Amended & Restated Collaboration Agreement

Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.



Exhibit 10.8



AMENDED AND RESTATED



COLLABORATION AND LICENSE AGREEMENT





TULARIK INC.





MERCK & CO., INC.

Exhibit 10.8



AMENDED AND RESTATED

COLLABORATION AND LICENSE AGREEMENT



THIS AGREEMENT is entered into as of the 22nd day of December 1996 (the "Amendment Date") by and between Tularik Inc., a California corporation ("Tularik"), and Merck & Co., Inc. ("Merck"), a corporation organized under the laws of New Jersey, and amends in part and restates the Collaboration and License Agreement dated as of December 22, 1993 by and between Tularik and Merck.





WHEREAS, Tularik and Merck have previously entered into the Original Agreement pursuant to which Tularik and Merck established a cooperative research relationship based on screening of their respective compound libraries using their respective assays and other jointly developed assays, and



WHEREAS, Tularik and Merck desire to continue their cooperative research relationship to develop and market novel therapeutic products based on compounds identified during such research as having viral regulatory properties;



NOW, THEREFORE, in consideration of the foregoing and the covenants and promises contained herein, the parties agree as follows:



DEFINITIONS



As used herein, the following terms shall have the following meanings:



1.1 "Affiliate" shall mean any entity that directly or indirectly Owns, is Owned by or is under common Ownership, with a party to this Agreement, where "Own" or "Ownership" means direct or indirect possession of at least fifty percent (50%) of the outstanding voting securities of a corporation or a comparable equity interest in any other type of entity.



1.2 "Agreement" shall mean this Amended and Restated Collaboration and License Agreement.



1.3 "Agreement Compounds" shall mean, collectively, the Option Compounds and the Program Compounds.



1.4 "Anti-Viral Activity" shall mean that level of activity of a Program Substance in a Program Assay which [ * ], as appropriate for the target, which is potentially or actually useful





[ * ]= Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





in the Field, as determined by the Research Committee.



1.5 "Confidential Information" shall mean, subject to the limitations set forth in Section 12.1 hereof, all information disclosed to one party by the other party.



1.6 "Core Targets" shall mean those targets applicable to the [ * ] set forth on Appendix A, or otherwise designated by a majority of the members of the entire Research Committee in writing, as well as any other targets designated by the Research Committee in writing for other viruses which the parties may from time to time designate or substitute.



1.7 "[ * ] Option Program" shall mean research and development pursuant to this Agreement of all Option Compounds relating to all Option Targets applicable to the [ * ].



1.8 "Effective Date" shall mean December 22, 1993.



1.9 "Exercise Data" shall mean data establishing the following criteria with respect to an Option Program:



a) [ * ];



b) [ * ];



c) [ * ];



d) [ * ]; and



e) [ * ].



1.10 "Exercise Date" shall mean the date on which both of the following have occurred (i) [ * ] and (ii) [ * ].



1.11 "FDA" shall mean the United States Food and Drug Administration.



1.12 "Field" shall mean all uses in the prevention or treatment of (i) [ * ].



1.13 "Full Time Equivalent" or "FTE" shall mean the equivalent of a full- time [ * ]. The portion of an FTE year devoted by a scientist or program manager to the Research Program shall be determined by dividing the number of days during any twelve (12) month period devoted by such employee to the Research Program by the total number of working days during such twelve (12) month period.



1.14 "GCP" means the Good Clinical Practice regulations promulgated by the FDA.





[ * ]= Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





1.15 "GLP" means the Good Laboratory Practice regulations promulgated by the FDA.



1.16 "GMP" means the Good Manufacturing Practice regulations promulgated by the FDA.



1.17 "Government Approval" shall mean any approvals, licenses, registrations or authorizations of any federal, state or local regulatory agency, department, bureau or other government entity, foreign or domestic, necessary for the manufacture, use, storage, import, transport or sale, of the Products in a regulatory jurisdiction.



1.18 "[ * ] Option Program" shall mean research and development pursuant to this Agreement of all Option Compounds relating to all Option Targets applicable to the [ * ].



1.19 "IND" or "Investigational New Drug Application" shall mean an application for regulatory approval by the FDA or its foreign equivalent in

[ * ], to commence human clinical testing of a drug, as defined by the FDA or the foreign equivalent.



1.20 "Lead Defense Party" shall have the meaning assigned to it in Section 8.2(e)(2) hereof.



1.21 "Merck Know-How" shall mean all materials and information that Merck owns, controls or has a license to (with a right to sublicense) as of the Effective Date and from time to time during the Research Term, which arise outside of the Research Program, but only insofar as the above are necessary or useful for the conduct of the activities under the Research Program.



1.22 "Merck Option" shall mean the option by Merck to conduct research and development activities with respect to any Option Program and to commercialize Option Compounds, as further described in this Agreement.



1.23 "Merck Patents" shall mean any and all patents, both foreign and domestic, which have not been held invalid or unenforceable by a court of competent jurisdiction from which no appeal has been or can be taken, including without limitation all substitutions, extensions, reissues, renewals, supplementary protection certificates and inventors' certificates, (a) which (i) are issued as of the Effective Date, (ii) subsequently issue from applications (including divisionals, continuations and continuations-in-part) pending as of the Effective Date, