. The Purchaser hereby agrees that the Purchaser will not sell, offer, pledge, contract to sell, grant any option or contract to purchase, purchase any option or contract to sell, grant any right or warrant to purchase, lend or otherwise transfer or encumber, directly or indirectly, any Shares or other securities of the Company, nor will the Purchaser enter

 

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into any swap, hedging or other arrangement that transfers to another, in whole or in part, any of the economic consequences of ownership of any Shares or other securities of the Company, during the period from the filing of the first registration statement of the Company under the Act that includes securities to be sold on behalf of the Company to the public in an underwritten public offering under the Act through the end of the 180-day period following the effective date of such registration statement (or such other period as may be requested by the Company or the underwriters to accommodate regulatory restrictions on (i) the publication or other distribution of research reports and (ii) analyst recommendations and opinions, including, without limitation, the restrictions contained in NASD Rule 2711, or any successor provisions or amendments thereto). Purchaser further agrees, if so requested by the Company or any representative of the underwriters, to enter into such underwriter’s standard form of “lockup” or “market standoff” agreement in a form satisfactory to the Company and such underwriter. The Company may impose stop-transfer instructions with respect to securities subject to the foregoing restrictions until the end of any such restriction period.

4.          Representations and Acknowledgments of the Purchaser. The Purchaser hereby represents, warrants, acknowledges and agrees that:

4.1       Investment. The Purchaser is accruing the Shares for the Purchaser’s own account, and not directly or indirectly for the account of any other person or entity. The Purchaser is acquiring the Shares for investment and not with a view to distribution or resale thereof except in compliance with the Act and any applicable state law regulating securities.

4.2       Access to Information. The Purchaser has had the opportunity to ask questions of, and to receive answers from, appropriate executive officers of the Company with respect to the terms and conditions of the transactions contemplated hereby and with respect to the business, affairs, financial condition and results of operations of the Company. The Purchaser has had access to such financial and other information as is necessary in order for the Purchaser to make a fully informed decision as to investment in the Company, and has had the opportunity to obtain any additional information necessary to verify any of such information to which the Purchaser has had access.

4.3       Pre-Existing Relationship. The Purchaser further represents and warrants that the Purchaser has either (a) a pre-existing relationship with the Company or one or more of its officers or directors consisting of personal or business contacts of a nature and duration which enable the Purchaser to be aware of the character, business acumen and general business and financial circumstances of the Company or the officer or director with whom such relationship exists or (b) such business or financial expertise as to be able to protect the Purchaser’s own interests in connection with the purchase of the Shares.

4.4       Speculative Investment. The Purchaser’s investment in the Company represented by the Shares is highly speculative in nature and is subject to a high degree of risk of loss in whole or in part; the amount of such investment is within the Purchaser’s risk capital means and is not so great in relation to the Purchaser’s total financial resources as would jeopardize the personal financial needs of the Purchaser and the Purchaser’s family in the event such investment were lost in whole or in part.

 

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4.5       Accredited Investor. The Purchaser represents and warrants that the Purchaser is an “accredited investor” as denned in Rule 501 of Regulation D of the Act.

4.6       Unregistered Securities.

 (a)      The Purchaser must bear the economic risk of investment for an indefinite period of time because the Shares have not been registered under the Act and therefore cannot and will not be sold unless they are subsequently registered under the Act or an exemption from such registration is available. The Company has made no agreements, covenants or undertakings whatsoever to register any of the Shares under the Act. The Company has made no representations, warranties or covenants whatsoever as to whether any exemption from the Act, including, without limitation, any exemption for limited sales in routine brokers’ transactions pursuant to Rule 144 under the Act, will become available and any such exemption pursuant to Rule 144, if available at all, will not be available unless: (i) a public trading market then exists in the Company’s common stock, (ii) adequate information as to the Company’s financial and other affairs and operations is then available to the public, and (iii) all other terms and conditions of Rule 144 have been satisfied.

 (b)      Transfer of the Shares has not been registered or qualified under any applicable state law regulating securities and therefore the Shares cannot and will not be sold unless they are subsequently registered or qualified under any such act or an exemption therefrom is available. The Company has made no agreements, covenants or undertakings whatsoever to register or qualify any of the Shares under any such act. The Company has made no representations, warranties or covenants whatsoever as to whether any exemption from any such act will become available.

5.          Tax Matters.

(a)       The Purchaser acknowledges that the Purchaser has not relied and will not rely upon the Company orthe Company’s counsel with respect to any tax consequences related to the ownership, purchase, or disposition of the Shares. The Purchaser assumes full responsibility for all such consequences and for the preparation and filing of all tax returns and elections which may or must be filed in connection with such Shares.

(b)       Purchaser understands that Section 83(a) of the Code taxes as ordinary income the difference between the amount paid for the Shares and the fair market value of the Shares as of the date any restrictions on the Shares lapse. In this context, “restriction” means the right of the Company to buy back the Shares pursuant to the Repurchase Right as set forth in Section 2.3. Purchaser understands that Purchaser may elect to be taxed at the time the Shares are purchased, rather than when and as the Repurchase Right expires, by filing an election under Section 83(b) (an “83(b) Election”) of the Code with the Internal Revenue Service within 30 days from the date of purchase. Even if the fair market value of the Shares at the time of the execution of this Agreement equals the amount paid for the Shares, the election must be made to avoid income under Section 83(a) in the future. Purchaser understands that failure to file such an election in a timely manner may result in adverse tax consequences for Purchaser. Purchaser further understands that an additional copy of such election form should be filed with his or her federal income tax return for the calendar year in which the date of this Agreement falls.

 

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Purchaser acknowledges that the foregoing is only a summary of the effect of United States federal income taxation with respect to purchase of the Shares hereunder, and does not purport to be complete. Purchaser further acknowledges that the Company has directed Purchaser to seek independent advice regarding the applicable provisions of the Code, the income tax laws of any municipality, state or foreign country in which Purchaser may reside, and the tax consequences of Purchaser’s death.

6.          No Commitment. Nothing in this Agreement constitutes an agreement that the Purchaser will be employed or retained by the Company for any term and the Purchaser acknowledges that the Purchaser serves “at will.”

7.          Escrow of Shares. For purposes of facilitating the enforcement of the provisions of Section 2 above, the Purchaser agrees, that any and all certificate(s) representing Unreleased Shares subject to the Repurchase Right shall be held in escrow by the Secretary of the Company, or the Secretary’s designee, together with such assignment documentation as the Company deems reasonably necessary to enforce the provisions of Section 2 above and to effectuate all such transfers and/or releases as are in accordance with the terms of this Agreement. The Purchaser hereby acknowledges that the Secretary of the Company, or the Secretary’s designee, is so appointed as the escrow holder with the foregoing authorities as a material inducement to make this Agreement and that said appointment is coupled with an interest and is accordingly irrevocable. The Purchaser agrees that said escrow holder shall not be liable to any party hereof (or to any other party). The escrow holder may rely upon any letter, notice or other document executed by any signature purported to be genuine and may resign at any time. The Purchaser agrees that if the Secretary of the Company, or the Secretary’s designee, resigns as escrow holder for any or no reason, the Board shall have the power to appoint a successor to serve as escrow holder pursuant to the terms of this Agreement. At the written request of the Purchaser, and subject to the conditions set forth in the Joint Escrow Instructions entered into by the Company and Purchaser on the date of the Prior Purchase Agreement, the Company will promptly provide to the Purchaser a certificate representing any Shares that are not Unreleased Shares.

8.          Arbitration. Purchaser and the Company agree that any and all disputes, claims, or controversies of any nature whatsoever arising out of, or relating to, this agreement, or its interpretation, enforcement, breach, performance or execution, will be resolved, to the fullest extent permitted by law, by final, binding and confidential arbitration in San Diego, CA conducted before a single arbitrator by Judicial Arbitration and Mediation Services, Inc. (“JAMS”) or its successor, under the then-applicable JAMS rules. By agreeing to this arbitration procedure, both Purchaser and the Company waive the right to resolve any such dispute, claim or demand through a trial by jury or judge or by administrative proceeding. Purchaser will have the right to be represented by legal counsel at any arbitration proceeding. The arbitrator will: (a) have the authority to compel adequate discovery for the resolution of the dispute and to award such relief as would otherwise be available under applicable law in a court proceeding; and (b) issue a written statement signed by the arbitrator regarding the disposition of each claim and the relief, if any, awarded as to each claim, the reasons for the award, and the arbitrator’s essential findings and conclusions on which the award is based. The arbitrator, and not a court, will be authorized to determine whether the provisions of this paragraph apply to a dispute, controversy, or claim sought to be resolved in accordance with these arbitration procedures. The Company will pay all JAMS’ arbitration fees. Nothing in this Agreement is intended to prevent either

 

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Purchaser or the Company from obtaining injunctive relief in court if necessary to prevent irreparable harm pending the conclusion of any arbitration,

9.          Integration. This Agreement, the Employment Agreement and any other agreements pursuant to which Purchaser has received, or is entitled to receive from the Company any equity securities or rights to acquire equity securities of the Company, constitute the entire agreement between the parties with respect to the subject matter hereof and supersedes all prior agreements between the parties with respect to any related subject matter, including without limitation the Prior Purchase Agreement.

10.        Successors. This Agreement will be binding on and inure to the benefit of the Purchaser, the Purchaser’s heirs, executors, administrators and other legal representatives and will be binding on and inure to the benefit of the Company and its respective successors and assigns.

11.        Enforceability. If any portion or provision of this Agreement will to any extent be declared illegal or unenforceable by a court of competent jurisdiction, then the remainder of this Agreement, or the application of such portion or provision in circumstances other than those as to which it is so declared illegal or unenforceable, will not be affected thereby, and each portion and provision of this Agreement will be valid and enforceable to the fullest extent permitted by law.

12.        Waiver. No waiver of any provision hereof will be effective unless made in writing and signed by the waiving party. The failure of any party to require the performance of any term or obligation of this Agreement, or the waiver by any party of any breach of this Agreement, will not prevent any subsequent enforcement of such term or obligation or be deemed a waiver of any subsequent breach.

13.        Notices. Any notices, requests, demands and other communications provided for by this Agreement will be sufficient if in writing and delivered in person or sent by a nationally recognized overnight courier service or by registered or certified mail, postage prepaid, return receipt requested, to the Purchaser at the last address the Purchaser has filed in writing with the Company at its main offices, attention of the Chief Executive Officer, and will be effective on the date of delivery in person or by courier or three days after the date mailed.

14.        Amendment. This Agreement may be amended or modified only by a written instrument signed by the Purchaser and the Company (where such amendment has been approved by a majority of the members of the Board of Directors (excluding Purchaser)).

15.        Governing Law. This contract will be construed under and be governed in all respects by the laws of the State of California, without giving effect to the conflict of laws principles. With respect to any disputes concerning federal law, such disputes will be determined in accordance with the law as it would be interpreted and applied by the appropriate United States Court of Appeals.

16.        Counterparts; Facsimiles. This Agreement may be executed in two or more counterparts, each of which will be deemed an original, but all of which together will constitute one and the same instrument, and such counterparts may be delivered via facsimile.

[remainder of this page intentionally left blank]

 

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IN WITNESS WHEREOF, this Agreement has been executed as a sealed instrument by the Company, by its duly authorized representative, and by Purchaser, as of the date first above written.

 

ATYR PHARMA, INC.				PURCHASER
By		/s/ Nancy D. Krueger		By:		/s/ John D. Mendlein

 

Name:		Nancy D. Krueger		Name: John D. Mendlein

 

Title:		V.P. Legal Affairs & Secretary		Date:

 

Date:

CONSENT OF SPOUSE

(if applicable)

By execution of this Agreement, the undersigned spouse of the Purchaser agrees to be bound by the terms of this Agreement as to his or her interest, whether as community property or otherwise, if any, in the Shares purchased hereby, including, without limitation, the terms of Section 2.

 

Exhibit 10.7

CERTAIN CONFIDENTIAL PORTIONS OF THIS EXHIBIT WERE OMITTED AND REPLACED WITH “[***]”. A COMPLETE VERSION OF THIS EXHIBIT HAS BEEN FILED SEPARATELY WITH THE SECRETARY OF THE SECURITIES AND EXCHANGE COMMISSION PURSUANT TO AN APPLICATION REQUESTING CONFIDENTIAL TREATMENT UNDER RULE 406 OF THE SECURITIES ACT OF 1933.

 

 

AMENDED AND RESTATED RESEARCH FUNDING AND OPTION AGREEMENT

by and between

THE SCRIPPS RESEARCH INSTITUTE

a California nonprofit

public benefit corporation

and

aTYR PHARMA, INC.

a Delaware corporation

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TABLE OF CONTENTS

 

							Page
1.		DEFINITIONS					1
		1.1		Affiliate			1
		1.2		Agreement Number			2
		1.3		Biological Materials			2
		1.4		Confidential Information			2
		1.5		Field			3
		1.6		Joint Technology			3
		1.7		Patent Rights			3
		1.8		Principal Investigator			3
		1.9		Process			3
		1.10		Product			3
		1.11		Research Program			3
		1.12		Research Tool			3
		1.13		Service			4
		1.14		Sponsor Technology			4
		1.15		Technology			4
		1.16		TSRI Technology			4
		1.17		Valid Claim			4
2.		CONDUCT OF RESEARCH PROGRAM					4
		2.1		Conduct of Research Program			4
		2.2		Supervision of Research Program			4
		2.3		Reports			4
		2.4		TSRI Policies and Procedures			5
		2.5		Financial and Staffing Obligations			5
3.		INTELLECTUAL PROPERTY AND LICENSE OPTION					6
		3.1		Disclosure of Technology			6
		3.2		Grant of Option			6
		3.3		Grant of License			7
		3.4		Exercise of Option			7
		3.5		Biological Materials			9
		3.6		Non-Patented Technology			9
		3.7		Equity			9
4.		INTERESTS AND RIGHTS IN INTELLECTUAL PROPERTY					9
		4.1		Title			9
		4.2		Governmental Interest			9
		4.3		Reservation of Rights			10
		4.4		Patent Prosecution			10

 

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5.		CONFIDENTIALITY AND PUBLICATION					10
		5.1		Treatment of Confidential Information			11
		5.2		Permitted Uses			11
		5.3		Publications			11
		5.4		Publicity			11
6.		WARRANTIES					12
		6.1		Limited Warranty			12
		6.2		Limitation on Damages			12
7.		TERM AND TERMINATION					13
		7.1		Term			13
		7.2		Termination by Sponsor			13
		7.3		Termination Upon Non-Payment			13
		7.4		Termination Upon Default			13
		7.5		Termination Upon Insolvency			13
		7.6		Effect of Expiration or Termination			14
8.		ASSIGNMENT; SUCCESSORS					14
		8.1		Assignment			14
		8.2		Binding Upon Successors and Assigns			15
9		GENERAL PROVISIONS					15
		9.1		Independent Contractors			15
		9.2		Arbitration			15
		9.3		Entire Agreement; Modification; Satisfaction and Termination of Affiliate Equity Obligation			16
		9.4		California Law			17
		9.5		No Use of Name			17
		9.6		Headings			17
		9.7		Severability			17
		9.8		No Waiver			17
		9.9		Attorneys’ Fees			17
		9.10		Notices			17
		9.11		Compliance with U.S. Laws			18
		9.12		Further Assurances			18
EXHIBIT A				Research Program
EXHIBIT B				Budget
EXHIBIT C				Form of Material Transfer Agreement
EXHIBIT D				Form of Option Agreement
EXHIBIT E				Form of License Agreement
EXHIBIT F				Form of Common Stock Purchase Agreement

 

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AMENDED AND RESTATED RESEARCH FUNDING AND OPTION AGREEMENT

This Agreement is entered into this 19th day of January 2015 (the “Effective Date”), by and between THE SCRIPPS RESEARCH INSTITUTE, a California nonprofit public benefit corporation located at 10550 North Torrey Pines Road, La Jolla, California 92037 (“TSRI”), and aTyr Pharma, Inc., a Delaware corporation located at 3545 John Hopkins Court, Suite #250, San Diego, CA 92121 (“Sponsor”), with respect to the facts set forth below.

RECITALS

A.        WHEREAS, TSRI is a non-profit institution engaged in fundamental scientific biomedical and biochemical research including research relating to the function of aminoacyl tRNA synthetases in translation;

B.        WHEREAS, Sponsor has provided, and desires to continue to provide, certain funding as part of TSRI’s research activities into the structure and biological functions of aminoacyl tRNA synthetases, their fragments and accessory proteins;

C.        WHEREAS, TSRI has the exclusive right to grant a license in and to any technology developed pursuant to the research program described herein, subject to any non-exclusive rights of the U.S. Government, resulting from the receipt by TSRI of U.S. Government funding, to use such technology for its own purposes;

D.        WHEREAS, TSRI is willing to grant to Sponsor an option to acquire, under commercially reasonable terms taking into consideration Sponsor’s status as an early-stage company with limited financial resources, rights and licenses to use, enhance and develop technology arising from the Research Program and develop, market and sell products and provide services in the field described below;

E.        WHEREAS, Sponsor and TSRI are parties to that certain Research Funding and Option Agreement, dated as of October 31, 2007, as amended by First Amendment to Research Funding and Option Agreement, dated May 7, 2010, Second Amendment to Research Funding and Option Agreement, dated May 27, 2011, and Third Amendment to Research Funding and Option Agreement, dated June 1, 2011 (collectively, the “Prior Agreement”), pursuant to which, among other things, Sponsor had previously agreed to cause to be issued to TSRI shares of common stock in certain Affiliates of Sponsor representing the Equity Percentage (as defined in the Prior Agreement) (such obligation, the “Affiliate Equity Obligation”); and

F.        WHEREAS, Sponsor and TSRI desire to amend and restate the Prior Agreement as set forth in this Agreement.

NOW, THEREFORE, in consideration of the mutual covenants and conditions contained herein, TSRI and Sponsor hereby agree as follows:

1.        DEFINITIONS.

1.1        Affiliate. The term “Affiliate” shall mean any entity which directly or indirectly controls, or is controlled by Sponsor. The term “control” as used herein means (a) in

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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the case of corporate entities, direct or indirect ownership of at least fifty percent (50%) of the stock or shares entitled to vote for the election of directors; or (b) in the case of non-corporate entities, direct or indirect ownership of at least fifty percent (50%) of the equity interest with the power to direct the management and policies of such non-corporate entities. Unless otherwise specified, the term Sponsor includes Affiliates.

1.2      Agreement Number. This Agreement is TSRI number SFP-1698.

1.3      Biological Materials. The term “Biological Materials” shall mean any Technology in the form of tangible materials together with any progeny, mutants or derivatives thereof developed in performance of the Research Program.

1.4      Confidential Information. The term “Confidential Information” shall mean any and all proprietary information of TSRI or Sponsor which may be exchanged between the parties at any time and from time to time during the term hereof. “Proprietary Information” shall include information of the disclosing party that the disclosing party would consider confidential or proprietary under the circumstances. The fact that a party may have marked or identified as confidential or proprietary any specific information shall be indicative that such party believes such information to be confidential or proprietary, but the failure to so mark information shall not conclusively determine that such information was or was not considered confidential information by such party. Information shall not be considered confidential to the extent that it:

(a)        Is publicly disclosed through no act or omission of the receiving party, either before or after it becomes known to the receiving party; or

(b)        Was known to the receiving party prior to the date of this Agreement as demonstrated by competent evidence, which knowledge was acquired independently and not from the other party hereto (including such party’s employees); or

(c)        Is subsequently disclosed to the receiving party in good faith by a third party who has a right to make such disclosure; or

(d)        Has been published by a third party as a matter of right; or

(e)        Is independently developed by the receiving party without reference to, aid from or reliance on the Confidential Information of the disclosing party as demonstrated by competent evidence.

If Confidential Information is required to be disclosed by law or court order the party required to make such disclosure shall limit the same to the minimum required to comply with the law or court order, and shall use reasonable efforts to attempt to seek confidential treatment for that disclosure, and prior to making such disclosure that party shall notify the other party, not later than ten (10) days (or such shorter period of time as may be reasonably practicable under the circumstances) before the disclosure in order to allow that other party to comment and/or to obtain a protective or other order, including extensions of time and the like, with respect to such disclosure.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

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1.5      Field. The term “Field” shall mean any therapeutic, prognostic, diagnostic, or cosmeceutical use.

1.6      Joint Technology. The term “Joint Technology” shall mean any Technology developed jointly under principles arising under the patent laws of the United States of America by at least one employee of Sponsor that has assigned or has an obligation to assign its rights in such technology to Sponsor and one employee of TSRI that has assigned, or has an obligation to assign, its rights in such Technology to TSRI.

1.7      Patent Rights. The term “Patent Rights” shall mean rights arising out of or resulting from (a) any U.S./PCT patent application(s) (including without limitation continuations and divisionals) directed to the Technology; (b) the foreign patent applications associated with the patent applications referenced in subsection (a); (c) the patents issued from the patent applications referenced in subsection (a) and (b); (d) divisionals, continuations, reissues, reexaminations, restorations (including supplemental protection certificates) and extensions of any patent or application set forth in (a)—(c) above; and (e) any claims of continuations in part that are entitled to the benefit of the priority date of the application(s) referenced in sub clause (a) above.

1.8      Principal Investigator. The term “Principal Investigator” shall mean Dr. Xianglei Yang, together with such replacement persons selected in accordance with the provisions of Section 2.2 hereof.

1.9      Process. The term “Process” shall mean any method or process (a) the use, importation, sale, supply or performance of which would, in the absence of the license granted under a License Agreement substantially in the form of Exhibit E upon Sponsor successfully exercising its option under Section 3.4 of the Agreement, infringe a Valid Claim within the Patent Rights, or (b) that utilizes or incorporates Biological Materials.

1.10    Product. The term “Product” shall mean any product (a) the manufacture, use, importation, sale or offer for sale of which would, in the absence of the license granted under a License Agreement substantially in the form of Exhibit E upon Sponsor successfully exercising its option under Section 3.4 of the Agreement, infringe a Valid Claim within the Patent Rights, or (b) that utilizes or incorporates Biological Materials.

1.11    Research Program. The term “Research Program” shall mean the research program to be undertaken by TSRI under the direction and control of the Principal Investigator as contemplated by Exhibit A.

1.12    Research Tool. The term “Research Tool” shall mean any TSRI Technology which meets all three of the following criteria: (i) its primary usefulness is as a tool for discovery, and it is a broad, enabling invention that will be useful to many scientists (and not mainly to perform the research, or to develop the Products or the Processes, under the Research Project); and (ii) it is not used to produce a Product or incorporated into a Product; and (iii) it is not used to perform a Process.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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1.13    Service. The term “Service” shall mean the performance of a service for a third party, which performance uses or incorporates a Product or a Process.

1.14    Sponsor Technology. The term “Sponsor Technology” shall mean any Technology developed solely by Sponsor under principles arising under the patent laws of the United States of America.

1.15    Technology. The term “Technology” shall mean any invention, discovery, know-how, Biological Material, software, information, results, reagents and data, whether patentable or not, conceived, developed or reduced to practice in performance of the Research Program.

1.16    TSRI Technology. The term “TSRI Technology” shall mean any Technology, excluding Joint Technology, developed in whole or in part by TSRI under principles arising under the patent laws of the United States of America.

1.17    Valid Claim. The term “Valid Claim” shall mean a claim of an issued patent within the Patent Rights that has not lapsed, expired, been canceled, or become abandoned, and has not been held invalid by a court or other appropriate body of competent jurisdiction, unappealable or unappealed within the time allowed for appeal and which has not been admitted to be invalid or unenforceable through reissue or disclaimer or otherwise. The term Valid Claim shall also include the claims of a pending patent application within the Patent Rights, but only to the extent that such claim has been pending [***].

2.        CONDUCT OF RESEARCH PROGRAM.

2.1      Conduct of Research Program. TSRI hereby agrees to use reasonable efforts to perform the Research Program subject to the provisions of this Agreement. Notwithstanding the foregoing, TSRI makes no warranties or representations regarding its ability to achieve, nor shall it be bound to accomplish, any particular research objective or results.

2.2      Supervision of Research Program. TSRI agrees that the Research Program at TSRI shall be conducted by or under the direct supervision of the Principal Investigator. In the event that the Principal Investigator leaves TSRI, or terminates his/her involvement in the Research Program, TSRI shall use its best efforts to find a replacement Principal Investigator acceptable to Sponsor, which acceptance shall not be unreasonably withheld. In the event that TSRI shall fail to appoint a replacement Principal Investigator reasonably acceptable to Sponsor, Sponsor shall have a right to terminate this Agreement upon delivery to TSRI of written notice of intent to terminate pursuant to this Section 2.2, which notice must be delivered to TSRI not less than [***] nor more than [***] after delivery by TSRI to Sponsor of the name of the replacement Principal Investigator.

2.3      Reports. TSRI agrees that within sixty (60) days following the last day of each calendar year during the term of this Agreement, TSRI shall furnish Sponsor with a written report summarizing the results of the research included within the scope of the Research Program conducted by TSRI during the immediately preceding calendar year, including but not limited to

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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all data, conclusions, results, observations and a detailed description of all procedures (each, an “Annual Report”). Within sixty (60) days following the expiration or termination of this Agreement, TSRI shall provide Sponsor with a final written report containing (i) a summary of the results of the research performed under the Research Program and all conclusions and observations derived therefrom, and (ii) all data and results generated, and a detailed description of all procedures undertaken, during the Research Program (the “Final Report” and collectively with the Annual Reports, the “Reports”). All Reports shall constitute Confidential Information of TSRI. In the event that, resulting from its review of a Report, Sponsor identifies any Technology to which it would like to exercise its option and which has not been previously disclosed to Sponsor by TSRI in accordance with Section 3.1, Sponsor shall notify TSRI of such in writing. Upon such notification, TSRI shall provide Sponsor with a Technology Disclosure in accordance with Section 3.1. Sponsor may exercise its option to the Technology covered by the Technology Disclosure as specifically set forth in Section 3.4. For the avoidance of doubt, TSRI’s obligation to provide an Annual Report pursuant to this Section 2.3 shall cease upon delivery to Sponsor of the Final Report.

2.4      TSRI Policies and Procedures. TSRI has developed internal policies and procedures regarding the dissemination of results, data, materials and other tangible information generated during sponsored research projects such as the Research Program. TSRI will instruct the Principal Investigator to comply with such policies and procedures during the performance of the Research Program.

2.5      Financial and Staffing Obligations.

(a)        Contributions of Parties to Research Program. Contributions in the form of financial support, equipment, personnel, technology and other necessary components for the conduct of the Research Program shall be made by the parties in accordance with the terms set forth on Exhibit B attached to this Agreement, which will be completed by the parties in good faith within thirty (30) days of the Effective Date for the next twelve (12) months thereafter, and then updated by the parties in good faith for each next succeeding twelve (12) month period during the term of this Agreement. All payments due to TSRI by Sponsor shall be payable in U.S. Dollars by Sponsor in quarterly installments in advance, within ten (10) days following the dates set forth in the following payment schedule; provided, that the due dates and payment amounts set forth below may be adjusted by the parties from time to time by mutual written agreement:

 

Due Date		Amount
2/28/2015		$[***]
5/31/2015		$[***]
8/31/2015		$[***]
11/30/2015		$[***]
On each anniversary of the foregoing dates during the term of this Agreement		$[***]

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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Each payment must reference the Research Project title, Agreement Number and Principal Investigator for purposes of identification. Payments under this Section shall be sent to:

The Scripps Research Institute

10550 North Torrey Pines Road, TPC-7

La Jolla, California 92037

Attn: Vice President, Sponsored Programs

Fax No.: (858) 784-8037

with a copy to:

The Scripps Research Institute

10550 North Torrey Pines Road, TPC-9

La Jolla, California 92037

Attn: Director, Technology Development

Fax No.: (858) 784-9910

TSRI shall not be obligated to perform any of the research specified herein or to take any other action required under this Agreement if the funding is not provided as set forth in Exhibit B and in accordance with the payment schedule as set forth in this Section 2.5(a). Sponsor and TSRI acknowledge and agree that as of the Effective Date, Sponsor has paid to TSRI all accrued amounts due to TSRI under the Prior Agreement.

(b)        Capital Equipment. Equipment purchased by TSRI with funds provided by Sponsor shall be the property of TSRI. All capital equipment provided under this Agreement by Sponsor for the use of TSRI remains the property of the Sponsor unless other disposition is mutually agreed upon in writing by the parties. If title to this equipment remains with the Sponsor, Sponsor is responsible for maintenance and repair of the equipment, insuring the equipment against damage or loss, and the costs of its transportation to and from the site where it will be used.

3.        INTELLECTUAL PROPERTY AND LICENSE OPTION.

3.1      Disclosure of Technology. After Principal Investigator submits an invention disclosure covering any Technology to TSRI’s Office of Technology Development, TSRI shall disclose such Technology in writing to Sponsor (the “Technology Disclosure”). TSRI shall use reasonable efforts to provide a Technology Disclosure that contains sufficient detail to (i) enable both parties to determine whether or not the particular Technology is TSRI Technology or Joint Technology; and (ii) enable Sponsor to evaluate the advisability of exercising the option granted under Section 3.2. All such Technology Disclosures shall be Confidential Information of TSRI.

3.2      Grant of Option. Subject to the terms of this Agreement and the reservation of rights specified in Sections 4.2 and 4.3 hereof, TSRI hereby grants to Sponsor:

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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(a)        an exclusive option to acquire an exclusive, worldwide license, including the right to sublicense, under TSRI’s rights in the Patent Rights to (i) practice the Patent Rights; (ii) make and have made, to use and have used, and to import Products, Services, Processes and Biological Materials in the Field; and (iii) offer for sale, sell and have sold Products, Services, Processes and Biological Materials in the Field. In the event that a Service or Process utilizes a Research Tool, such Research Tool shall be made available to Sponsor solely on a nonexclusive basis as set forth in Section 3.2(b); and

(b)        an exclusive option to acquire a nonexclusive, worldwide license to make and have made, to use and have used, to sell and have sold, to offer to sell and to import any Biological Materials and Research Tools in the Field and the right to sublicense solely for research and development, manufacturing and/or distribution purposes.

3.3      Grant of License. Subject to Sections 4.2 and 4.3, TSRI hereby grants to Sponsor a nonexclusive, royalty-free, non-transferable license to make and use TSRI Technology solely for Sponsor’s internal research purposes. Any transfer of materials to Sponsor under this Section 3.3 shall require the execution of a Material Transfer Agreement. The terms of such Material Transfer Agreement shall be materially consistent with the form Material Transfer Agreement attached hereto as Exhibit C. Subject to Sections 4.2 and 4.3, Sponsor has the right to acquire an exclusive, non-transferable, non-commercial license to make and use TSRI Technology (except for TSRI Technology that constitutes a Research Tool) for internal research purposes, pursuant to the terms and conditions of a non-commercial license agreement to be negotiated in good faith between the parties. Sponsor shall notify TSRI in writing within [***] following receipt of the particular Technology Disclosure of its desire to exclusively license such TSRI Technology pursuant to this Section 3.3. TSRI and Sponsor shall have a period of [***] from the date of that notification to execute a non-commercial, exclusive license agreement.

3.4      Exercise of Option.

(a)        Good Faith Negotiations. TSRI and Sponsor covenant to negotiate with reasonable diligence and in good faith to enter into a License Agreement (as defined below) in the event the Sponsor elects to exercise the option granted in Section 3.2 hereof.

(b)        Option Period. Sponsor shall have a period of [***] from receipt of the Technology Disclosure from TSRI within which to exercise its option in accordance with this Section 3.4 (the “Option Period”).

(c)        Option Notice. Subject to subsection (d) hereof, Sponsor shall exercise the option granted under Section 3.2 by delivering to TSRI a written notice within the Option Period (the “Option Notice”) which specifies (i) the particular Technology Disclosure for which the option is being exercised; and (ii) the type of license that Sponsor wishes to obtain. Upon such notification, Sponsor and TSRI shall have a period of [***] from the date of the Option Notice (or such longer period as the parties mutually agree) to negotiate with reasonable diligence and in good faith to enter into an Option Agreement in the form attached hereto as Exhibit D, specifying license fees, royalty rates, commercial development obligations and other business terms of a license agreement (the “License Agreement”). The terms of the License Agreement shall be materially consistent with terms set forth in the Form of License Agreement

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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attached hereto as Exhibit E. The “Field” in such License Agreement shall be as broad as the Field defined herein. Upon execution of the Option Agreement, and at Sponsor’s expense, TSRI shall prepare, file and prosecute any patent applications necessary to protect the proprietary positions of both parties in the Technology in accordance with Section 4.4 hereof. TSRI and Sponsor shall have [***] from the filing of a patent application in which to execute a License Agreement to the resulting Patent Right.

(d)        Patent Notice. In lieu of exercising its option in accordance with Section 3.4(c), Sponsor may, in its sole discretion, elect to pay for the filing of a provisional patent application claiming or covering the Technology that is the subject of the Technology Disclosure. In the event that the Sponsor determines it will support and pay the filing of a provisional patent application, it shall send written notice to TSRI within the Option Period, that it will pay for the filing of one or more provisional patent applications in respect of such Technology (the “Patent Notice”). The parties hereby agree that TSRI shall prepare and file such provisional patent application for the Technology identified by Sponsor in the Patent Notice in accordance with Section 4.4 hereof. Sponsor shall have [***] from the date of filing a patent application in which to deliver to TSRI an Option Notice for the patent application. Upon delivery of the Option Notice pursuant to this Section 3.4(d), the parties shall have [***] in which to negotiate with reasonable diligence and in good faith to enter into a License Agreement for the patent application, which shall be materially consistent with the terms of the License Agreement set forth in Exhibit E.

(e)        Failure to Exercise Option. Upon the expiration of the Option Period, if TSRI has not received an Option Notice or a Patent Notice with respect to TSRI Technology disclosed in a Technology Disclosure, except as set forth in subsection (f) of this Section 3.4 the Sponsor’s option with respect to such Technology shall be of no further force and effect. TSRI may thereafter file a patent application at its own expense for such TSRI Technology. In the event TSRI has not received an Option Notice or a Patent Notice with respect to Joint Technology disclosed in a Technology Disclosure, both parties shall (i) have no further obligations to each other with respect to such Joint Technology and any resulting Patent Rights; and (ii) subject to subsection (f) of this Section 3.4 be free to independently license or otherwise dispose of their rights to such Joint Technology and any resulting Patent Rights on a worldwide basis, with no obligation to obtain consent of the other party or to account to the other party for profits or otherwise.

(f)        [***]

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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3.5      Biological Materials. In the event Sponsor exercises its option under Section 3.2(b) to obtain a non-exclusive license to Biological Materials, the parties shall execute a material transfer agreement in substantially the form attached hereto as Exhibit C.

3.6      Non-Patented Technology. In the event that Sponsor exercises its option under Section 3.2(b) to obtain a non-exclusive license to Biological Material or Research Tools, and the parties agree not to obtain patent protection on such Biological Material or Research Tools, TSRI and Sponsor shall have [***] from the date of exercise of the option by Sponsor in which to execute a mutually acceptable license agreement to such Biological Material or Research Tools which agreement shall be on terms and conditions which are reasonable and customary for an agreement between an academic institution and a small company.

3.7      Equity. Within thirty (30) days of the Effective Date, Sponsor will issue 953,228 shares of its common stock, par value $0.001 per share (the “Shares”), to TSRI, at a price of $0.001 per share. Sponsor and TSRI shall enter into a Common Stock Purchase Agreement, in substantially the form attached hereto as Exhibit F (the “Common Stock Purchase Agreement”), in order to memorialize the purchase and sale of the Shares. The parties acknowledge that the shares to be issued pursuant to the Common Stock Purchase Agreement represent all of the shares of the capital stock of Sponsor that TSRI is currently entitled to receive pursuant to the TSRI Agreements (as defined below).

4.        INTERESTS AND RIGHTS IN INTELLECTUAL PROPERTY.

4.1      Title. TSRI shall retain sole ownership and title to TSRI Technology and to all intellectual property rights related thereto. TSRI shall, in the good faith exercise of its discretion, undertake reasonable efforts to preserve and maintain its ownership and title as TSRI deems appropriate, provided, however, that TSRI cannot, by transfer of ownership, title or otherwise, take any action that would prevent TSRI from granting the rights to Sponsor under the option set forth in Section 3.2 or under a License Agreement, provided Sponsor properly exercises its rights thereunder. Ownership of and title to Joint Technology shall be vested jointly in TSRI and Sponsor, with each owning an undivided interest therein. Sponsor shall retain sole ownership and title to Sponsor Technology, and nothing in this Agreement shall be construed as granting TSRI any interest, express or implied, in the Sponsor Technology. Ownership of Patent Rights shall follow inventorship under principles arising under the patent laws of the United States of America.

4.2      Governmental Interest. TSRI and Sponsor acknowledge that TSRI has received, and expects to continue to receive, funding from the United States Government in support of TSRI’s research activities. TSRI and Sponsor acknowledge and agree that their respective rights and obligations pursuant to this Agreement shall be subject to the rights of the United States Government, existing and as amended, which may arise or result from TSRI’s receipt of research support from the United States Government, including but not limited to,

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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37 CFR 401, the NIH Grants Policy Statement and the NIH Guidelines for Obtaining and Disseminating Biomedical Research Resources.

4.3      Reservation of Rights. TSRI reserves the right to use for any non-commercial research or educational purposes any Patent Rights, Biological Materials or Research Tools licensed hereunder, without TSRI being obligated to pay Sponsor any royalties or other compensation. In addition, TSRI reserves the right to grant non-commercial, non-exclusive research and educational use licenses to other nonprofit or academic institutions to Patent Rights, Biological Materials or Research Tools, without the other non-profit entity being obligated to pay Sponsor any royalties or other compensation. TSRI shall have no obligation to notify or inform Sponsor of such use or licenses.

4.4      Patent Prosecution.

(a)        TSRI shall direct and control the preparation, filing and prosecution of the United States and foreign patent applications within Patent Rights (including without limitation any reissues, reexaminations, appeals to appropriate patent offices and/or courts, interferences and foreign oppositions). TSRI shall select the patent attorney, subject to Sponsor’s written approval, which approval shall not be unreasonably withheld. The parties agree that TSRI shall have the right, at its sole discretion, to utilize TSRI’s Office of Patent Counsel in addition to independent counsel for patent prosecution and maintenance described herein, and the fees and expenses associated with the work done by such Office of Patent Counsel and/or independent counsel shall be paid as set forth below. Sponsor shall have full rights of consultation with the patent attorney so selected on all matters relating to the Patent Rights. TSRI shall implement all reasonable and timely requests made by Sponsor with regard to the preparation, filing, prosecution and/or maintenance of the patent applications and/or patents within the Patent Rights, including without limitation requests relating to the jurisdictions in which TSRI shall prepare, file, prosecute and maintain patent applications. Pursuant to this Section 4.4(a) and as of the Effective Date, TSRI and Sponsor are using the services of Cooley LLP for matters related to the prosecution and maintenance of the Patent Rights.

(b)        TSRI shall keep Sponsor timely informed with regard to the patent application and maintenance processes. TSRI shall deliver to Sponsor copies of all patent applications, amendments, related correspondence, and other related matters in a timely matter.

(c)        Sponsor agrees to pay and shall pay all reasonable patent costs and expenses incurred by TSRI for the filing, prosecution and maintenance the United States and foreign patent applications as set forth in Section 3.4(c) and 3.4(d) hereof. Sponsor agrees to pay and shall pay all such reasonable expenses within thirty (30) days after Sponsor receives an itemized invoice therefor. Payment shall be made to TSRI. Failure of Sponsor to pay patent costs and expenses as set forth herein shall immediately relieve TSRI from its obligation to incur further patent costs and expenses or to continue to prosecute the patent applications, provided, however, that TSRI’s obligation to incur patent costs and expenses and to prosecute the patent applications shall, to the extent possible, be immediately restored upon Sponsor’s payment of such patent costs and expenses.

5.        CONFIDENTIALITY AND PUBLICATION.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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5.1       Treatment of Confidential Information. The parties agree that during the term of this Agreement, and for a period of five (5) years after this Agreement terminates, a party receiving Confidential Information of the other party will (a) maintain in confidence such Confidential Information to the same extent such party maintains its own proprietary information, provided that such standard shall be not less than reasonable care; (b) not disclose such Confidential Information to any third party without the prior written consent of the other party; and (c) not use such Confidential Information for any purpose except those permitted by this Agreement.

5.2       Permitted Uses. Notwithstanding Section 5.1 above, the receiving party may use or disclose Confidential Information of the disclosing party only to the extent necessary to prepare, file and prosecute patent applications.

5.3       Publications. Sponsor acknowledges that it is the general policy of TSRI to encourage publication of research results in technical or scientific journals; and Sponsor agrees that TSRI shall have a right to publish in accordance with its general policy. For purposes of this Section 5, “publish” and “publication” shall include all types of written publication or dissemination of research results or data to third parties that have been actually submitted to TSRI’s Office of Technology Development for review in accordance with TSRI’s policies and procedures. TSRI shall submit to Sponsor copies of all proposed publications which describe Technology and afford Sponsor a period of [***] to review such publication to (i) ascertain whether Sponsor’s Confidential Information would be disclosed by the publication; and (ii) ascertain whether or not the publication discloses any Technology to which Sponsor wishes to exercise its option. If such publication discloses Sponsor’s Confidential Information and upon Sponsor’s written request, TSRI shall at Sponsor’s election remove such Confidential Information and/or delay publication for up to an additional [***] to allow Sponsor to protect its Confidential Information by filing a patent application(s). In the event that Sponsor identifies any Technology for which Sponsor may want to exercise its option, Sponsor shall notify TSRI of such in writing within the above [***] period. Upon such notification, TSRI may (i) file any patent applications necessary to protect the proprietary positions of both parties in the Technology in accordance with Section 4.4 hereof; and (ii) shall provide Sponsor with a Technology Disclosure in accordance with Section 3.1 hereof. Absent receipt by TSRI of any written instruction by Sponsor within the [***] review period, TSRI shall be free to make the proposed disclosure or publish the proposed publication.

5.4       Publicity. Except as otherwise provided herein, each party agrees not to disclose any terms of this Agreement to any third party without the prior written consent of the other party, except (i) as required by securities or other applicable laws and regulations, (ii) to existing and prospective investors, (iii) to existing or potential business partners or acquirers, (iv) to agencies of the government or private foundations for purposes of obtaining grants or other funding or providing reports to such agencies or foundations, and, (v) to accountants, attorneys and other professional advisors of such party, provided that except for subclause (ii) and (iii) above, such third parties have signed written confidentiality agreements at least as restrictive as the confidentiality obligations herein, or such third parties shall be under a duty of confidentiality, before any such disclosures, and with respect to subclause (i) above the disclosing party uses reasonable efforts to seek confidential treatment for the disclosure of any

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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terms of this Agreement that the disclosing party reasonably believes are likely to cause substantial competitive harm to the parties if disclosed. Scientific publications published in accordance with Section 5.3 of this Agreement shall not be construed as publicity governed by this Section 5.4.

6.       WARRANTIES.

6.1       Limited Warranty. TSRI hereby represents and warrants that it has full right and power to enter into this Agreement and to perform its obligations hereunder, to grant the options, licenses and other rights provided herein, and that this Agreement does not conflict with any other agreement or understanding to which TSRI is a party or by which TSRI may be bound. TSRI MAKES NO OTHER WARRANTIES CONCERNING PATENT RIGHTS, TECHNOLOGY, BIOLOGICAL MATERIALS, RESEARCH TOOLS OR ANY OTHER MATTER WHATSOEVER, INCLUDING WITHOUT LIMITATION, THE EXPRESS OR IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE, NON-INFRINGEMENT OF THIRD PARTY RIGHTS OR ARISING OUT OF COURSE OF CONDUCT OR TRADE CUSTOM OR USAGE, AND TSRI DISCLAIMS ALL SUCH EXPRESS OR IMPLIED WARRANTIES. TSRI MAKES NO WARRANTY OR REPRESENTATION AS TO THE VALIDITY OR SCOPE OF PATENT RIGHTS, OR THAT ANY PRODUCT, TECHNOLOGY, PROCESS, SERVICE, RESEARCH TOOL, OR BIOLOGICAL MATERIALS WILL BE FREE FROM AN INFRINGEMENT ON PATENTS OR OTHER INTELLECTUAL PROPERTY RIGHTS OF THIRD PARTIES, OR THAT NO THIRD PARTIES ARE IN ANY WAY INFRINGING UPON ANY PATENT RIGHTS, TECHNOLOGY, BIOLOGICAL MATERIALS OR RESEARCH TOOLS COVERED BY THIS AGREEMENT. FURTHER, TSRI HAS MADE NO INVESTIGATION AND MAKES NO REPRESENTATION THAT THE TECHNOLOGY, PATENT RIGHTS, BIOLOGICAL MATERIALS OR RESEARCH TOOLS ARE SUITABLE FOR SPONSOR’S PURPOSES.

6.2       Limitation on Damages. IN NO EVENT SHALL EITHER PARTY BE LIABLE FOR ANY INDIRECT, SPECIAL, INCIDENTAL, EXEMPLARY, PUNITIVE OR CONSEQUENTIAL DAMAGES (INCLUDING, WITHOUT LIMITATION, DAMAGES FOR LOSS OF PROFITS OR EXPECTED SAVINGS OR OTHER ECONOMIC LOSSES, OR FOR INJURY TO PERSONS OR PROPERTY) ARISING OUT OF OR IN CONNECTION WITH THIS AGREEMENT OR ITS SUBJECT MATTER. [***] AGGREGATE LIABILITY FOR ALL DAMAGES OF ANY KIND RELATING TO THIS AGREEMENT OR ITS SUBJECT MATTER SHALL NOT EXCEED THE AMOUNT PAID BY SPONSOR TO TSRI UNDER THIS AGREEMENT. THE FOREGOING EXCLUSIONS AND LIMITATIONS SHALL APPLY TO ALL CLAIMS AND ACTIONS OF ANY KIND AND ON ANY THEORY OF LIABILITY, WHETHER BASED ON CONTRACT, TORT (INCLUDING, BUT NOT LIMITED TO NEGLIGENCE OR STRICT LIABILITY), OR ANY OTHER GROUNDS, AND REGARDLESS OF WHETHER SUCH PARTY HAS BEEN ADVISED, OR SHOULD HAVE KNOWN, OF THE POSSIBILITY OF SUCH DAMAGES, AND NOTWITHSTANDING ANY FAILURE OF ESSENTIAL PURPOSE OF ANY LIMITED REMEDY. THE PARTIES FURTHER AGREE THAT EACH WARRANTY DISCLAIMER, EXCLUSION OF DAMAGES OR OTHER LIMITATION OF LIABILITY HEREIN IS INTENDED TO BE

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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SEVERABLE AND INDEPENDENT OF THE OTHER PROVISIONS SINCE THEY EACH REPRESENT SEPARATE ELEMENTS OF RISK ALLOCATION BETWEEN THE PARTIES.

7.       TERM AND TERMINATION.

7.1       Term. Unless terminated sooner, the initial term of this Agreement shall commence on the Effective Date and terminate at 5:00 p.m. California time on May 30, 2015, and thereafter shall renew automatically for successive twelve (12) month periods from 9:00 a.m. California time on May 31^st of one year until 5:00 p.m. California time on May 30th of the following year, unless Sponsor elects to terminate this Agreement effective on May 30, 2015 or on any May 30^th thereafter by written notice to TSRI at least thirty (30) days before the applicable May 30^th. Notwithstanding the foregoing, if a Technology Disclosure has previously been delivered to Sponsor or is delivered to Sponsor upon the expiration or termination of this Agreement pursuant to Section 7.6(b), the term of this Agreement shall automatically be extended until the earlier of the execution of a License Agreement with respect to such Technology or the expiration of any and all rights of Sponsor to enter into a License Agreement with respect to the Technology in accordance with Section 3.4.

7.2       Termination by Sponsor. This Agreement may be terminated at any time by Sponsor by giving six (6) months prior written notice to TSRI. In the absence of a written agreement to the contrary, no such termination shall have the effect of relieving Sponsor of its monetary obligations to fund the Research Program, to pay patent costs or other monetary obligations hereunder which shall have accrued up and to the date of such termination.

7.3       Termination Upon Non-Payment. In the event that Sponsor fails to pay to TSRI any payment within the time frame set forth in Section 2.5(a), TSRI shall not be obligated to perform any of the research specified herein or to take any other action required under this Agreement and may terminate this Agreement if TSRI has not received payment within ten (10) days after TSRI furnishes to Sponsor written notice of such non-payment. Termination pursuant to this Section 7.3 shall not relieve Sponsor of any liability under this Agreement that accrued prior to such termination.

7.4       Termination Upon Default. Except as specified in Sections 7.3 and 7.5, the failure of a party to perform any obligation required of it to be performed hereunder and the failure to cure within sixty (60) days after receipt of notice from the other party specifying in reasonable detail the nature of such default, shall constitute an event of default hereunder. Upon the occurrence of an event of default, the non-defaulting party may deliver to the defaulting party written notice of intent to terminate, such termination to be effective upon the date set forth in such notice. Such termination rights shall be in addition to and not in substitution for any other remedies that may be available to the non-defaulting party serving such notice against the defaulting party. Termination pursuant to this Section 7.4 shall not relieve the defaulting party of liability and damages to the non-defaulting party for breach of this Agreement. Waiver by any party of a single default or a succession of defaults shall not deprive such party of any right to terminate this Agreement arising by reason of any subsequent default.

7.5       Termination Upon Insolvency. This Agreement may be terminated as to any party (“Insolvent Party”) by another party giving written notice of termination to the

 

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Insolvent Party upon the filing of bankruptcy or bankruptcy of the Insolvent Party or the appointment of a receiver of any of the Insolvent Party’s assets, or the making by the Insolvent Party of any assignment for the benefit of creditors, or the institution of any proceedings against the Insolvent Party under any bankruptcy law which proceeding has not been terminated or dismissed after ninety (90) days. Termination shall be effective upon the date specified in this notice.

7.6       Effect of Expiration or Termination.

(a)       Termination Upon Default of Sponsor. Upon the termination of this Agreement by reason of a default by Sponsor, neither party shall have any further rights or obligations with respect to this Agreement, other than the obligation of Sponsor to make any and all final payments accrued prior to the date of termination and the obligation of the parties to make all reports required hereunder. Upon such termination of this Agreement, the parties shall continue to abide by their non-disclosure obligations as described in Section 5.1 and each party hereto shall fulfill any other obligations incurred prior to such termination. Any such termination of this Agreement shall not constitute the termination of any license or any other agreements between the parties which are then in effect except as expressly provided therein. In addition, upon such termination, Sponsor’s options under Section 3 shall be deemed automatically cancelled, and Sections 4, 6, 7 and 9 shall survive any such termination.

(b)       Expiration or Termination upon Default of TSRI. Upon the expiration of this Agreement at its regularly scheduled expiration date, or upon a termination of this Agreement on account of a default by TSRI, then TSRI shall prepare and submit the Final Report in accordance with Section 2.3 and make the disclosures required by Section 3.1 for TSRI Technology conceived or reduced to practice up to the date of said expiration or termination; and Sponsor shall have the right to exercise its option with respect to said TSRI Technology in accordance with the schedule and procedures specified in Sections 3.2 and 3.4 above. Additionally, each party shall perform all other obligations up to the date of said expiration or termination; and the parties shall continue to abide by their non-disclosure obligations described in Section 5.1. Following receipt of a notice of termination from Sponsor, TSRI shall use its reasonable efforts to avoid incurring any additional non-cancelable commitments in connection with the Research Program without Sponsor’s prior written approval. Any such expiration or termination of this Agreement shall not constitute the termination of any license or any other agreements between the parties which are then in effect except as expressly provided therein. Upon such expiration or termination, Sections 4, 6, 7 and 9 shall survive.

8.       ASSIGNMENT; SUCCESSORS.

8.1       Assignment. This Agreement may not be assigned or otherwise transferred by either party without the prior express written consent of the other party, which consent shall not be unreasonably withheld; provided, however, that a party may, without such consent, assign this Agreement and its rights and obligations hereunder (i) to an Affiliate, (ii) in connection with a merger, acquisition, consolidation or a sale involving all or substantially all of the assets of such party. Any attempted assignment or transfer in violation of this Section 8.1 shall be void.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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8.2       Binding Upon Successors and Assigns. Subject to the limitations on assignment set forth herein, this Agreement shall be binding upon and inure to the benefit of any successors in interest and assigns of TSRI and Sponsor. Any such successor to or assignee of a party’s interest shall expressly assume in writing the performance of all the terms and conditions of this Agreement to be performed by such party and such written assumption shall be delivered to the other party.

9.       GENERAL PROVISIONS.

9.1       Independent Contractors. The relationship between TSRI and Sponsor is that of independent contractors. TSRI and Sponsor are not joint venturers, partners, principal and agent, master and servant, employer or employee, and have no other relationship other than independent contracting parties. TSRI and Sponsor shall have no power to bind or obligate each other in any manner, other than as is expressly set forth in this Agreement.

9.2       Arbitration. Any controversy or claim arising out of or relating to this Agreement, or the breach thereof, shall be settled by binding confidential arbitration in accordance with the Commercial Arbitration Rules of the American Arbitration Association (“AAA”), and the procedures set forth below. In the event of any inconsistency between the Rules of AAA and the procedures set forth below, the procedures set forth below shall control. Judgment upon the award rendered by the arbitrators may be enforced in any court having jurisdiction thereof.

(a)       Location. The location of the arbitration shall be the County of San Diego, California. TSRI and Sponsor hereby irrevocably submit to the exclusive personal jurisdiction and venue of the American Arbitration Association arbitration panel selected by the parties and located in San Diego County, California for any dispute regarding this Agreement, and to the exclusive personal jurisdiction and venue of the federal and state courts located in San Diego County, California for any action or proceeding to enforce an arbitration award or as otherwise provided in Section 9.2(e) below, and waive any right to contest or otherwise object to such jurisdiction or venue.

(b)       Selection of Arbitrators. The arbitration shall be conducted by a panel of three neutral arbitrators who are independent and disinterested with respect to the parties, this Agreement, and the outcome of the arbitration. Each party shall appoint one neutral arbitrator, and the two arbitrators so selected by the parties shall then select the third arbitrator. Each arbitrator must have at least ten (10) years’ experience in mediating or arbitrating cases regarding the same or substantially similar subject matter as the dispute between TSRI and Sponsor. If one party has given written notice to the other party as to the identity of the arbitrator appointed by the party, and the party thereafter makes a written demand on the other party to appoint its designated arbitrator within the next ten days, and the other party fails to appoint its designated arbitrator within ten days after receiving said written demand, then the arbitrator who has already been designated shall appoint the other two arbitrators.

(c)       Discovery. The arbitrators shall decide any disputes and shall control the process concerning these pre-hearing discovery matters. Pursuant to the Rules of AAA, the parties may subpoena witnesses and documents for presentation at the hearing.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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(d)       Case Management. Prompt resolution of any dispute is important to both parties; and the parties agree that the arbitration of any dispute shall be conducted expeditiously. The arbitrators are instructed and directed to assume case management initiative and control over the arbitration process (including scheduling of events, pre-hearing discovery and activities, and the -conduct of the hearing), in order to complete the arbitration as expeditiously as is reasonably practical for obtaining a just resolution of the dispute.

(e)       Remedies. The arbitrators may grant any legal or equitable remedy or relief that the arbitrators deem just and equitable, to the same extent that remedies or relief could be granted by a state or federal court, provided however, that no punitive damages shall be awarded. No court action shall be maintained seeking punitive damages. The decision of any two of the three arbitrators appointed shall be binding upon the parties. Notwithstanding anything to the contrary in this Agreement, prior to or while an arbitration proceeding is pending, either party has the right to seek and obtain injunctive and other equitable relief from a court of competent jurisdiction to enforce that party’s rights hereunder.

(f)       Expenses. The expenses of the arbitration, including the arbitrators’ fees, expert witness fees, and attorney’s fees, may be awarded to the prevailing party, in the discretion of the arbitrators, or may be apportioned between the parties in any manner deemed appropriate by the arbitrators. Unless and until the arbitrators decide that one party is to pay for all (or a share) of such expenses, both parties shall share equally in the payment of the arbitrators’ fees as and when billed by the arbitrators.

(g)       Confidentiality. Except as set forth below, and as necessary to obtain or enforce a judgment upon any arbitration award, the parties shall keep confidential the fact of the arbitration, the dispute being arbitrated, and the decision of the arbitrators. Notwithstanding the foregoing, the parties may disclose information about the arbitration to persons who have a need to know, such as directors, trustees, management employees, witnesses, experts, investors, attorneys, lenders, insurers, and others who may be directly affected. Additionally, if a party has stock which is publicly traded, the party may make such disclosures as are required by applicable securities laws but will use commercially reasonably efforts to seek confidential treatment for such disclosure.

9.3       Entire Agreement; Modification; Satisfaction and Termination of Affiliate Equity Obligation. This Agreement sets forth the entire agreement and understanding between the parties as to the subject matter hereof and supersedes all prior oral or written agreements or understandings with respect to the subject matter hereof, including without limitation the Prior Agreement. There shall be no amendments or modifications to this Agreement, except by a written document which is signed by both parties. Sponsor and TSRI hereby acknowledge and agree that notwithstanding anything to the contrary set forth in the Prior Agreement (including, without limitation the Affiliate Equity Obligation) or in any other agreement between the Sponsor and TSRI (collectively, the “TSRI Agreements”), the Affiliate Equity Obligation was satisfied in full prior to the date hereof. TSRI further acknowledges and agrees that upon the execution and delivery of this Agreement and the Assignment Agreement between Sponsor and TSRI with respect to certain patent applications relating to Structures of Human Histidyl-tRNA

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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Synthetase and Methods of Use, the Affiliate Equity Obligation shall be cancelled and extinguished in full, and shall be of no further force or effect.

9.4       California Law. This Agreement shall be construed and enforced in accordance with the laws of the State of California notwithstanding any conflict of laws provisions.

9.5       No Use of Name. The use of the name “The Scripps Research Institute”, “Scripps”, “TSRI” or any variation thereof in connection with the advertising, sale or performance of Products, Processes, Services, Biological Materials or Research Tools is expressly prohibited. For the avoidance of doubt, nothing in this Section 9.5 shall prevent Sponsor from identifying TSRI as a contracting partner in connection with any disclosure permitted under Section 5.

9.6       Headings. The headings for each article and section in this Agreement have been inserted for the convenience of reference only and are not intended to limit or expand on the meaning of the language contained in the particular article or section.

9.7       Severability. Should any one or more of the provisions of this Agreement be held invalid or unenforceable by a court of competent jurisdiction, it shall be considered severed from this Agreement and shall not serve to invalidate the remaining provisions thereof. The parties shall make a good faith effort to replace any invalid or unenforceable provision with a valid and enforceable one such that the objectives contemplated by them when entering this Agreement may be realized.

9.8       No Waiver. Any delay in enforcing a party’s rights under this Agreement or any waiver as to a particular default or other matter shall not constitute a waiver of such party’s rights to the future enforcement of its rights under this Agreement, excepting only as to an express written and signed waiver as to a particular matter for a particular period of time.

9.9       Attorneys’ Fees. In the event of a dispute among the parties hereto or in the event of any default hereunder, the party prevailing in the resolution of any such dispute or default shall be entitled to recover its reasonable attorneys’ fees and other costs incurred in connection with resolving such dispute or default.

9.10     Notices. Any notices required by this Agreement shall be in writing, shall specifically refer to this Agreement and shall be sent by registered or certified airmail, postage prepaid, or by telefax, telex or cable, charges prepaid, or by overnight courier, postage prepaid, and shall be forwarded to the respective addresses set forth below unless subsequently changed by written notice to the other party:

 

FOR TSRI:		The Scripps Research Institute 10550 North Torrey Pines Road, TPC-9 La Jolla, California 92037 Attn: Director, Technology Development Fax No.: (858)784-9910

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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With a copy to:		The Scripps Research Institute 10550 North Torrey Pines Road, TPC-8 La Jolla, California 92037 Attention: General Counsel Fax No.: (858) 784-9910
FOR SPONSOR:		aTyr Pharma, Inc. 3545 John Hopkins Court, Suite #250 San Diego, California 92121 Attn: Chief Executive Officer Fax No.: (858) 731-8394
With a copy to:		Goodwin Procter LLP Exchange Place, 53 State Street Boston, MA 02109 Attn: Kingsley L. Taft, Esq. Fax No. (617) 801-8857

Notices shall be deemed delivered upon the earlier of (i) when received; (ii) three (3) days after deposit into the U.S. mail; (iii) the date notice is sent via facsimile; or (iv) the day immediately following delivery to an overnight courier guaranteeing next-day delivery (except Sundays and holidays).

9.11     Compliance with U.S. Laws. Nothing contained in this Agreement shall require or permit TSRI or Sponsor to do any act inconsistent with the requirements of any United States law, regulation or executive order as the same may be in effect from time to time.

9.12     Further Assurances. Each Party agrees to execute, acknowledge and deliver such further reasonable instructions, and to do all such other reasonable acts, as may be necessary or appropriate in order to carry out the purposes and intent of this Agreement.

IN WITNESS WHEREOF, the parties have executed this Agreement by their duly authorized representatives as of the date set forth above.

 

TSRI: The Scripps Research Institute				SPONSOR: aTyr Pharma, Inc.
By: /s/ Scott Forrest                                                     Name:  Scott Forrest                                                     Title:   VP, Business Development				By: /s/ Andrew Cubitt                     Name: Andrew Cubitt                                 Title:   VP, Product Protection

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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EXHIBIT A

RESEARCH PROGRAM

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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Structural analysis of components of mammalian translation apparatus and analysis of alternative functions

Introduction

This project focuses on a subgroup of the components of the translation apparatus that, in some instances, are known to have functions beyond translation. This subgroup is known as the aminoacyl tRNA synthetases (AARSs), enzymes that catalyze the first step of protein synthesis by aminoacylation of transfer RNAs. Their alternative functions in mammalian cells suggest a broad connection of translation to signal transduction pathways in angiogenesis, inflammation, and neurogenesis (Park, Ewalt et al. 2005). Little is known about structural features of AARSs that are needed for functions beyond translation. Also, beyond the few examples known so far, little is known about the full scope of alternative functions carried out by these proteins. Two specific aims are given here. These aims lay the foundation for a deeper understanding of the particular structural features of these proteins that are needed for alternative functions and, in further work, define and analyze some of the alternative functions themselves.

X-ray crystallographic analysis of the 3-dimensional structures of specific human tRNA synthetases and their fragments will be determined. The proteins will be isolated, where possible, in large quantities from bacterial cells harboring plasmids encoding the human enzymes. Special plasmid constructions have already been generated for this purpose. The high-throughput Mosquito screening systems that is established in the laboratory will be used to obtain conditions specific for each protein for obtaining crystals that diffract to high resolution.

A series of assays will be deployed to investigate potential alternative functions of specific tRNA synthetases and their fragments. In the cases studied so far, some of the proteins are activated for cytokine functions by proteolysis or alternative splicing of mRNA. Thus, while the native protein is inactive for cytokine function (but active in protein synthesis), the cytokine function is unmasked when the protein is split. Structural information will be used to attempt to estimate likely places where a split could occur. In addition, antibody-based assays of whole cell extracts will search for naturally produced fragments. The fragments so identified will be put through assays for inflammation, angiogenesis, and neurogenesis.

Background

In the first step of protein synthesis, aminoacylation by an AARS occurs in a two step reaction. The amino acid AA is first activated by condensation with ATP to form the aminoacyl adenylate (AA-AMP), simultaneous with release of pyrophosphate (PPi). The adenylate then reacts with the cognate tRNA to yield AA-tRNA.

AARS + AA + ATP AARS (AA-AMP) + Ppi                  (1)

AARS (AA-AMP) + tRNA AA-tRNA + AMP + AARS  (2)

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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For each of the 20 amino acids, there is a distinct AARS and a group of isoaccepting tRNAs. The genetic code is established through equations 1 and 2, because the reactions link each amino acid to a nucleotide triplet. That triplet is the anticodon imbedded in the specific tRNA (or tRNA isoacceptors) that is cognate to the amino acid. Not surprisingly, the AARSs are essential to all life forms, and appeared at the time of the last common ancestor which eventually split into the 3 great kingdoms of the tree of life—archae, bacteria, and eukarya. Interestingly, in most instances, each cytoplasmic tRNA synthetase is encoded by only a single gene. Therefore, a single point mutation that ablates the activity of a synthetase is lethal. Mitochondria have a separate set of tRNA synthetases, the genes for which are all nuclear encoded. Thus, the mitochondrial synthetases are imported from the cytoplasm, where they are produced, into the mitochondria.

 

In mammalian cells, the synthetases are gathered together with other, accessory proteins, into a large complex
		known as the ‘multi-synthetase complex’ (Lee, Cho et al. 2004). Whether all of the synthetases are present in the complex, or only a subset of 9 are present, is not clear. What is clear, however, is that some are more tightly associated in the complex than others, along with specific accessory proteins known simply as p18, p38, and p43. This organization into a complex may facilitate protein synthesis, in a way that is not understood. Additionally or alternatively, the complex itself may be a reservoir or depository of un-activated cytokines. Here the idea is that, because some synthetases are known to have expanded functions, these functions can be mobilized by release of a synthetase from the complex.

 

For example, y-interferon induction mobilizes a specific fused tRNA synthetase pair—the Glu-Pro fusion synthetase that is present in higher eukaryotes (Sampath, Mazumder et al. 2004). The released fusion synthetase then enters the cytoplasm to act, through a multi-step mechanism with other proteins, as a translational repressor. After l-interferon induction, the fusion protein is phosphorylated, followed by release from the multi-synthetase complex. Ultimately, the phosphorylated protein becomes part of the GAIT complex (y-interferon-activated inhibitor of translation complex), where it shuts down translation by binding to a stem-loop structure of ceruloplasmin mRNA.

Ceruloplasmin is active in circuits for inflammation and iron homeostasis. The binding of the Glu-Pro fusion protein to the stem-loop structure (in the 3’-untranslated region) of the ceruloplasmin mRNA is speculated to occur through the linker that joins together the two synthetases.

In another example, TyrRS is secreted under certain conditions and, subsequently split into 2 cytokines (Wakasugi and Schimmel 1999), by the action of an extracellular protease such as leukocyte elastase. Each of the fragments, one harboring the active site domain (for aminoacylation) and the other a domain homologous to EMAP II (endothelial monocyte activating protein Ii) is a cytokine. Each of these fragments is a distinct cytokine, demonstrating

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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activities in either angiogenesis or inflammatory pathways. In contrast, the full-length, native TyrRS is inactive as a cytokine. Thus, the splitting of the protein is the way that cytokine activation occurs. Similarly, TrpRS is activated as an angiostatic cytokine, by generation of fragments that come from either alternative splicing or natural proteolysis (Wakasugi, Slike et al. 2002). These and other examples illustrate how components of the translation apparatus can have expanded functions that go well beyond translation itself. These expanded functions make a connection of translation with the broader biological system, with the variety of activities essential for cell development, homeostasis, and growth.

Research Design and Methods

[***] In the past, we have successfully overexpressed functional human synthetases in E. coli. In order to enhance protein expression and solubility, all 6 human genes have been codon-optimized for translation in E. coli using the proprietary algorithms developed by CODA Genomics, Inc (http://www.codagenomics.com/). We have cloned the genes into pBAD vectors. Five out of the 6 genes have been expressed, and of these, two have good solubility.

Aminoacyl-tRNA synthetases have modular structures with distinct domains that are joined together (Jasin, Regan et al. 1983). Each domain is responsible for a specific task—for example, the catalytic domain for aminoacylation, anti-codon recognition domain for recognition of the triplet anti-codon embedded in the tRNA, and editing domain for clearance of the misactivated non-cognate amino acids or the mischarged tRNAs. Mammalian tRNA synthetases usually have acquired additional domains, each of which belongs to one of 3 types of structures; glutathione S-transferase (GST), helix-turn-helix (HTH), and endothelial monocyte activating peptide II (EMAP II). The extra domains often are dispensable for aminoacylation, and may provide a regulatory mechanism for non-canonical functions, as demonstrated for TyrRS and TrpRS. In addition, the extra domains may be involved with specific interactions between members of the multi-synthetase complex. With these considerations, we have also cloned domain fragments from the above 6 genes. As an additional benefit, most of the fragments have better expressions and improved solubility relative to the full-length proteins.

 

Gene		Fragment		Tag		MW (KD)		Expression		Solubility
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]

 

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[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]		[***]

2.         X-ray crystallographic analysis of the 3-dimensional structures of specific

human tRNA synthetases and their fragments

We will attempt to crystallize, if available, all 6 full-length proteins, 3 binary complexes with full-length proteins, and binary complexes between full-length proteins and fragments, and between different fragments. Because the laboratory is set up with our own high-throughput crystallization robot (Mosquito, Molecular Dimensions) and a microscopic imaging system (CrystalPro, TriTek) to monitor crystal growth, these attempts are realistic. The automated crystallization robot can setup 96 crystallization conditions in a 96-well plate in less then 2 minutes with minimal sample consumption (about 10 µl per plate). The crystallization plates are followed up at regular intervals using the microscopic imaging system that captures digital images for comparison as crystals grow. The obtained crystals will be evaluated by X-ray diffraction in house. We share X-ray facility with the Wilson lab at Scripps, which is equipped with a Rigaku FR-D high brilliance rotating anode X-ray generator, and a Mar 345mm CCD detector. An additional Siemens/Bruker system is also available in the facility. High resolution data collection will be performed at the Stanford Synchrotron Research Laboratory, where Scripps has it own beamline. Our laboratory has beam time on a regular basis.

2. A series of assays will be deployed to investigate potential alternative functions of specific tRNA synthetases and their fragments.

The full-length proteins and the fragments we generated will be put into cell-based assays to screen for alternative functions. We will start with a cell migration assay and chick chorioallantoic membrane (CAM) angiogenesis assay. Different cell types including leucocytes, endothelial cells, and so on (??) will be tested for migration in an AP48 chemotaxis chamber (Neuro Probe, Gaithersburg, MD). The protein samples will be placed in the lower chamber, and cell suspensions will be added to the upper chamber with a polycarbonate filter separating the two chambers. Cells will be allowed to migrate into the filter for 45 min at 37 °C in a 5% C02 incubator. After incubation, non-migrating cells will be removed, and migrating cells which are retained in the filter are stained with the Diff-Quik stain set (Dade Behring, Newark, DE), and are counted under a light microscope in high power fields (HPFs). Both a negative control, like medium alone, and a positive control, like IL-8 or VEGF, will be used to establish the boundaries of the activities. The assay can also be used to test for inhibition of cell migration.

 

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The CAM angiogenesis assay will be performed with samples that show promising results in the cell migration assay. The assay is performed on the chorioallantoic membrane of fertilized complement fixation for avian leukocysis virus (COFAL)-negative eggs (Charles River Labs, Storrs, CT). Eggs will be incubated for 3.5 days at 38 0 C / 60% humidity. Eggs are then opened and the embryos will be transferred into sterile plastic weigh boats. Embryos will be covered and incubated at 37.5 ‘C/ 90% humidity. After five days, collagen/mesh implants containing PBS (as negative control), VEGF/bFGF (as positive control) or protein samples will be placed onto the CAM membrane of the embryos, and incubated for an additional 66 hours. The upper mesh layers of the implants will be examined under a stereomicroscope and scored for the proportion of “boxes” (i.e., three dimensional regions defined by the mesh fibers), which contain a blood vessel relative to the total number of boxes.

In the cases of TyrRS and TrpRS, fragmentation happens naturally by either proteolysis or alternative splicing. Only the specific fragments, not the full-length proteins, have alternative functions. With this perspective in mind, we will also use antibody-based assays of whole cell extracts to search for naturally produced fragments. The fragments so identified will be produced by overexpression, and put through assays for inflammation, angiogenesis, or neurogenesis, depending on in what cell types the specific fragments are discovered. Structural analysis of these fragments can also be carried out.

Concluding Remarks

This project attempts to more broadly define the alternative activities of human tRNA synthetases and their fragments, and at the same time to define the structural motifs that are needed for these activities and the structural basis for how they bind together in a larger complex. [***] While we are initiating studies with a defined set of synthetases described above, as the work progresses we will expand the project to include all of the enzymes.

References

Jasin, M., L. Regan, et al. (1983). “Modular arrangement of functional domains along the sequence of an aminoacyl tRNA synthetase.” Nature 306(5942): 441-7.

Lee, S. W., B. H. Cho, et al. (2004), “Aminoacyl-tRNA synthetase complexes: beyond translation.” J Cell Sci 117(Pt 17): 3725-34.

Park, S. G., K. L. Ewalt, et al. (2005). “Functional expansion of aminoacyl-tRNA synthetases and their interacting factors: new perspectives on housekeepers.” Trends Biochem Sci 30(10): 569-74.

Sampath, P., B. Mazumder, et al. (2004). “Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation.” Cell 119(2): 195-208.

Wakasugi, K. and P. Schimmel (1999). “Two distinct cytokines released from a human aminoacyl-tRNA synthetase [see comments].” Science 284(5411): 147-51.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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Wakasugi, K., B. M. Slike, et al. (2002). “A human aminoacyl-tRNA synthetase as a regulator of angiogenesis.” Proc Natl Acad Sci U S A 99(1): 173-7.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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EXHIBIT B

BUDGET

Listed below is an exemplary budget for this Agreement that is provided for illustrative purposes only:

 

Name		Months		Salary		Fringe		Total
[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]
[***]		[***]		[***]		[***]		[***]
Salary Subtotal								[***]
Equipment
[***]								[***]
Travel
[***]								[***]
Other Costs
[***]								[***]
[***]								[***]
[***]								[***]
Computer costs								[***]
[***]								[***]
[***]								[***]
Total Costs								[***]

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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EXHIBIT C

FORM OF MATERIAL TRANSFER AGREEMENT

THE SCRIPPS RESEARCH INSTITUTE

MATERIAL TRANSFER AGREEMENT

[Date]

[Contact Name]

aTyr Pharma, Inc.

3545 John Hopkins Court, Suite #250

San Diego, California 92121

Dear Dr. [Name]:

This is to acknowledge your request for the [Materials Requested] to be provided by The Scripps Research Institute (TSRI) pursuant to [Section 3.3] [Section 3.5] of the Amended and Restated Research Funding and Option Agreement between TSRI and aTyr Pharma, Inc. (‘‘Sponsor”) dated January 19, 2015. This material and any progeny, mutants or derivatives of this material are referred to herein as “Materials.”

TSRI is pleased to cooperate with Sponsor’s use of these Materials for your scientific research. However, before forwarding them to you, TSRI needs you to agree to the following terms and conditions:

(1)        that TSRI hereby grants Sponsor a nonexclusive, royalty-free, non-transferable license to make and use the Materials solely for internal research purposes;

(2)        that the Materials shall be received by Sponsor only for use in scientific research in Sponsor’s laboratories and that all applicable guidelines set forth by the National Institutes of Health (NIH), U.S. Department of Agriculture (USDA) or other government agencies regarding the use of these Materials shall be followed;

(3)        that the Materials can be transferred by you to a third party contract provider, strategic partner or collaborator provided that such third party contract provider, strategic partner or collaborator has entered into a material transfer agreement with TSRI on terms substantially similar to this agreement.

Common provisions:

(3)        these Materials are provided as a service to the research community. THE MATERIALS ARE BEING SUPPLIED TO YOU WITH NO WARRANTIES, EXPRESS OR IMPLIED, INCLUDING WITHOUT LIMITATION ANY WARRANTY OF MERCHANTABILITY OF ANY KIND, FITNESS FOR A PARTICULAR PURPOSE, NON-INFRINGEMENT OF THIRD PARTY RIGHTS, OR ARISING OUT OF COURSE OF

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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CONDUCT OR TRADE CUSTOM OR USAGE, ALL OF WHICH ARE DISCLAIMED BY TSRI;

(4)        that Sponsor shall bear all risk to itself and/or any others resulting from any use, directly or indirectly, to which Sponsor puts the Materials or any other materials that could not have been made but for these Materials;

(5)        that Sponsor hereby defends, indemnifies, and holds harmless TSRI, its affiliates, its trustees, officers, employees and agents from any loss, claim, damage, or liability of any kind whatsoever, including without limitation reasonable attorney’s fees, expert witness fees and costs, whether or not a lawsuit or other proceeding is filed, which may arise from Sponsor’s use, storage or disposal of the Materials or any other material that could not have been made but for the Materials, except to the extent such arise due to the gross negligence or willful misconduct of TSRI;

(6)        that you provide us with your Federal Express account number or an account number for another courier service, so that we may ship the Materials to you.

The Materials are to be used with caution and prudence in any experimental work, since all of their characteristics are not known. Moreover, they are not to be used for testing in or treatment of humans.

If you agree to accept these Materials under the above conditions, please sign the enclosed duplicate copy of this letter, have it signed by an authorized representative of Sponsor and return one original to me. Upon receipt of that confirmation I will forward the Materials to you.

 

THE SCRIPPS RESEARCH INSTITUTE
[Name]
Director, Technology Development
[Date]
ACCEPTED:
Recipient’s Signature				Authorized Institutional Rep. Signature
Recipient’s Printed Name and Title				Authorized Rep. Printed Name and Title
Date				Date

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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EXHIBIT D

FORM OF OPTION AGREEMENT

[Date]

[Contact Name]

aTyr Pharma. Inc.

3545 John Hopkins Court, Suite #250

San Diego, California 92121

RE:        Option to Technology Disclosure No.                    

Dear [Contact]:

Pursuant to the Amended and Restated Research Funding and Option Agreement dated January 19, 2015 (the “Research Agreement”) by and among The Scripps Research Institute (“TSRI”) and aTyr Pharma, Inc. (“Sponsor”), Sponsor hereby executes its option to acquire (i) an exclusive, worldwide license, including the right to sublicense, to make, have made, use, have used, practice, import and have imported Products, Services, Processes and Biological Materials in the Field, and (ii) an exclusive, worldwide license, including the right to sublicense, to offer for sale, sell and perform Products, Services and Processes in the Field, under one or more patent applications to be filed (“Scripps Patent Rights”) which shall cover the Technology disclosed in TSRI Technology Disclosure No.              entitled “                    ” (“Patent Application(s)”) and which inventions were reduced to practice as of the date of the applicable TSRI Technology Disclosure. The License Agreement shall be substantially as set forth in Exhibit F to the Research Agreement. Unless otherwise set forth herein, all capitalized terms shall have the meaning ascribed to them in the Research Agreement.

This option, as to each TSRI Technology Disclosure, shall be effective as of the date hereof, and shall automatically terminate on the date that is [***] after the date when Sponsor receives from TSRI written notice of the filing of a patent application covering said TSRI Technology Disclosure (“Option Period”),

After the filing of the Patent Application, and prior to the expiration of the Option Period, TSRI and Sponsor shall enter into a License Agreement that is materially consistent with the form of License Agreement attached as Exhibit F to the Research Agreement.

As consideration for the option, Sponsor shall pay all fees and costs related to the preparation, filing, prosecution and maintenance of Scripps Patent Rights associated with work performed by TSRI’s Office of Patent Counsel and any independent counsel. Payment shall be made within [***] after Sponsor receives an invoice therefor. Failure of Sponsor to pay patent costs and expenses as set forth herein shall immediately relieve TSRI from its obligation to incur further patent costs and expenses or to continue to prosecute the patent applications, provided, however, that TSRI’s obligation to incur patent costs and expenses and to prosecute the patent applications shall, to the extent possible, be immediately restored upon Sponsor’s payment of such patent costs and expenses. Subject to the terms and conditions of the License Agreement, Sponsor’s

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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obligation to pay all patent fees and costs incurred pursuant to the Research Agreement shall survive the termination or expiration of the Research Agreement with respect to costs and expenses which accrued during the term of the Research Agreement. Both parties hereto agree that TSRI may, at its sole discretion, utilize TSRI’s Office of Patent Counsel in lieu of or in addition to independent counsel for patent prosecution and maintenance of Patent Application(s). Sponsor shall have full rights of consultation with the patent attorney so selected on all matters relating to Patent Application(s). TSRI shall implement all reasonable and timely requests made by Sponsor with regard to the preparation, filing, prosecution and/or maintenance of the Patent Application(s), including without limitation requests relating to the jurisdictions in which TSRI shall prepare, file, prosecute and maintain patent applications.

TSRI agrees that it shall not grant any additional licenses, or additional options to enter into licenses covering Scripps Patent Rights, until the expiration of the time for Sponsor and TSRI to negotiate a License Agreement in accordance with Section 3.4(b) or 3.4(c), as applicable, of the Research Agreement, except to the U.S. Government and to nonprofit and academic institutions as set forth below. If the parties fail to execute a License Agreement for the Scripps Patent Rights within the time periods described in Sections 3.4(b) or 3.4 (c) of the Research Agreement, then TSRI shall be free thereafter to seek other licensees to such Scripps Patent Rights and shall have no further obligations to Sponsor with respect thereto.

TSRI reserves the right to use for any research or educational purposes any Scripps Patent Rights, Biological Materials or Research Tools, without TSRI being obligated to pay Sponsor any royalties or other compensation or to account to Sponsor in any way. In addition, TSRI reserves the right to grant non-exclusive, non-commercial research and educational use licenses to other nonprofit or academic institutions to TSRI Patent Rights, Biological Materials or Research Tools, without the other nonprofit or academic entity being obligated to pay Sponsor any royalties or other compensation or to account to Sponsor in any way.

Sponsor and TSRI acknowledge that TSRI has received, and expects to continue to receive, funding from the United States Government in support of TSRI’s research activities. Sponsor and TSRI acknowledge and agree that their respective rights and obligations pursuant to this Agreement shall be subject to the rights of the United States Government which may arise or result from TSRI’s receipt of research support from the United States Government.

If Sponsor agrees and accepts these terms, please sign below:

 

Sincerely,
Director, Technology Development
Acknowledge and Agree:				Acknowledge and Agree:
TSRI				aTYR PHARMA, INC.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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Name:____________________________				Name:____________________________
Title:_____________________________				Title:_____________________________

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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EXHIBIT E

FORM OF LICENSE AGREEMENT

This License Agreement (this “Agreement”) is entered into and made effective as of this              day of                     ,              (the “Effective Date”), by and between THE SCRIPPS RESEARCH INSTITUTE, a California nonprofit public benefit corporation located at 10550 North Torrey Pines Road, La Jolla, California 92037 (“TSRI”), and aTYR PHARMA, INC., a Delaware corporation (“Licensee”) located at 3545 John Hopkins Court, Suite # 250, San Diego, CA 92121 with respect to the facts set forth below.

RECITALS

A.        WHEREAS, TSRI and Licensee are parties to that certain Amended and Restated Research Funding and Option Agreement dated January 19, 2015 (as amended from time to time, the “Research Agreement”), pursuant to which Licensee agreed to sponsor certain research activities at TSRI related to aminoacyl tRNA synthetases, their fragments and accessory proteins, and in exchange TSRI granted Licensee an option to license the inventions resulting from those research activities;

B.        WHEREAS, pursuant to the Research Agreement TSRI has disclosed to Licensee certain Technology (as defined in the Research Agreement), and TSRI and Licensee have prepared and filed a patent application covering or claiming such Technology; and

C.        WHEREAS, TSRI has the right to grant an exclusive license to the Technology, subject to certain rights of the U.S. Government resulting from the receipt by TSRI of certain funding from the U.S. Government, and Licensee wishes to acquire from TSRI such license pursuant to the terms and conditions set forth herein.

AGREEMENT

NOW, THEREFORE, in consideration of the mutual covenants and conditions set forth herein, TSRI and Licensee hereby agree as follows:

1.        Definitions. Capitalized terms shall have the meaning set forth herein.

1.1      AAA. The term “AAA” is defined in Section 15.8.

1.2      Affiliate. The term “Affiliate” shall mean any entity, which directly or indirectly controls, or is controlled by Licensee. The term “control” as used herein means (a) in the case of corporate entities, direct or indirect ownership of at least fifty percent (50%) of the stock or shares entitled to vote for the election of directors; or (b) in the case of non-corporate entities, direct or indirect ownership of at least fifty percent (50%) of the equity interest with the power to direct the management and policies of such non-corporate entities. Unless otherwise specified, the term Licensee includes Affiliates.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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1.3      BLA. The term “BLA” shall mean a Biologics License Application, or similar application, that is submitted to the FDA, or a foreign equivalent of the FDA, for marketing approval of a Licensed Product in a jurisdiction.

1.4      Challenge. The term “Challenge” is defined in Section 3.1(b).

1.5      Claim. The term “Claim” is defined in Section 9.1.

1.6      Confidential Information. The term “Confidential Information” shall mean any and all proprietary information of TSRI or Licensee, which may be exchanged between the parties at any time and from time to time during the term hereof. “Proprietary Information” shall include information of the disclosing party that the disclosing party would consider confidential or proprietary under the circumstances. The fact that a party may have marked or identified as confidential or proprietary any specific information shall be indicative that such party believes such information to be confidential or proprietary, but the failure to so mark information shall not conclusively determine that such information was or was not considered confidential information by such party. Information shall not be considered confidential to the extent that it:

(a)        Is publicly disclosed through no act or omission of the receiving party, either before or after it becomes known to the receiving party; or

(b)        Was known to the receiving party prior to the date of this Agreement, as demonstrated by competent evidence, which knowledge was acquired independently and not from the other party hereto (including such party’s employees); or

(c)        Is subsequently disclosed to the receiving party in good faith by a third party who has a right to make such disclosure; or

(d)        Has been published by a third party as a matter of right; or

(e)        Is independently developed by the receiving party without reference to, aid from or reliance on the Confidential Information of the disclosing party, as demonstrated by competent evidence.

If Confidential Information is required to be disclosed by law or court order, then the party required to make such disclosure shall limit the same to the minimum required to comply with the law or court order, and shall use reasonable efforts to attempt to seek confidential treatment for that disclosure, and prior to making such disclosure that party shall notify the other party, not later than ten (10) days (or such shorter period of time as may be reasonably practicable under the circumstances) before the disclosure in order to allow the other party to comment and/or to

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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obtain a protective or other order, including extensions of time and the like, with respect to such disclosure.

1.7      FDA. The term “FDA” shall mean the United States Food and Drug Administration, or any successor agency thereto, having the administrative authority to regulate the marketing of human pharmaceutical products or biological therapeutic products, delivery systems and devices in the United States of America.

1.8      Field. The term “Field” shall mean any reagent, therapeutic, prognostic, diagnostic or cosmeceutical use.

1.9      First Commercial Sale. The term “First Commercial Sale” shall mean the first transfer for consideration by or on behalf of Licensee of a Licensed Product, or the first performance for consideration by or on behalf of Licensee of a Licensed Process or Licensed Service, that takes place after final regulatory approval in the country of sale of such Licensed Product, Licensed Process and/or Licensed Service; provided, however, that a First Commercial Sale shall not be deemed to have occurred solely by reason of (a) transfers or performance for product testing or control; (b) promotional distribution or demonstration to potential purchasers; (c) distribution or performance for research on behalf of Licensee or any of its sublicensees; (d) any transfer or performance made in connection with a Regulatory Approval process; or (e) transfer to an Affiliate or sublicensee of Licensee for later resale to or use by an end consumer.

1.10    IND. The term “IND” shall mean an Investigational New Drug Application filed with the FDA, or the equivalent application or filing filed with any equivalent Regulatory Authority outside the United States of America (including any supra-national agency, such as in the European Union) necessary to commence human clinical trials in such jurisdiction.

1.11    Indemnitees. The term “Indemnitees” is defined in Section 9.1.

1.12    Licensed Patent Rights. The term “Licensed Patent Rights” shall mean (a) the U.S. patent application(s) listed on Exhibit A hereto; (b) foreign counterparts of the patent application(s) referenced in subsection (a); (c) the patents issued from the patent applications referenced in subsection (a) and (b); (d) divisionals, continuations, reissues, reexaminations, restorations (including supplemental protection certificates) and extensions of any patent or application set forth in subsections (a) - (c); and (e) any claims of continuations in part that are directed to subject matter in the applications referenced in subsection (a); and in all cases (b)-(e) entitled to the benefit of the priority date of the application(s) referenced in sub clause (a) above.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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1.13    Licensed Product. The term “Licensed Product” shall mean any product the manufacture, use, importation, sale or offer for sale of which would, but for the license granted herein, infringe a Valid Claim under the Licensed Patent Rights.

1.14    Licensed Process. The term “Licensed Process” shall mean any method or process the manufacture, use, importation, sale or offer for sale of which would, but for the license granted herein, infringe a Valid Claim under the Licensed Patent Rights.

1.15    Licensed Service. The term “Licensed Service” shall mean the performance of a service for a third party, which performance uses or incorporates a Licensed Product or Licensed Process.

1.16    Major Market Country. The term “Major Market Country” shall mean any of the following countries: the United States of America, the United Kingdom, France, Germany, Spain, Italy, Japan or Canada.

1.17    NDA. The term “NDA” shall mean a New Drug Application (as more fully defined in 21 C.F.R. 314.5 et seq.) and all amendments and supplements thereto filed with the FDA, or the equivalent application filed with any equivalent Regulatory Authority outside the United States of America (including any supra-national agency, such as in the European Union).

1.18    Net Sales. The term “Net Sales” shall mean the gross amount invoiced by Licensee, or sublicensees, or any of its Affiliates, on all sales of Licensed Products, Licensed Processes and Licensed Services less (a) trade, cash and quantity discounts or rebates actually allowed or taken, including discounts or rebates to governmental or managed care organizations; (b) credits or allowances actually given or made for rejection of or return of, previously sold Licensed Products or for retroactive price reductions (including Medicare and similar types of rebates); (c) any charges for insurance, freight, and other transportation costs directly related to the delivery of Licensed Product to the extent included in the gross invoiced sales price; (d) any tax, tariff, duty or governmental charge levied on the sales, transfer, transportation or delivery of a Licensed Product (including any tax such as a value added or similar tax or government charge) borne by the seller thereof, other than franchise or income tax of any kind whatsoever; (e) any import or export duties or their equivalent borne by the seller. Net Sales shall include all consideration charged by Licensee, sublicensees or its Affiliates in exchange for any Licensed Products, Licensed Processes, and Licensed Services, including, without limitation, any monetary payments or any other property whatsoever; and (f) [***]

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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For purposes of determining Net Sales, a sale shall be deemed to have occurred when an invoice therefor shall be generated or the Licensed Product is shipped for delivery, Licensed Process is completed, or Licensed Service is provided. Sales of Licensed Products by Licensee, or sublicensee of Licensee to any Affiliate or sublicensee which is a reseller thereof shall be excluded, and only the subsequent sale of such Licensed Products by Affiliates or sublicensees of Licensee to unrelated parties shall be deemed Net Sales hereunder. For the avoidance of doubt, “Net Sales” shall not include (i) transfers for product testing or control; (ii) promotional distribution to potential purchasers; (iii) distribution for research on behalf of Licensee or any of its sublicensees; or (iv) any transfer made in connection with a Regulatory Approval process; or (v) transfer of a Licensed Product or performance of a Licensed Process or Licensed Service, by Licensee to an Affiliate or sublicensee for later resale to or use by an end customer, provided, however, that if the price invoiced by Licensee for the transfer to such Affiliate or sublicensee is higher than the price invoiced by such Affiliate or sublicensee for the subsequent resale to or use by the end customer, the Net Sales shall be determined on the gross amount invoiced by Licensee to such Affiliate or sublicensee, and not on the gross amount invoiced by such Affiliate or sublicensee to the end consumer.

1.19    Phase 1 Trial. The term “Phase 1 Trial” shall mean a human clinical trial conducted on a limited number of study subjects for the purpose of gaining evidence of the safety and tolerability of, and information regarding pharmacokinetics and potential pharmacological activity for, a product or compound, as described in 21 C.F.R. § 312.21(a) (including any such clinical study in any country other than the United States).

1.20    Phase 2 Trial. The term “Phase 2 Trial” shall mean a human clinical trial conducted on study subjects with the disease or condition being studied for the principal purpose of achieving a preliminary determination of efficacy or appropriate dosage ranges, as further described in 21 C.F.R. §312.21(b) (including any such clinical study in any country other than the United States).

1.21    Phase 3 Trial. The term “Phase 3 Trial” shall mean a pivotal clinical trial in humans performed to gain evidence with statistical significance of the efficacy of a product in a target population, and to obtain expanded evidence of safety for such product that is needed to evaluate the overall benefit-risk relationship of such product, to form the basis for the filing for approval of an NDA or BLA by a Regulatory Authority and to provide an adequate basis for physician labeling, as described in 21 C.F.R. § 312.21(c) or the corresponding regulation in jurisdictions other than the United States.

1.22    Regulatory Approval. The term “Regulatory Approval” shall mean any and all approvals (including pricing and reimbursement approvals), product and establishment licenses, registrations or authorizations of any kind of the FDA or its foreign equivalent necessary for the development, clinical testing, manufacture, quality testing, supply, use, storage, importation, export, transport, marketing and sale of a Licensed Product (or any component thereof) for use in the Field in any country or other jurisdiction.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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1.23    Regulatory Authority. The term “Regulatory Authority” shall mean the governmental authority or agency having the administrative authority to regulate the marketing of human pharmaceutical products or biological therapeutic products, delivery systems and devices in a particular country or jurisdiction, including, without limitation, the FDA.

1.24    Royalty Report. The term “Royalty Report” is defined in Section 6.4.

1.25    Sublicense Revenues. The term “Sublicense Revenues” is defined in Section 4.1.

1.26    Valid Claim. The term “Valid Claim” shall mean a claim of an issued patent within the Patent Rights that has not lapsed, expired, been canceled, or become abandoned, and has not been held invalid by a court or other appropriate body of competent jurisdiction, unappealable or unappealed within the time allowed for appeal and which has not been admitted to be invalid or unenforceable through reissue or disclaimer or otherwise. The term Valid Claim shall also include the claims of a pending patent application within the Patent Rights, but only to the extent that such claim has been pending [***].

2.        Grant of License.

2.1      Grant of License for Licensed Products. TSRI hereby grants to Licensee and its Affiliates, subject to the terms and conditions of this Agreement, including, without limitation, Sections 2.6 and 2.7, an exclusive, worldwide license under TSRI’s interest in the Licensed Patent Rights to develop, make and have made, to use and have used, to import and have imported, and to offer to sell, to sell and have sold Licensed Products in the Field.

2.2      Grant of License for Licensed Processes. TSRI hereby grants to Licensee and its Affiliates, subject to the terms and conditions of this Agreement, including, without limitation, Sections 2.6 and 2.7, an exclusive, worldwide license under TSRI’s interest in the Licensed Patent Rights to develop, make and have made, to use and have used, to import and have imported, and to offer to sell, to sell and have sold Licensed Processes in the Field.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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2.3      Grant of License for Licensed Services. TSRI hereby grants to Licensee and its Affiliates, subject to the terms and conditions of this Agreement, including, without limitation, Sections 2.6 and 2.7, an exclusive, worldwide license under TSRI’s interest in the Licensed Patent Rights to develop, make and have made, to use and have used, to import and have imported, and to offer to sell, to sell and have sold Licensed Services in the Field.

2.4      Sublicensing. Licensee and its Affiliates shall have the right to grant sublicenses to any third party with respect to the licenses granted to Licensee under this Agreement, provided, however, that any such sublicense shall be subject in all respects to the provisions contained in this Agreement. Sublicensees shall not further sublicense without TSRI prior written consent, which consent cannot unreasonably be withheld. Licensee shall forward to TSRI a copy of any and all fully executed sublicense agreements within thirty (30) days following execution.

2.5      No Other License. This Agreement confers no license or rights by implication, estoppel or otherwise under any patent applications or patents of TSRI, other than Licensed Patent Rights, regardless of whether such patents are dominant or subordinate to Licensed Patent Rights.

2.6      Governmental Interest. Licensee and TSRI acknowledge that TSRI has received, and expects to continue to receive, funding from the United States Government in support of TSRI’s research activities. Licensee and TSRI acknowledge and agree that their respective rights and obligations pursuant to this Agreement shall be subject to the rights of the United States Government, existing and as amended, which may arise or result from TSRI’s receipt of research support from the United States Government, including, but not limited to, 37 CFR 401, the NIH Grants Policy Statement and the NIH Guidelines for Obtaining and Disseminating Biomedical Research Resources.

2.7      Reservation of Rights. TSRI reserves the right to use for any non-commercial research or educational purposes any Licensed Patent Rights licensed hereunder, without TSRI being obligated to pay Licensee any royalties or other compensation. In addition, TSRI reserves the right to grant non-exclusive, non-commercial research and educational use licenses to other nonprofit or academic institutions to use any Licensed Patent Rights licensed hereunder, without the other nonprofit entity being obligated to pay Licensee any royalties or other compensation, provided, however, that TSRI shall use reasonable efforts to provide Licensee with a list of such non-exclusive research and educational licenses within sixty (60) days of written request by Licensee (but no more frequently than quarterly).

3.        Royalties.

3.1      Running Royalties

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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(a)       Running Royalties for Licensed Products. Licensee agrees to pay and shall pay to TSRI a running royalty on a country by country basis in the amount [***] on annual Net Sales less than $[***], [***] on annual Net Sales between $[***] and $[***] and [***] on annual Net Sales above $[***], in each case of Licensed Products made by Licensee, sublicensees and its Affiliates.

(b)       Royalty Increase for Licensed Products. Notwithstanding Section 3.1(a), in the event Licensee directly or indirectly alleges in any formal legal or administrative action or proceeding that (i) any of the Licensed Patent Rights are invalid or unenforceable, or (ii) no royalties, Sublicense Payments, milestone payments, patent costs or other monies are due or required to be paid to TSRI under this Agreement because the applicable Licensed Patent Rights are invalid or unenforceable (collectively “Challenges”), the royalty rate specified in Section 3.1 (a) shall increase by [***] during and after the pendency of such Challenges from the date Licensee first institutes or makes such Challenges.

(c)       Running Royalties for Licensed Processes. Licensee agrees to pay and shall pay to TSRI a running royalty on a country by country basis in the amount [***] of Net Sales of products made using a Licensed Process.

(d)       Royalty Increase for Licensed Processes. Notwithstanding Section 3.1 (c), in the event Licensee directly institutes or makes any Challenges, the royalty rate specified in Section 3.1 (c) shall be increased by [***] during and after the pendency of such Challenges from the date Licensee first institutes or makes such Challenges.

(e)       Running Royalties for Licensed Services. Licensee agrees to pay and shall pay to TSRI [***] of any and all Net Sales of Licensed Services.

(f)         Royalty Increase for Licensed Services. Notwithstanding Section 3.1 (e), in the event Licensee directly institutes or makes any Challenges, the royalty rate specified in Section 3.1 (e) shall be increased by [***] during and after the pendency of such Challenges from the date Licensee first institutes or makes such Challenges.

3.2      Multiple Royalties. No multiple royalties shall be due because any Licensed Product, Licensed Service or Licensed Process is covered by more than one of the Licensed Patent Rights. In such case, Licensee shall pay the highest applicable royalty actually owed to TSRI for such Licensed Patent Rights.

3.3      Arms-Length Transactions. On sales of Licensed Products, Licensed Services and Licensed Processes, which are made in other than an arm’s-length transaction, the value of the Net Sales attributed under Section 3.1 to such a transaction shall be that which would have been received in an arm’s-length transaction, based on sales of like quality and quantity products on or about the time of such transaction.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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3.4      [***]

3.5      [***]

4.        Non-royalty Revenues.

4.1      Sublicense Payments.

(a)       Any and all revenues, other consideration, equity interests and other property received by Licensee in consideration for granting a sublicense hereunder, other than (i) royalties, (ii) payments for the milestones set forth in Section 4.2, (iii) funding or reimbursement for specific research and development expenses as specified in such sublicense and incurred after the effective date of such sublicense, and (iv) amounts received in consideration for the issuance and sale of equity securities or debt of the Company, except to the extent such amounts exceed the fair market value of such equity or debt securities as determined in good faith by the Licensee’s Board of Directors (collectively “Sublicense Revenues”) shall be reported to TSRI by Licensee within thirty (30) days of receipt by Licensee.

(b)       Licensee shall pay to TSRI a non-creditable, non-refundable percentage of these Sublicense Revenues according to the following schedule (‘‘Sublicense Payments”):

 

Time of Sublicense Grant		Percentage
Prior to the dosing of first patient in a Phase 2 Trial		[***]
From dosing of first patient in a Phase 2 Trial and beyond		[***]

4.2      Product Development Milestones. Licensee agrees to pay and shall pay to TSRI the following non-creditable, non-refundable product development milestones within thirty (30) days after the first Licensed Product has reached the milestone set forth below (or its equivalent), in the first Major Market Country in which such milestone is reached, as follows:

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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For the avoidance of doubt, Licensee shall pay each such milestone payment only once, regardless of how many times, and in how many Major Market Countries, Licensee reaches such milestone.

5.        Royalty and Revenue Payments.

5.1      Payment Terms. The amounts payable pursuant to Sections 3 and 4 shall be paid by Licensee quarterly, within sixty (60) days after the end of the calendar quarter in which such payment obligation accrued.

5.2      Combination Products and Other Licenses. Licensee may adjust the payment obligations to TSRI by one (but not both) of the following means:

(a)       If a Licensed Product is sold in combination with another active ingredient, or needs to be modified or delivered using products acquired from a third party, which other active ingredients or products if sold alone would not be subject to a royalty payment hereunder, then Net Sales from such combination sales, for purposes of calculating the amounts due under Section 3 hereof, shall be calculated by multiplying the net selling price of the combination product by the fraction A/(A+B), where A is the gross selling price, during the royalty period in question, of the Licensed Product sold separately, and B is the gross selling price, during the royalty period in question, of the other ingredients and/or products sold separately. If the additional ingredients and/or products are not sold separately during that royalty period, then Net Sales for purposes of determining royalty payments shall be calculated by multiplying the net selling price of the combination product by the fraction C/(C+D), where C is the fair market value of the Licensed Product and D is the fair market value of such ingredients and/or products, or

(b)       If, in any royalty period, Licensee or any of its Affiliates or sublicensees, in order to exploit the licenses granted under Section 2 of this Agreement in any country, is required to make royalty payments to one or more third parties (“Third Party Payments”) to make, use, sell and/or import a Licensed Product, Licensed Process or Licensed Service, and the aggregate royalty payments to TSRI and such third party exceeds [***], then

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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Licensee shall have the right to reduce the royalties otherwise due to Licensor pursuant to Section 3 hereof for such Licensed Product, Licensed Process or Licensed Service by [***] of such Third Party Payments, provided, however, that if the agreement between Licensee and such third party does not allow Licensee to offset against Licensee’s royalty obligation to such third party a portion of the royalty payments made to TSRI hereunder, then the Third Party Payment to such third party will not count towards such [***] threshold. Notwithstanding the foregoing, the reductions pursuant to this Section 5.2(b) shall in no event reduce the royalty for such Licensed Product, Licensed Process or Licensed Service in any country to less than [***] of the royalties Licensor would have been entitled to pursuant to Section 3 hereof, but for such Third Party Payment.

6.        Diligence; Commercial Development Plan; Reports.

6.1      Diligence. Licensee will exercise its commercially reasonable efforts and diligence in developing and commercializing Licensed Products, Licensed Processes and Licensed Services in each Major Market Country in accordance with its business, legal, medical and scientific judgment, and in obtaining Regulatory Approvals, as necessary, to market Licensed Products, Licensed Processes and Licensed Services, such commercially reasonable efforts and diligence to be in accordance with the efforts and resources Licensee would use for a pharmaceutical or diagnostic product or service owned by it or to which it has rights, which is of similar market potential at a similar stage in development as the applicable Licensed Product, Licensed Process or Licensed Service, taking into account the competitiveness of the marketplace, the proprietary position of the Licensed Product, Licensed Process or Licensed Service, the relative potential safety and efficacy, the regulatory requirements involved in its development, manufacture, commercialization and Regulatory Approval, the cost of goods and availability of capacity to manufacture, perform and/or supply the Licensed Products, Licensed Processes and/or Licensed Services and other relevant factors, including, without limitation, technical, legal, scientific or medical factors.

6.2      Commercial Development Plan. Prior to signing this Agreement, Licensee has provided to TSRI the Commercial Development Plan attached hereto as Exhibit B, under which Licensee intends to bring the subject matter of the Licensed Patent Rights to the point of commercial use. This Commercial Development Plan is hereby incorporated by reference into this Agreement. Based on this Commercial Development Plan, performance Benchmarks will be determined as specified in Exhibit C.

6.3      Progress Reports on Commercial Development Plan and Benchmarks. Licensee shall provide to TSRI a copy of Licensee’s written annual reports on Licensee’s product development progress and efforts to commercialize under the Commercial Development Plan

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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within thirty (30) days after June 30 of each calendar year. These progress reports shall include progress on research and development, status of applications for regulatory approvals, as well as plans for the present calendar year. TSRI also encourages these reports to include information on any of Licensee’s public service activities that relate to the Licensed Patent Rights. If reported progress differs materially from that projected in the Commercial Development Plan and Benchmarks, Licensee shall explain the reasons for such differences. In any such annual report, Licensee may propose amendments to the Commercial Development Plan, the acceptance of which by TSRI may not be denied unreasonably. Licensee agrees to provide any additional information reasonably required by TSRI to evaluate Licensee’s performance under this Agreement, subject to Licensee’s obligations of confidentiality to third parties. Licensee may amend the Benchmarks at any time upon written consent by TSRI, which consent cannot unreasonably be withheld. TSRI shall not unreasonably withhold approval of any request of Licensee to extend the time periods of this schedule if such request is supported by a reasonable showing by Licensee of diligence in its performance under the Commercial Development Plan and toward bringing the Licensed Products to the point of commercial use.

At any time after [***] from the Effective Date of this Agreement, TSRI may terminate this Agreement if the progress reports furnished by Licensee do not demonstrate, as determined in good faith by TSRI, that Licensee is engaged in research, development, manufacturing, marketing or sublicensing activities reasonably appropriate to put the licensed subject matter into commercial use in the country or countries hereby licensed, directly or through a sublicense, and to keep the licensed subject matter reasonably available to the public, taking into consideration scientific and/or development progress, regulatory requirements, relevant market factors and the size and financial resources of Licensee. Achievement of the Benchmarks specified in Exhibit C shall be considered fulfillment of Licensee’s obligations hereunder. In the event TSRI determines that Licensee has not met its obligations under this Section 6.3, TSRI and Licensee shall meet and in good faith discuss the steps necessary to be undertaken by Licensee to satisfy TSRI’s diligence requirements, and a timeline therefor. In addition, Licensee shall report to TSRI the dates for achieving Benchmarks specified in Exhibit C and Licensee’s first achievement of the milestones set forth in Section 4.1 hereof, and the First Commercial Sale of a Licensed Product in each country, in each case within thirty (30) days following such occurrences. All reports provided to TSRI under this Section 6.3 shall constitute Confidential Information of Licensee, except that TSRI may disclose any Confidential Information contained in such reports to the U.S. government, consistent with its government reporting obligations; provided, however, that such disclosures shall be limited to the information minimally required for TSRI to comply with such reporting obligations.

6.4      Reports on Revenues and Payments. Licensee shall submit to TSRI, no later than sixty (60) days after the end of each calendar quarter, a royalty report (the “Royalty Report”) setting forth for such quarter at least the following information:

(a)       the number of Licensed Products sold by Licensee and its sublicensees;

 

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(b)       the gross amounts due or charged for such Licensed Products;

(c)       the gross amounts due or charged for all Licensed Processes used or sold by Licensee and its sublicensees;

(d)       the gross amounts due or charged for all Licensed Services performed by Licensee and its sublicensees;

(e)       deductions applicable to determine the Net Sales of Licensed Products, Licensed Processes and Licensed Services pursuant to Section 1.14;

(f)       the amount of Sublicense Revenues received by Licensee; and

(g)       the amount of royalty due pursuant to Section 3 hereof, or if no royalties are due to TSRI for any reporting period, the statement that no royalties are due and a detailed explanation why they are not due for that quarterly period.

Such Royalty Report shall be certified as correct in all material respects by an officer of Licensee and shall include a detailed listing of all deductions from royalties. Such Royalty Report shall constitute Confidential Information of Licensee.

6.5      Royalty Payments. Licensee agrees to pay and shall pay to TSRI with each Royalty Report the amount of royalty due with respect to such quarter. If multiple technologies are covered by the license granted hereunder, Licensee shall specify which Licensed Patent Rights are utilized for each Licensed Product, Licensed Process and/or Licensed Service included in the Royalty Report. All payments due hereunder shall be deemed received when funds are transferred to TSRI’s bank account (which bank account shall be designated in writing to Licensee), and shall be payable by check or wire transfer in United States Dollars.

6.6      Foreign Sales. The remittance of royalties payable on sales outside the United States shall be payable to TSRI in United States Dollar equivalents at the official rate of exchange of the currency of the country from which the royalties are payable, as quoted in the Wall Street Journal for the last business day of the calendar quarter in which the royalties are payable. If the transfer of or the conversion into the United States Dollar equivalents of any such remittance in any such instance is not lawful or possible, the payment of such part of the royalties as is necessary shall be made by the deposit thereof, in the currency of the country where the sale was made on which the royalty was based to the credit and account of TSRI or its nominee in any commercial bank or trust company of TSRI’s choice located in that country, prompt written notice of which shall be given by Licensee to TSRI.

 

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6.7      Foreign Taxes. Any tax required to be withheld by Licensee under the laws of any foreign country for any royalties or other amounts due hereunder or for the accounts of TSRI shall be promptly paid by Licensee for and on behalf of TSRI to the appropriate governmental authority, and Licensee shall furnish TSRI with proof of payment of such tax together with official or other appropriate evidence issued by the applicable government authority. Any such tax actually paid on TSRI’s behalf shall be deducted from royalty payments due TSRI.

7.        Record Keeping.

7.1      Record Keeping and Audits. Licensee shall keep, and shall require its Affiliates and sublicensees to keep, accurate records (together with supporting documentation) of Licensed Products, Licensed Services and/or Licensed Processes sold under this Agreement, appropriate to determine the amount of royalties, Sublicense Payments, milestone payments and other monies due to TSRI hereunder. Such records shall be retained for at least three (3) years following the end of the reporting period to which such records pertain. They shall be available with ten (10) days prior written notice during normal business hours for examination and copying by an accountant selected by TSRI, for the purpose of verifying Licensee’s reports and payments hereunder and its compliance with this Agreement. In conducting examinations pursuant to this Section 7, TSRI’s accountant shall have access to, and may disclose to TSRI, all records which such accountant reasonably believes to be relevant to the calculation of payments under Section 3, non-royalty revenues under Section 4 and Licensee’s compliance with its payment obligations under this Agreement. Except as set forth above, TSRI’s accountant shall not disclose to TSRI any information other than information relating to the accuracy of reports and payments made hereunder and to Licensee’s compliance with its payment obligations under this Agreement. Such examination by TSRI’s accountant shall be at TSRI’s expense, except as set forth in Section 7.2 hereof.

7.2      Underpayments. In the event the examination described in Section 7.1 reveals an underreporting or underpayment, TSRI shall submit to Licensee a written notice of such discrepancy, which notice shall be accompanied by a written report prepared by TSRI’s accountant setting forth, in reasonable detail, the basis of the alleged underreporting or underpayment. If Licensee does not notify TSRI that Licensee disputes the findings set forth in such report within thirty (30) days after receipt thereof, Licensee shall pay to TSRI the full amount of the underpayment in question at the end of such thirty (30) day period. If the underreporting or underpayment exceeds [***] for any twelve (12) month period, and Licensee does not dispute the result of such examination, or such examination or the discrepancy in excess of [***] is found to be correct following the dispute resolution procedure set forth in Section 7.3 hereof, then Licensee shall pay TSRI’s costs of such examination (including, without limitation, TSRI’s reasonable (i) attorney’s fees, (ii) accountant’s fees and (iii) other costs) as well as any additional sum that would have been

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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payable to TSRI had the Licensee reported correctly, plus interest on such sum at the rate of [***] per month.

7.3      Royalty Disputes. If Licensee disputes the findings set forth in the written report, it shall so notify TSRI in writing within thirty (30) days after the receipt of such report. Representatives of TSRI and Licensee shall meet and, in good faith, seek to resolve the dispute through negotiation; provided, however, that if such dispute is not resolved within thirty (30) days of Licensee notifying TSRI of such dispute, TSRI and Licensee shall promptly retain, at Licensee’s cost and expense, a mutually agreeable, regionally-recognized independent certified public accounting firm and the specific certified public accountant who has at least ten (10) years’ experience with auditing life science royalty and similar reports, which firm or accountant does not have a current business or other relationship with either party, to resolve such dispute. The determination of such accountant in regard to the accuracy of the payments made by Licensee to TSRI shall be final and binding upon the parties, shall not be subject to appeal or review by any court or governmental agency and shall be enforceable in the appropriate California courts. If such review reveals that Licensee has failed to pay to TSRI the full amount of a royalty payment due pursuant to this Agreement, Licensee shall pay the full amount of such discrepancy, plus interest on such amount at the rate of [***] per month, to TSRI within thirty (30) days of the date of the report of such accountants. If such review reveals that Licensee has overpaid TSRI any royalty amounts due pursuant to this Agreement, Licensee shall, on the Royalty Reports submitted to TSRI, claim such overpaid amounts as a credit against Licensee’s royalty obligations (if any) for the subsequent calendar quarter(s), and shall be entitled to reduce its royalty payments to TSRI accordingly until such time as the full amount of such overpayment has been credited to Licensee against royalty obligations otherwise due to TSRI hereunder.

8.        Patent Matters.

8.1      Patent Prosecution and Maintenance. From and after the date of this Agreement, the provisions of this Section 8 shall control the prosecution of any patent application and maintenance of any patent included within Licensed Patent Rights. Subject to the requirements, limitations and conditions set forth in this Agreement, TSRI shall select the patent attorney, subject to Licensee’s written approval, which approval shall not be unreasonably withheld. The parties agree that TSRI shall have the right, at its sole discretion, to utilize TSRI’s Office of Patent Counsel in addition to independent counsel for patent prosecution and maintenance described herein and the reasonable attorney’s fees and expenses associated with the work done by such Office of Patent Counsel and/or independent counsel shall be paid as set forth below. Licensee shall have full rights of consultation on all matters relating to the Licensed Patent Rights. TSRI shall implement all reasonable and timely requests made by Licensee with regard to the preparation, filing, prosecution and/or maintenance of the patent applications and/or patents within the Licensed Patent Rights, including, without

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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limitation, requests relating to the jurisdictions in which TSRI shall prepare, file, prosecute and maintain patent applications and the type of patent application to file. As of the Effective Date, TSRI and Licensee shall continue to use the services of Cooley LLP for matters relating to the prosecution and maintenance of the Licensed Patent Rights.

8.2      Information to Licensee. TSRI shall keep Licensee timely and fully informed of the progress of all patent applications, patents and other submissions relating thereto and give Licensee and Licensee’s counsel reasonable opportunity to review and comment on the text of each patent application within Licensed Patent Rights and other submissions relating thereto before filing, including, but not limited to, the type and the scope of the useful claims and the nature of supporting disclosures. TSRI shall provide Licensee with a copy of such patent application as filed, together with notice of its filing date and serial number, and each such submission. TSRI shall provide Licensee with copies of all patent applications, amendments, related correspondence and other relevant documentation relating to such prosecution. [***]

8.3      Patent Costs. Licensee acknowledges and agrees that the license granted hereunder is in partial consideration for Licensee’s assumption of patent costs and expenses as described herein. Licensee agrees to pay and shall pay for all reasonable expenses referenced in Section 8.1 hereof for work performed by TSRI’s Office of Patent Counsel and its independent counsel. In addition, Licensee agrees to reimburse and shall reimburse TSRI for all reasonable patent costs and expenses previously paid or associated with Licensed Patent Rights. Licensee agrees to pay and shall pay all such reasonable expenses within thirty (30) days after Licensee receives an itemized invoice therefor. Failure of Licensee to pay patent costs and expenses as set forth in this Section 8.3 shall immediately relieve TSRI from its obligation to incur further patent costs and expenses or to continue to prosecute the patent applications; provided, however, that TSRI’s obligation to incur patent costs and expenses and to prosecute the patent applications shall, to the extent possible, be immediately restored upon Licensee’s payment of such patent costs and expenses. Licensee may elect with a minimum of ninety (90) days prior written notice to TSRI, to discontinue payment for the filing, prosecution and/or maintenance of any patent application and/or patent within Licensed Patent Rights in those jurisdictions specified in such written notice. Licensee shall remain liable for all patent prosecution and maintenance costs of such patents or patent applications incurred prior to the date of notice of election and for a ninety (90) day period following date of such notice. Any such patent application or patent so elected shall, for the jurisdictions specified in the written notice, immediately be excluded from the definition of Licensed Patent Rights and from the scope of the licenses granted under this Agreement, and all rights relating thereto shall revert to TSRI and may be freely licensed by TSRI.

 

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8.4      Ownership. The patent applications filed and the patents obtained by TSRI pursuant to Section 8.1 hereof shall be owned solely by TSRI, assigned solely to TSRI and deemed a part of Licensed Patent Rights. For the avoidance of doubt, the foregoing shall not apply to patent applications and patents within the Licensed Patent Rights that are jointly owned by TSRI and Licensee.

8.5      Prosecution and Maintenance of Patents after Termination. If at any time during the term of this Agreement, Licensee’s rights under this Agreement with respect to Licensed Patent Rights owned solely by TSRI are terminated, TSRI shall have the right to take whatever action TSRI deems appropriate to obtain or maintain the corresponding patent protection. If TSRI pursues patents under this Section 8.5, Licensee agrees to provide reasonable cooperation, including by providing, at TSRI’s cost and expenses, all appropriate technical data and executing all necessary legal documents.

8.6      Infringement Actions.

(a)       Licensee and TSRI shall each inform the other party promptly in writing of any alleged infringement by a third party of the Licensed Patent Rights covering Licensed Products, Licensed Services and/or Licensed Processes, which comes to their attention and of any available evidence thereof.

(b)       During the term of this Agreement, the parties shall consult with each other regarding the infringement of any patent within the Licensed Patent Rights. During or following such consultation, Licensee shall have the first and sole right and obligation (except as provided below) to take steps to abate the infringement and/or to institute, prosecute and control, at its own expense, any action or proceeding with respect to any infringement of such patent by a third party and, in furtherance of such right, TSRI hereby agrees that Licensee may include and join TSRI as a party plaintiff in any such suit, without expense to TSRI; provided, however, that if Licensee determines, and provides TSRI with its reasons, that such action against an infringer would be commercially unreasonable, as determined in good faith by Licensee’s Board of Directors, then Licensee shall not have the obligation to take any such action or institute any such proceeding. In this regard, Licensee shall be entitled to use its reasonable commercial discretion in determining (a) whether to contact and/or institute any action or proceeding against an alleged third party infringer; (b) the timing of any contact with an alleged third party infringer and/or action or proceeding to be instituted against an alleged third party infringer; (c) the location of any action or proceeding to be instituted against an alleged third party infringer; and (d) should there be more than one alleged third party infringer, which alleged infringer to contact regarding its alleged infringement or against whom any action or proceeding is to be brought, it being further understood and agreed that, during such time as Licensee is pursuing any action or proceeding against one alleged third party infringer, Licensee shall have no obligation to contact and/or pursue additional alleged infringers.

 

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(c)       If, in the case of a third party infringement for which Licensee decides not to pursue an action and provides TSRI its reasons why such action is commercially unreasonable, TSRI disagrees with Licensee’s assessment that such actions are commercially unreasonable, and TSRI desires to pursue an action to prevent such infringement, then TSRI may initiate an arbitration as provided in Section 15.8 below for a determination of whether Licensee’s position is correct that it is commercially unreasonable to take action against such infringer. In the event such arbitrator finds that Licensee’s reasons for not pursuing an action are legitimate (i.e., that an action would be commercially unreasonable), then Licensee shall have no further obligation with respect thereto and TSRI shall have no right to pursue the infringement action. In the event such arbitrator finds that Licensee’s reasons are insufficient and that an action would be commercially reasonable, then Licensee or its sublicensee, at Licensee’s option, may pursue an action against such third party infringer. In the event that Licensee or its sublicensee does not pursue such action, then TSRI shall have the right to pursue the infringement action against such third party infringer, in which case TSRI shall indemnify, defend and hold Licensee harmless from any costs, expenses or liability with respect to all such actions undertaken by TSRI. In the event that TSRI does take action against such third party infringer, then Licensee will pay up to [***] of TSRI’s litigation expenses, including reasonable attorney’s fees. In the event that TSRI recovers money as a result of a judgment or settlement in such action, Licensee shall receive [***] of such judgment or settlement, after reimbursement to TSRI and Licensee of the litigation expenses incurred by each party. Alternatively, at Licensee’s option, Licensee may, upon written notice to TSRI, terminate its license to the patents within Licensed Patent Rights that are the subject of such action, in the jurisdictions where Licensee fails to pursue such action, in which case Licensee shall not have an obligation to pay for TSRI’s litigation expenses in those jurisdictions. If TSRI takes no action against such third party infringer, then Licensee will have no obligation to TSRI.

(d)       In the event that Licensee determines to bring suit against an alleged third party infringer, any recovery of damages shall be distributed pursuant to Section 8.6 (e) below. In the event such infringement adversely affects the scope or validity of the Licensed Patent Rights, no settlement, consent judgment or other voluntary disposition of any such suit may be entered into without the consent of TSRI, which consent shall not be unreasonably withheld or delayed. TSRI shall have fifteen (15) days from the date of Licensee’s written notice to TSRI either to consent or object in writing, stating in reasonable detail the reasons for withholding consent. No response within such period shall be deemed to constitute TSRI’s consent. Licensee shall indemnify TSRI against any order for costs that may be made against TSRI as a result of any action or inaction by Licensee in such proceedings. Notwithstanding the foregoing, TSRI may elect at its option to participate in the prosecution of any such infringement action through counsel of its own choice at its own expense.

(e)       In the event Licensee shall undertake the enforcement of the Licensed Patent Rights covering the Licensed Products, Licensed Services or Licensed Processes, any recovery of damages by Licensee as a result of a judgment or settlement in such action, shall first be applied in satisfaction of any litigation expenses of Licensee and TSRI relating to such suit and TSRI shall receive [***] of the balance remaining from any such recovery.

 

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(f)         In any infringement suit which either party may institute to enforce the Licensed Patent Rights pursuant to this Agreement, or in a suit for patent infringement, which is brought by a third party against TSRI or Licensee, which either party or both parties are required or elect to defend, the other party hereto shall, at the request and the expense of the party initiating or defending such suit, cooperate in all reasonable respects and, to the extent reasonably possible, have its employees testify when requested and make available relevant records, papers, information, samples, specimens and the like.

(g)         Licensee shall have the sole right, subject to the terms and conditions hereof, to sublicense to any alleged infringer its rights within the Licensed Patent Rights to make, have made, use, sell, offer to sell and/or import Licensed Products, Licensed Services or Licensed Processes. Any upfront fees paid to Licensee in consideration for the sublicense granted as part of a settlement of the infringement action shall be applied first in satisfaction of any expenses and legal fees of Licensee relating to such suit and the balance remaining from any such recovery distributed as set forth in Section 4.1 above as it relates to Sublicense Revenues. Any other consideration (including, without limitation, actual and statutory damages) paid to Licensee shall be apportioned in accordance with Section 8.6(e) hereof.

(h)         Licensee shall defend any suit in a Major Market Country against Licensee or sublicensees, which suit alleges infringement of any third party patent right due to the development and/or commercialization of Licensed Products, Licensed Services or Licensed Processes by Licensee, unless otherwise agreed to between TSRI and Licensee. Licensee shall notify TSRI if Licensee has a good faith belief that the defense of such suit will have no reasonable likelihood of success, and if TSRI disagrees with such assessment, TSRI and Licensee shall retain, at Licensee’s expense, an independent attorney with at least ten (10) years of experience in litigating patent disputes relating to biological therapeutics to determine whether the defense of such suit will have no reasonable likelihood of success. Licensee shall not have to defend such suit pursuant to this Section 8.6(h) if the independent patent attorney finds that the defense of such suit will have no reasonable likelihood of success. If the alleged infringement results from the exercise of Licensed Patent Rights and not solely from the exercise of any other patent rights owned or controlled by Licensee, then this Section 8.6(h) shall apply. Licensee shall promptly notify TSRI, and TSRI and Licensee shall confer with each other and cooperate during the defense of any such action. If Licensee finds it necessary or desirable for TSRI to become a party to such action, TSRI shall execute all papers or perform such other acts as may reasonably be required by Licensee. Licensee shall bear the costs and expenses associated with any such suit or action. TSRI shall be entitled to, at its expense, participate in and have counsel selected by it participate in any such action. In no event shall TSRI have any out-of-pocket liability for costs of litigation or royalties, damages and/or settlement amounts due to any third party (except for costs of its own counsel as provided above). If the third party patent right is held not to be infringed, unenforceable or invalid, by a court or other tribunal from which no appeal can be or is taken, any recovery of damages for such suit shall first be applied to reimburse any fees and litigation expenses of the parties hereto, and Licensee shall be entitled to keep the balance remaining from any such recovery.

 

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9.        Indemnity and Insurance.

9.1        Indemnity. Licensee hereby agrees to indemnify, defend and hold harmless TSRI and any parent, subsidiary or other affiliated entity and their trustees, directors, officers, employees, scientists, agents, successors, assigns and other representatives (collectively, the “Indemnitees”) from and against all damages, claims, liabilities, losses and other expenses, including, without limitation, reasonable attorney’s fees, expert witness fees and costs, whether or not a lawsuit or other proceeding is filed (“Claim”), that arise out of or relate to (a) Licensee’s or any sublicensee’s use of any of the Licensed Patent Rights, (b) alleged defects or other problems with any of the Licensed Products, Licensed Services or Licensed Processes manufactured, sold, distributed or rendered by Licensee or any sublicensee, including, without limitation, any personal injuries, death or property damages related thereto, (c) any advertising or other promotion of the Licensed Products, Licensed Services or Licensed Processes by Licensee or any sublicensees, (d) any allegations that the Licensed Products, Licensed Services or Licensed Processes developed, manufactured, sold, distributed or rendered by Licensee or any sublicensee and/or any trademarks, service marks, logos, symbols, slogans or other materials used in connection with or to market Licensed Products, Licensed Services or Licensed Processes violate or infringe upon the trademarks, service marks, trade dress, trade names, copyrights, patents, works of authorship, inventorship rights, trade secrets, database rights, rights under unfair competition laws, rights of publicity, privacy or defamation, or any other intellectual or industrial property rights of any third party, (e) Licensee’s or any sublicensee’s failure to comply with any applicable laws, rules or regulations, (f) Licensee’s or any sublicensee’s transactions with third parties or the operation of their respective businesses, and/or (g) the grossly negligent or willful acts or omissions of Licensee or any sublicensee, provided, however, that Licensee’ s liability for damages under its indemnification obligation shall be reduced or apportioned to the extent such Claim are proximately caused by the grossly negligent or willful act or omission of TSRI or an Indemnitee. TSRI agrees to provide reasonable assistance of a technical nature, which Licensee may require in any litigation arising in accordance with the provisions of this Section 9.1, for which Licensee shall pay to TSRI a reasonable hourly rate of compensation. Licensee shall not enter into any settlement of such Claims that involve TSRI admitting any liability, paying any money or taking any action that would have an adverse effect on TSRI’s reputation or business without TSRI’s prior written consent. Notwithstanding the above, Indemnitees, at their expense, shall have the right to retain separate independent counsel to assist in defending any such Claims. In the event Licensee fails to promptly indemnify and defend such Claims and/or pay Indemnitees’ expenses as provided above, Indemnitees shall have the right to defend themselves, and in that case, Licensee shall reimburse Indemnitees for all of their reasonable attorney’s fees, costs and damages incurred in settling or defending such Claims within thirty (30) days following each of Indemnitees’ written requests. This indemnity shall be a direct payment obligation and not merely a reimbursement obligation of Licensee to Indemnitees.

 

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9.2        Insurance. Licensee shall name TSRI and Indemnitees as “additional insureds” on any commercial general liability and product liability insurance policies maintained by Licensee, its Affiliates and sublicensees applicable to the Licensed Products, Licensed Processes and Licensed Services.

(a)        Beginning by the time there is a first use on a human (including clinical studies) with any Licensed Product, Licensed Process or Licensed Service, Licensee shall, at its sole cost and expense, procure and maintain commercial general liability insurance (including product liability coverage) in amounts not less than $[***] per incident and $[***] annual aggregate and naming the Indemnitees as additional insureds. During clinical trials involving any Licensed Product, Licensed Process or Licensed Service, Licensee shall, at its sole cost and expense, procure and maintain commercial general liability insurance in such equal or lesser amount as TSRI shall require, naming the Indemnitees as additional insureds. Such commercial general liability insurance shall provide broad form contractual liability coverage for all of Licensee’s obligations under this Agreement. If Licensee elects to self-insure all or part of the limits described above (including deductibles or retentions, which are in excess of $250,000 annual aggregate) such self-insurance program must be acceptable to TSRI, which consent cannot unreasonably be withheld. The insurance coverage amounts specified herein or the maintenance of such insurance policies shall not in any way limit Licensee’s indemnity or other liability under this Agreement.

(b)        In addition, Licensee, on behalf of itself and its insurance carriers, waives any and all claims and rights of recovery against TSRI and the Indemnitees, including, without limitation, all rights of subrogation, with respect to either party’s performance under this Agreement or for any loss of or damage to Licensee or its property or the property of others under its control. Licensee’s commercial general liability insurance policy shall also include a waiver of subrogation consistent with this paragraph in favor of TSRI and the Indemnitees. Licensee shall be responsible for obtaining such waiver of subrogation from its insurance carriers. Licensee’s insurance policies shall be primary and not contributory to any insurance carried by its sublicensees or by TSRI. Upon TSRI’s request, Licensee shall deliver to TSRI copies of insurance certificates or binders and such waiver of subrogation that complies with the requirements of this Section 9.

(c)        Licensee shall provide TSRI with written notice at least thirty (30) days prior to the cancellation, nonrenewal or material change, in each case by Licensee, in such insurance. If Licensee does not obtain replacement insurance providing comparable coverage (including, without limitation, self-insurance) within such thirty (30) day period, TSRI shall have the right to terminate this Agreement effective at the end of such thirty (30) day period without notice or any additional waiting periods.

(d)        Licensee shall maintain such commercial general liability insurance beyond the expiration or termination of this Agreement during (a) the period that any Licensed Product, Licensed Process or Licensed Service is being commercially distributed or sold by Licensee or by a sublicensee, Affiliate or agent of Licensee; and (b) a reasonable period after the period referred to in Section 9.2(a) above.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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(e)        Pre-Challenge Requirements. In the event Licensee intends to institute a Challenge, Licensee will first provide written notice (the “Challenge Notice”) to TSRI thereof for the purpose of allowing the parties to reach an amicable resolution. Licensee will include with such Challenge Notice [***]. As soon as practical after delivery of the Challenge Notice, Licensee and TSRI shall meet and with reasonable diligence and in good faith attempt to negotiate a resolution to the issues underlying such Challenge. Licensee and TSRI shall use reasonable efforts to undertake such negotiations for a period of time not exceeding [***] after the delivery by Licensee of the Challenge Notice. Licensee and TSRI shall in good faith provide each other with sufficient information and documentation, subject to each party’s obligations of confidentiality to third parties, reasonably necessary to resolve such issues pursuant to this Section 9.2(e). If the parties fail to reach a mutually agreeable resolution within such [***] period, subject to provisions of this Agreement, Licensee may proceed with such Challenge. TSRI may not, for a period of [***] following the expiration of the [***] negotiation period, initiate the same or substantially similar proceeding that was the subject of the Challenge Notice with respect to the patent applications or patents within the Licensed Patent Right that were the subject of such Challenge Notice. Nothing herein shall prevent TSRI from engaging in (i) interactions with the US Patent and Trademark office, or its foreign equivalents, in the ordinary course of prosecuting and maintaining such patent applications and patents (including, without limitation, preparing, filing and prosecuting new patent applications), and (ii) proceedings or suits involving such patent applications or patents that were contemplated prior to the delivery of the Challenge Notice, as documented by written evidence; provided, however, that in the preparation or prosecution of any such proceeding or suit, TSRI cannot use or reference any information provided by Licensee to TSRI pursuant to this Section 9.2(e), except to the extent necessary to comply with TSRI’s disclosure obligations to the US Patent and Trademark office or its foreign equivalents.

10.        Limited Warranty.

10.1        Limited Warranty. TSRI hereby represents and warrants that it has full right and power to enter into this Agreement and to perform its obligations hereunder, that it has the right to grant the licenses hereunder, and that this Agreement does not conflict with any other agreement to which TSRI is a party or by which TSRI may be bound. TSRI MAKES NO OTHER WARRANTIES CONCERNING LICENSED PATENT RIGHTS OR ANY OTHER MATTER WHATSOEVER, INCLUDING, WITHOUT LIMITATION, ANY EXPRESS OR IMPLIED WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, NON-INFRINGEMENT OF THIRD PARTY RIGHTS OR ARISING OUT OF COURSE OF CONDUCT OR TRADE CUSTOM OR USAGE, AND TSRI DISCLAIMS ALL SUCH EXPRESS OR IMPLIED WARRANTIES. TSRI MAKES NO WARRANTY OR REPRESENTATION AS TO THE VALIDITY OR SCOPE OF LICENSED PATENT RIGHTS, OR THAT ANY LICENSED PRODUCT, LICENSED PROCESS OR LICENSED SERVICE WILL BE FREE FROM AN INFRINGEMENT ON PATENTS OR OTHER INTELLECTUAL PROPERTY RIGHTS OF

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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THIRD PARTIES, OR THAT ANY THIRD PARTIES ARE IN ANY WAY INFRINGING UPON ANY LICENSED PATENT RIGHTS COVERED BY THIS AGREEMENT. FURTHER, TSRI HAS MADE NO INVESTIGATION AND MAKES NO REPRESENTATION THAT THE LICENSED PATENT RIGHTS ARE SUITABLE FOR LICENSEE’S PURPOSES.

10.2        Limitation on Damages. EXCEPT FOR LICENSEE’S INDEMNITY OBLIGATIONS UNDER SECTION 9.1, IN NO EVENT SHALL EITHER PARTY BE LIABLE FOR ANY INDIRECT, SPECIAL, INCIDENTAL, EXEMPLARY, PUNITIVE OR CONSEQUENTIAL DAMAGES (INCLUDING, WITHOUT LIMITATION, DAMAGES FOR LOSS OF PROFITS OR EXPECTED SAVINGS OR OTHER ECONOMIC LOSSES, OR FOR INJURY TO PERSONS OR PROPERTY) ARISING OUT OF OR IN CONNECTION WITH THIS AGREEMENT OR ITS SUBJECT MATTER. TSRI’S AGGREGATE LIABILITY, IF ANY, FOR ALL DAMAGES OF ANY KIND RELATING TO THIS AGREEMENT OR ITS SUBJECT MATTER SHALL NOT EXCEED THE AMOUNT PAID BY LICENSEE TO TSRI UNDER THIS AGREEMENT. THE FOREGOING EXCLUSIONS AND LIMITATIONS SHALL APPLY TO ALL CLAIMS AND ACTIONS OF ANY KIND AND ON ANY THEORY OF LIABILITY, WHETHER BASED ON CONTRACT, TORT (INCLUDING, BUT NOT LIMITED TO NEGLIGENCE OR STRICT LIABILITY), OR ANY OTHER GROUNDS, AND REGARDLESS OF WHETHER SUCH PARTY HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH DAMAGES, AND NOTWITHSTANDING ANY FAILURE OF ESSENTIAL PURPOSE OF ANY LIMITED REMEDY. THE PARTIES FURTHER AGREE THAT EACH WARRANTY DISCLAIMER, EXCLUSION OF DAMAGES OR OTHER LIMITATION OF LIABILITY HEREIN IS INTENDED TO BE SEVERABLE AND INDEPENDENT OF THE OTHER PROVISIONS SINCE THEY EACH REPRESENT SEPARATE ELEMENTS OF RISK ALLOCATION BETWEEN THE PARTIES.

11.        Confidentiality and Publication.

11.1        Treatment of Confidential Information. The parties agree that during the term of this Agreement, and for a period of five (5) years after this Agreement terminates, a party receiving Confidential Information of the other party will (a) maintain in confidence such Confidential Information to the same extent such party maintains its own proprietary information, provided that such standard shall be not less than reasonable care; (b) not disclose such Confidential Information to any third party without the prior written consent of the other party; and (c) not use such Confidential Information for any purpose, except those permitted by this Agreement.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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11.2        Publications. Licensee acknowledges that it is the general policy of TSRI to publish research results in technical or scientific journals. Licensee agrees that, subject to this Section 11, TSRI shall have a right to publish in accordance with its general policy. For the avoidance of doubt, this Section 11.2 applies only to the Technology subject to this Agreement, and nothing herein is intended to limit TSRI’s obligations with respect to other information, results and data generated by TSRI and its employees or agents under the Research Agreement.

11.3        Publicity. Except as otherwise provided herein, each party agrees not to disclose any terms of this Agreement to any third party, without the prior written consent of the other party, except (i) as required by securities or other applicable laws and regulations, (ii) to existing and prospective investors, (iii) to existing or potential business partners or acquirers, (iv) to agencies of the government or private foundations for purposes of obtaining grants or other funding or providing reports to such agencies or foundations, and (v) to accountants, attorneys and other professional advisors of such party, provided that except for subclause (i), (ii) and (iii) above, such third parties have signed written confidentiality agreements at least as restrictive as the confidentiality obligations herein, or such third parties are under a duty of confidentiality, before any such disclosures, and, with respect to subclause (i) above, the disclosing party uses reasonable efforts to seek confidential treatment for the disclosure of any terms of this Agreement that the disclosing party reasonably believes are likely to cause substantial competitive harm to the parties if disclosed. Scientific publications published in accordance with Section 11.2 of this Agreement shall not be construed as publicity governed by this Section 11.3.

12.        Term and Termination.

12.1        Term. Unless terminated sooner in accordance with the terms set forth herein, this Agreement, and the licenses granted hereunder, shall terminate as provided in Section 3.4 hereof.

12.2        Termination Upon Mutual Agreement. This Agreement may be terminated by mutual written agreement of the parties.

12.3        Termination by TSRI. TSRI may terminate this Agreement as follows:

(a)        If Licensee does not make a payment due hereunder and fails to cure such non-payment (including the payment of interest in accordance with Section 15.2) within thirty (30) days after the delivery to Licensee of a written notice of such non-payment by TSRI;

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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(b)        If Licensee defaults in its indemnification and insurance obligations under Section 9 and fails to cure such default within thirty (30) days after delivery to Licensee of a written notice of such default by TSRI;

(c)        If, at any time after [***] from the date of this Agreement, TSRI determines in good faith that the Agreement should be terminated pursuant to Section 6.3;

(d)        If Licensee becomes insolvent, makes an assignment for the benefit of creditors, or has a petition in bankruptcy filed for or against it which petition is not challenged or dismissed with prejudice within ninety (90) days after filing, then such termination shall be effective immediately upon TSRI giving written notice to Licensee;

(e)        If an examination by TSRI’s accountant pursuant to Section 7 shows an underreporting or underpayment by Licensee in excess of [***] in any calendar year, and a subsequent audit shows a similar under reporting of underpayment by Licensee in excess of [***] in any subsequent calendar year, in each case if either Licensee does not dispute the result of such examinations or such examinations are determined to be accurate in accordance with Section 7.3 hereof;

(f)        If Licensee is convicted of a felony relating to the manufacture, use or sale of Licensed Products, Licensed Services or Licensed Processes, which conviction is upheld after final appeal;

(g)        If Licensee institutes or makes any Challenges, then TSRI has the right to immediately terminate this Agreement without any liability and without any opportunity to cure by Licensee upon written notice to Licensee; or

(h)        Except as provided in subparagraphs (a)—(e) above, if Licensee defaults in the performance of any material obligation under this Agreement and the default has not been remedied within sixty (60) days after the delivery to Licensee of a written notice of such default by TSRI.

12.4        Termination by Licensee. Licensee may terminate this Agreement in its entirety, or on a jurisdiction-by-jurisdiction and patent-by-patent basis, by giving ninety (90) days advance written notice of termination to TSRI.

12.5        Rights Upon Expiration. Neither party shall have any further rights or obligations upon the expiration of this Agreement upon its regularly scheduled expiration date other than the obligation of Licensee to make any and all reports and payments for the final quarterly period; provided, however, that upon such expiration, each party shall be required to continue to abide by its non-disclosure obligations as described in Section 11, which shall survive such expiration. Sections 2.6, 2.7, 7, 8.3, 8.4, 9, 10, 12 and 15 shall also survive the expiration of this Agreement.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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12.6        Rights Upon Termination. Notwithstanding any other provision of this Agreement, upon any termination of this Agreement prior to the regularly scheduled expiration date of this Agreement, the licenses granted hereunder shall terminate and revert to TSRI, and all sublicenses granted by Licensee shall terminate automatically. Except as otherwise provided in Section 12.7 of this Agreement with respect to work-in-progress, upon such termination, Licensee shall have no further right to develop, manufacture or market any Licensed Product, Licensed Service or Licensed Process or to otherwise use any Licensed Patent Rights, which are owned solely by TSRI. Upon any such termination, Licensee shall promptly return all materials, samples, documents, information and other materials, which embody or disclose Licensed Patent Rights owned solely by TSRI; provided, however, that Licensee shall not be obligated to provide TSRI with proprietary information, which Licensee can show that it independently developed. Any such termination shall not relieve either party from any obligations accrued to the date of such termination. Upon such termination, each party shall be required to abide by its non-disclosure obligations as described in Section 11, which shall survive such termination. Sections 2.6, 2.7, 7, 8.3, 8.4, 9, 10, 12 and 15 shall also survive the termination of this Agreement.

12.7        Work-in-Progress. Upon any such early termination of the license granted hereunder in accordance with this Agreement, Licensee shall be entitled to finish any work-in-progress and to sell any completed inventory of a Licensed Product covered by such license, which remain on hand as of the date of the termination, so long as Licensee sells such inventory in the normal course of business and at regular selling prices and pays to TSRI the royalties applicable to such subsequent sales in accordance with the terms and conditions set forth in this Agreement, provided that no such sales shall be permitted after the expiration of six (6) months after the date of termination.

12.8        Final Royalty Report. Upon termination or expiration of this Agreement, Licensee shall submit a final report to TSRI, and any payments due TSRI and unreimbursed patent expenses invoiced by TSRI shall become immediately payable.

13.        Assignment; Successors. This Agreement may not be assigned or otherwise transferred by either party without the prior written consent of the other party, which consent shall not be unreasonably withheld; provided, however, that a party may, without such consent, assign this Agreement and its rights and obligations hereunder (i) to an Affiliate, (ii) in connection with a merger, acquisition, consolidation or a sale involving all or substantially all of the assets of such party. Any attempted assignment or transfer in violation of this Section 13 shall be void.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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14.        Binding Upon Successors and Assigns. Subject to the limitations on assignment set forth herein, this Agreement shall be binding upon and inure to the benefit of any successors in interest and assigns of TSRI and Licensee. Any such successor to or assignee of a party’s interest shall expressly assume in writing the performance of all of the terms and conditions of this Agreement to be performed by such party and such written assumption shall be delivered to the other party.

15.        General Provisions.

15.1    Independent Contractors. The relationship between TSRI and Licensee is that of independent contractors. TSRI and Licensee are not joint venturers, partners, principal and agent, master and servant, employer or employee, and have no other relationship other than independent contracting parties. TSRI and Licensee shall have no power to bind or obligate each other in any manner, other than as is expressly set forth in this Agreement.

15.2        Late Payments. Except as otherwise set forth in Section 7 hereof, late payments of any and all payments due hereunder shall be subject to a charge of one and one-half percent (1.5%) per month.

15.3        Governmental Approvals and Marketing of Licensed Products. Licensee shall be responsible for obtaining all necessary governmental approvals for the development, production, distribution, performance, sale and use of any Licensed Product, Licensed Services or Licensed Process, at Licensee’s expense, including, without limitation, any safety studies. Licensee shall have sole responsibility for any warning labels, packaging and instructions as to the use of Licensed Products and for the quality control for any Licensed Products.

15.4        Patent Marking. To the extent required by applicable law, Licensee shall mark all Licensed Products or their containers in accordance with the applicable patent marking laws.

15.5        No Use of Name. The use of the name “The Scripps Research Institute”, “Scripps”, “TSRI” or any variation thereof in connection with the advertising, sale or performance of Licensed Products, Licensed Processes or Licensed Services is expressly prohibited. For the avoidance of doubt, nothing in this Section 15.5 shall prevent Licensee from identifying TSRI as a contracting partner in connection with any disclosure permitted under Section 11.3 hereof.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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15.6        U.S. Manufacture. To the extent applicable, Licensee agrees to abide by the Preference for United States Industry as set forth in 37 CFR 401.14 (I).

15.7        Foreign Registration. Licensee agrees to register this Agreement with any foreign governmental agency, which requires such registration, and Licensee shall pay all costs and legal fees in connection therewith. In addition, Licensee shall ensure that all foreign laws affecting this Agreement or the sale of Licensed Products, Licensed Processes and Licensed Services are fully satisfied.

15.8        Arbitration. Any controversy or claim arising out of or relating to this Agreement, or the breach thereof, including, without limitation, any and all Challenges, shall be settled by binding confidential arbitration in accordance with the then-current Commercial Arbitration Rules of the American Arbitration Association (“AAA”), and the procedures set forth below. In the event of any inconsistency between the Commercial Arbitration Rules and the procedures set forth below, the procedures set forth below shall control. Judgment upon the award rendered by the arbitrators may be enforced in any court having jurisdiction thereof.

(a)        Location. The location of the arbitration shall be in the County of San Diego. TSRI and Licensee hereby irrevocably submit to the exclusive personal jurisdiction and venue of the American Arbitration Association arbitration panel selected by the parties and located in San Diego County, California for any dispute regarding this Agreement, including, without limitation, any Challenges, and to the exclusive personal jurisdiction and venue of the federal and state courts located in San Diego County, California for any action or proceeding to enforce an arbitration award or as otherwise provided in Section 15.8(e) below, and waive any right to contest or otherwise object to such jurisdiction or venue.

(b)        Selection of Arbitrators. The arbitration shall be conducted by a panel of three neutral arbitrators who are independent and disinterested with respect to the parties, this Agreement and the outcome of the arbitration. Each party shall appoint one neutral arbitrator, and these two arbitrators so selected by the parties shall then select the third arbitrator, and all arbitrators must have at least ten (10) years’ experience in mediating or arbitrating cases regarding the same or substantially similar subject matter as the dispute between Licensee and TSRI. If one party has given written notice to the other party as to the identity of the arbitrator appointed by the party, and the party thereafter makes a written demand on the other party to appoint its designated arbitrator within the next ten days, and the other party fails to appoint its designated arbitrator within ten days after receiving such written demand, then the arbitrator who has already been designated shall appoint the other two arbitrators.

(c)        Discovery. The arbitrators shall decide any disputes and shall control the process concerning these pre-hearing discovery matters. Pursuant to the Commercial Arbitration Rules, the parties may subpoena witnesses and documents for presentation at the hearing.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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(d)        Case Management. Prompt resolution of any dispute is important to both parties. The parties agree that the arbitration of any dispute shall be conducted expeditiously. The arbitrators are instructed and directed to assume case management initiative and control over the arbitration process (including scheduling of events, pre-hearing discovery and activities, and the conduct of the hearing), in order to complete the arbitration as expeditiously as is reasonably practical for obtaining a just resolution of the dispute.

(e)        Remedies. The arbitrators may grant any legal or equitable remedy or relief that the arbitrators deem just and equitable, to the same extent that remedies or relief could be granted by a state or federal court; provided, however, that no punitive damages may be awarded. No court action shall be maintained seeking punitive damages. The decision of any two of the three arbitrators appointed shall be binding upon the parties. Notwithstanding anything to the contrary in this Agreement, prior to or while an arbitration proceeding is pending, either party has the right to seek and obtain injunctive and other equitable relief from a court of competent jurisdiction to enforce that party’s rights hereunder.

(f)        Expenses. The expenses of the arbitration, including the arbitrators’ fees, expert witness fees and attorney’s fees, may be awarded to the prevailing party, in the discretion of the arbitrators, or may be apportioned between the parties in any manner deemed appropriate by the arbitrators. Unless and until the arbitrators decide that one party is to pay for all (or a share) of such expenses, both parties shall share equally in the payment of the arbitrators’ fees as and when billed by the arbitrators.

(g)        Confidentiality. Except as set forth below, and as necessary to obtain or enforce a judgment upon any arbitration award, the parties shall keep confidential the fact of the arbitration, the dispute being arbitrated, and the decision of the arbitrators. Notwithstanding the foregoing, the parties may disclose information about the arbitration to persons who have a need to know, such as directors, trustees, management employees, witnesses, experts, investors, attorneys, lenders, insurers and others who may be directly affected. Additionally, if a party has stock, which is publicly traded, then such party may make such disclosures as are required by applicable securities laws, but will use commercially reasonable efforts to seek confidential treatment for such disclosure.

15.9        Entire Agreement; Modification. This Agreement and all of the attached Exhibits set forth the entire agreement and understanding between the parties as to the subject matter hereof, and supersede all prior or contemporaneous agreements or understandings, whether oral or written. There shall be no amendments or modifications to this Agreement, except by a written document, which is signed by both parties. In the event of a conflict between this Agreement and the Research Agreement with respect to the subject matter hereof, the terms and conditions of this Agreement shall control.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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15.10        California Law. This Agreement shall be construed and enforced in accordance with the laws of the State of California, without regard to its conflicts or choice of laws principles thereof.

15.11        Headings. The headings for each article and section in this Agreement have been inserted for convenience of reference only and are not intended to limit or expand on the meaning of the language contained in the particular article or section.

15.12        Severability. If one or more of the provisions of this Agreement is held invalid or unenforceable by a court of competent jurisdiction, then it shall be considered severed from this Agreement and shall not serve to invalidate the remaining provisions thereof. The parties shall make a good faith effort to replace any invalid or unenforceable provision with a valid and enforceable one such that the objectives contemplated by the parties when entering this Agreement may be realized.

15.13        No Waiver. Any delay in enforcing a party’s rights under this Agreement or any waiver as to a particular default or other matter shall not constitute a waiver of such party’s rights to the future enforcement of its rights under this Agreement, except only as to an express written and signed waiver as to a particular matter for a particular period of time.

15.14        Name. Whenever there has been an assignment by Licensee as permitted by this Agreement, the term “Licensee” as used in this Agreement shall also include and refer to, if appropriate, such assignee.

15.15        Attorneys’ Fees. In the event of a dispute between the parties hereto or in the event of any default hereunder, the party prevailing in the resolution of any such dispute or default shall be entitled to recover its reasonable attorneys’ fees and other costs incurred in connection with resolving such dispute or default. Notwithstanding anything to the contrary herein, the parties agree that this Section 15.15 shall not apply and attorney’s fees and costs shall not be awarded to either party with respect to any Challenge or any action where Licensee alleges that it is not required to comply with or perform some or all of the provisions of this Agreement based upon a good faith claim that any of the Licensed Patent Rights are invalid or unenforceable. TSRI and Licensee each represent that it has been represented by its own counsel in the negotiation and execution of this Agreement. Each party further represents that it has relied solely on the advice and representation of its respective counsel in agreeing to this Section 15.15 and all of the other provisions of this Agreement.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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15.16        Notices. Any notices required by this Agreement shall be in writing, shall specifically refer to this Agreement and shall be sent by registered or certified mail, postage prepaid, or by facsimile, or by overnight courier, postage prepaid and shall be forwarded to the respective addresses set forth below unless subsequently changed by written notice to the other party:

 

Notices shall be deemed delivered upon the earlier of (a) when received; (b) three (3) days after deposit into the U.S. mail; (c) the date notice is sent via facsimile; or (d) the day immediately following delivery to an overnight courier guaranteeing next-day delivery (except Sundays and holidays).

15.17 Compliance with U.S. Laws. Nothing contained in this Agreement shall require or permit TSRI or Licensee to do any act inconsistent with the requirements of any United States law, regulation or executive order as the same may be in effect from time to time.

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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IN WITNESS WHEREOF, the parties have executed this Agreement by their duly authorized representatives as of the date set forth above.

 

TSRI:		LICENSEE:
THE SCRIPPS RESEARCH INSTITUTE		aTYR PHARMA, INC.
By:		By:
Name:		Name:
Its:		Its:

 

*       Confidential Information, indicated by [***], has been omitted from this filing and filed separately with the Securities and Exchange Commission

 

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EXHIBIT A

LICENSED PATENT RIGHTS

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EXHIBIT B

COMMERCIAL DEVELOPMENT PLAN

 

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EXHIBIT C

BENCHMARKS

 

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EXHIBIT F

FORM OF COMMON STOCK PURCHASE AGREEMENT

THIS COMMON STOCK PURCHASE AGREEMENT (this “Agreement”) is made and entered into as of _____________, 2015 by and between aTyr Pharma, Inc., a Delaware corporation (the “Company”), and The Scripps Research Institute, a California nonprofit public benefit corporation (the “Purchaser”).

WHEREAS, on January 19, 2015, the Company and the Purchaser entered into that certain Amended and Restated Research Funding and Option Agreement (as amended through the date hereof, the “Research Agreement”), which amended, restated and superseded the Research Funding and Option Agreement by and between the Company and the Purchaser, dated October 31, 2007, as amended by the First Amendment dated May 7, 2010, the Second Amendment dated May 27, 2011 and the Third Amendment dated June 1, 2011 (the “Prior Research Agreement”) in its entirety;

WHEREAS, on January 19, 2015, the Company and the Purchaser entered into an Assignment Agreement with respect to certain patent applications relating to Structures of Human Histidyl-tRNA Synthetase and Methods of Use (the “Assignment Agreement”) and terminated that certain License Agreement, dated March 26, 2013, by and between the Company and the Purchaser (the “Prior License Agreement”);

WHEREAS, the Company has agreed to issue and sell to the Purchaser an aggregate of Nine Hundred Fifty Three Thousand Two Hundred Twenty Eight (953,228) shares of the Company’s Common Stock, $0.001 par value per share (the “Stock”), in accordance with the terms and conditions of this Agreement, in consideration for (i) certain of the rights granted by the Purchaser to the Company under the Research Agreement and (ii) certain of the rights granted by the Purchaser to the Company under the Assignment Agreement and the Purchaser’s agreement to terminate the Prior License Agreement.

NOW, THEREFORE, in consideration for the mutual promises and covenants set forth herein and for other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, the parties hereto hereby agree as follows:

1.        Number of Shares and Price Per Share. The Purchaser hereby agrees to purchase from the Company and the Company agrees to sell to Purchaser the Stock, for an aggregate purchase price of $953.23, in consideration for (i) certain of the rights granted by the Purchaser to the Company under the Research Agreement and (ii) certain of the rights granted by the Purchaser to the Company under the Assignment Agreement and the Purchaser’s agreement to terminate the Prior License Agreement. The closing of the sale and purchase of the Stock shall occur immediately upon execution of this Agreement.

 

 

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2.        Right of First Refusal.

(a)        Notice of Transfer. In the event that the Purchaser proposes to sell, assign, pledge, encumber, transfer or otherwise dispose of (“Transfer”) any of Purchaser’s Stock, Purchaser shall give the Company written notice of Purchaser’s intention (“Transfer Notice”), describing the number of shares of Stock offered (“Offered Shares”), the identity of the prospective transferee and the consideration and the material terms and conditions upon which the proposed Transfer is to be made. The Transfer Notice shall certify that the Purchaser has received a firm offer from the prospective transferee and in good faith believes a binding agreement for Transfer is obtainable on the terms set forth, and shall also include a copy of any written proposal or letter of intent or other agreement relating to the proposed Transfer.

(b)        Right of First Refusal. With respect to any proposed Transfer, the Company shall have an option to purchase all or none of the Offered Shares (the “Right of First Refusal”). To exercise such option, the Company must notify the Purchaser in writing before the expiration of the thirty (30) day period following the delivery of the Transfer Notice to the Company. If the Company elects to purchase the Offered Shares, it shall pay consideration for the Offered Shares no less favorable in price and material terms and conditions than are described in the Transfer Notice.

(c)        Closing Procedures; Subsequent Transfers. If the Company exercises the Right of First Refusal, the Company and the Purchaser shall consummate the sale of the Offered Shares on the terms set forth in the Transfer Notice by the date sixty (60) days after the delivery of the Transfer Notice to the Company; provided, however, that, in the event the Transfer Notice provides for the payment for the shares of Stock other than in cash, the Company shall have the option to pay for the shares of Stock by the discounted cash equivalent of the consideration described in the Transfer Notice as reasonably determined by the Company. If the Company fails to exercise in full the Right of First Refusal on a timely basis, then the Purchaser may, not later than one hundred twenty (120) days following delivery to the Company of the Transfer Notice, conclude the Transfer subject to the Transfer Notice on the terms and conditions described in such notice. Any proposed transfer on terms and conditions different from those described in the Transfer Notice, as well as any proposed transfer by the Purchaser more than one hundred twenty (120) days following delivery of the Transfer Notice, shall again be subject to the Right of First Refusal and shall require the Purchaser to deliver a new Transfer Notice to the Company and to comply with the procedures described in this Section 2 with respect to such different or new Transfer.

(d)        Condition to Transfer. All transferees of shares of Stock or any interest therein other than the Company shall be required as a condition of such transfer to agree in writing (in a form satisfactory to the Company) that they will receive and hold such shares of Stock or interest subject to the provisions of this Agreement, including the Right of First Refusal.

(e)        Consent to Purchase. The Purchaser hereby consents to the purchase by the Company of less than all of the Offered Shares in connection with the exercise of the Right of First Refusal.

(f)        Termination of Right. The Right of First Refusal shall terminate at such time as a public market exists for the Company’s Common Stock (or any other stock issued by the Company, or any successor, in exchange for the Stock). For the purpose of this Agreement, a

 

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“public market” shall be deemed to exist if (i) such stock is listed on a national securities exchange or (ii) such stock is traded on the over-the-counter market and prices therefor are published daily on business days in a recognized financial journal.

(g)        Limitation on Right. Notwithstanding the provisions of this Section 2, the Right of First Refusal set forth in this Section 2 shall not apply to:

(i)        any sale or transfer of the Stock in a public offering of securities of the Company registered under the Securities Act of 1933, as amended (the “Securities Act”);

(ii)        any sale or transfer of the Stock in connection with or pursuant to (i) a merger or consolidation or the sale, or exchange by the stockholders of the Company of all or substantially all of the capital stock of the Company, where the stockholders of the Company immediately before such transaction do not obtain or retain, directly or indirectly, a majority of the beneficial interest in the voting stock or other voting equity of the surviving or acquiring corporation or other surviving or acquiring entity, in substantially the same proportion as before such transaction, or (ii) the sale or exchange of all or substantially all of the Company’s assets (other than a sale or transfer to a subsidiary of the Company as defined in section 424(f) of the Internal Revenue Code of 1986, as amended (the “Code”)) where the stockholders of the Company immediately before such sale or exchange do not obtain or retain, directly or indirectly, a majority of the beneficial interest in the voting stock or other voting equity of the corporation or other entity acquiring the Company’s assets, in substantially the same proportion as before such transaction; and

(iii)        any transfer of the Stock to employees of the Purchaser who were inventors of technology subject to the TSRI Agreements; provided that in each case the transferee first agrees in writing, pursuant to an agreement in a form reasonably requested by the Company, to be subject to and bound by the terms of this Agreement to the same extent as if such transferee were the original Purchaser hereunder.

3.        Assignment of Purchase Rights. The Company shall have the right to assign the Right of First Refusal to such person or persons as it may select.

4.        Stock Dividends, Etc. If, from time to time, there is any stock dividend, stock split or other change in the character or amount of any of the outstanding stock of the Company, then in such event any and all new substituted or additional securities to which the Purchaser is entitled by reason of the Purchaser’s ownership of the Stock acquired pursuant to this Agreement shall be considered Stock and shall be immediately subject to the Right of First Refusal and all other terms of this Agreement to the same extent as the Stock owned by the Purchaser immediately before such event.

5.        Legends. All certificates representing any shares of Stock subject to the provisions of this Agreement shall have endorsed thereon the following legends:

(a)        “THE TRANSFER OF THE SHARES REPRESENTED BY THIS CERTIFICATE ARE RESTRICTED PURSUANT TO AN AGREEMENT BETWEEN THE COMPANY AND THE HOLDER OF THESE SHARES, OR HIS OR HER PREDECESSOR IN INTEREST, A COPY OF WHICH IS ON FILE AT THE PRINCIPAL OFFICE OF THIS COMPANY.”

 

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(b)        “THE SECURITIES EVIDENCED BY THIS CERTIFICATE HAVE NOT BEEN REGISTERED UNDER THE SECURITIES ACT OF 1933, AS AMENDED, AND MAY NOT BE SOLD, TRANSFERRED, ASSIGNED OR HYPOTHECATED UNLESS THERE IS AN EFFECTIVE REGISTRATION STATEMENT UNDER SUCH ACT COVERING SUCH SECURITIES, THE SALE IS MADE IN ACCORDANCE WITH RULE 144 UNDER THE ACT, OR THE COMPANY RECEIVES AN OPINION OF COUNSEL FOR THE HOLDER OF THESE SECURITIES REASONABLY SATISFACTORY TO THE COMPANY, STATING THAT SUCH SALE, TRANSFER, ASSIGNMENT OR HYPOTHECATION IS EXEMPT FROM THE REGISTRATION AND PROSPECTUS DELIVERY REQUIREMENTS OF SUCH ACT.”

(c)        Any legend required to be placed thereon under applicable state securities laws.

6.        Representations and Warranties. In connection with the proposed purchase of the Stock, the Purchaser hereby agrees, represents and warrants as follows:

(a)        The Purchaser is purchasing the Stock solely for the Purchaser’s own account for investment and not with a view to, or for resale in connection with, any distribution thereof within the meaning of the Securities Act.

(b)        The Purchaser realizes that Purchaser’s purchase of the Stock will be a highly speculative investment, and Purchaser is able, without impairing Purchaser’s financial condition, to hold the Stock for an indefinite period of time and to suffer a complete loss of Purchaser’s investment.

(c)        The Company has disclosed to the Purchaser that:

(i)        The sale of the Stock has not been registered under the Securities Act, and the Stock must be held indefinitely unless a transfer of it is subsequently registered under the Securities Act or an exemption from such registration is available, and that the Company is under no obligation to register the Stock; and

(ii)        The Company will make a notation in its records of the aforementioned restrictions on transfer and legends.

(d)        The Purchaser is aware of the provisions of Rule 144, promulgated under the Securities Act, which, in substance, permits limited public resale of “restricted securities” acquired, directly or indirectly, from the issuer thereof (or an affiliate of such issuer), in a non-public offering subject to the satisfaction of certain conditions, including among other things: the resale occurring not less than six months from the date the Purchaser has purchased and paid for the Stock and the availability of certain public information concerning the Company. The Purchaser further represents that Purchaser understands that at the time

 

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Purchaser wishes to sell the Stock there may be no public market upon which to make such a sale, and that, even if such a public market then exists, the Company may not be satisfying the current public information requirements of Rule 144, and that, in such event, the Purchaser would be precluded from selling the Stock under Rule 144 even if the six-month minimum holding period had been satisfied.

(e)        The Purchaser is an accredited investor as defined in Rule 501(a) of Regulation D promulgated under the Securities Act.

(f)        Without in any way limiting the Purchaser’s representations and warranties set forth above, the Purchaser further agrees that the Purchaser shall in no event make any disposition of all or any portion of the Stock which the Purchaser is purchasing unless and until:

(i)        There is then in effect a Registration Statement under the Securities Act covering such proposed disposition and such disposition is made in accordance with said Registration Statement; or

(ii)        The Purchaser shall have (1) notified the Company of the proposed disposition and furnished the Company with a detailed statement of the circumstances surrounding the proposed disposition, and (2) if reasonably requested by the Company, furnished the Company with an opinion of the Purchaser’s own counsel to the effect that such disposition will not require registration of such shares under the Securities Act, and such opinion of the Purchaser’s counsel shall have been concurred in by counsel for the Company, and the Company shall have advised the Purchaser of such concurrence.

7.        “Market Stand-Off” Agreement. Purchaser shall not sell, dispose of, transfer, make any short sale of, grant any option for the purchase of, or enter into any hedging or similar transaction with the same economic effect as a sale, any Common Stock or other securities of the Company held by Purchaser (other than those included in the registration), including the Stock (the “Restricted Securities”), during the 180-day period following the effective date of the Company’s first firm commitment underwritten public offering of its Common Stock (or such longer period, not to exceed 34 days after the expiration of the 180-day period, as the underwriters or the Company shall request in order to facilitate compliance with NASD Rule 2711 or NYSE Member Rule 472 or any successor or similar rule or regulation). Purchaser agrees to execute and deliver such other agreements as may be reasonably requested by the Company and/or the managing underwriters which are consistent with the foregoing or which are necessary to give further effect thereto. In order to enforce the foregoing covenant, the Company may impose stop transfer instructions with respect to Purchaser’s Restricted Securities until the end of such period. The underwriters of the Company’s stock are intended third party beneficiaries of this Section 7 and shall have the right, power and authority to enforce the provisions hereof as though they were a party hereto.

8.        Transfers in Violation of Agreement. The Company shall not be required (i) to transfer on its books any shares of Stock of the Company which shall have been sold or transferred in violation of any of the provisions set forth in this Agreement or (ii) to treat as owner of such shares or to accord the right to vote as such owner or to pay dividends to any transferee to whom such shares shall have been so transferred.

 

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9.        Miscellaneous.

(a)        Further Instruments. The parties agree to execute such further instruments and to take such further action as may reasonably be necessary to carry out the intent of this Agreement.

(b)        Notice. All notices required or permitted hereunder shall be in writing and shall be deemed effectively given (i) upon personal delivery, (ii) when sent by confirmed facsimile, if sent during normal business hours of recipient, or if not, then on the next business day, or (iii) one (1) day after deposit with a nationally recognized overnight courier, specifying next day delivery, with written verification of receipt. All communications shall be sent to the party to be notified at the address as set forth on the signature pages hereof or at such other address as such party may designate by ten (10) days advance written notice to the other parties hereto.

(c)        Successors and Assigns. This Agreement shall inure to the benefit of the successors and assigns of the Company and, subject to the restrictions on transfer herein set forth, be binding upon the Purchaser, the Purchaser’s heirs, executors, administrators, successors and assigns.

(d)        Applicable Law; Entire Agreement; Amendments. This Agreement shall be governed by and construed in accordance with the laws of the State of California as it applies to agreements between California residents, entered into and to be performed entirely within California and constitutes the entire agreement of the parties with respect to the subject matter hereof superseding all prior written or oral agreements, and no amendment or addition hereto shall be deemed effective unless agreed to in writing by the parties hereto.

(e)        Right to Specific Performance. The Purchaser agrees that the Company shall be entitled to a decree of specific performance of the terms hereof or an injunction restraining violation of this Agreement, said right to be in addition to any other remedies available to the Company.

(f)        Severability. If any provision of this Agreement is held by a court to be invalid, void or unenforceable, the remaining provisions shall nevertheless continue in full force and effect without being impaired or invalidated in any way and shall be construed in accordance with the purposes and tenor and effect of this Agreement.

(g)        Arbitration. Any dispute or claim arising out of this agreement will be subject to final and binding arbitration. One arbitrator who is a member of the American Arbitration Association (“AAA”), and will be governed by the Commercial Arbitration Rules of the AAA will conduct the arbitration. The arbitration will be held in San Diego, California, and the arbitrator will apply California substantive law in all respects. The arbitrator shall have all authority to determine the arbitrability of any claim and enter a final, binding judgment at the conclusion of any proceedings. Any final judgment only may be appealed on the grounds of improper bias or improper conduct of the arbitrator. The party prevailing in the resolution of any

 

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claim will be entitled, in addition to such other relief as may be granted, to an award of all attorneys’ fees and costs incurred in the claim, without regard to any statute, schedule, or rule of court purported to restrict such award.

(h)        Counterparts; Facsimiles. This Agreement may be executed in counterparts, each of which shall be an original, but all of which together shall constitute one instrument and such counterparts may be delivered via facsimile.

(i)        California Corporate Securities Law. THE SALE OF THE SECURITIES THAT ARE THE SUBJECT OF THIS AGREEMENT HAS NOT BEEN QUALIFIED WITH THE COMMISSIONER OF CORPORATIONS OF THE STATE OF CALIFORNIA AND THE ISSUANCE OF SUCH SECURITIES OR THE PAYMENT OR RECEIPT OF ANY PART OF THE CONSIDERATION THEREFOR PRIOR TO THE QUALIFICATION IS UNLAWFUL, UNLESS THE SALE OF SECURITIES IS EXEMPT FROM THE QUALIFICATION BY SECTIONS 25100, 25102, OR 25105 OF THE CALIFORNIA CORPORATIONS CODE. THE RIGHTS OF ALL PARTIES TO THIS AGREEMENT ARE EXPRESSLY CONDITIONED UPON THE QUALIFICATION BEING OBTAINED, UNLESS THE SALE IS SO EXEMPT.

[REMAINDER OF PAGE LEFT INTENTIONALLY BLANK]

 

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IN WITNESS WHEREOF, the parties hereto have executed this Agreement as of the date first above written.

 

“PURCHASER”						“COMPANY”
THE SCRIPPS RESEARCH INSTITUTE						aTYR PHARMA, INC.
By:						By:
Name:						Name:
Title						Title:

 

Address:		10550 North Torrey Pines Road,				Address:		3545 John Hopkins Court, #250
		TPL-9						San Diego, California 92121
		La Jolla, California 92037

 

 

[SIGNATURE PAGE TO COMMON STOCK PURCHASE AGREEMENT]

 

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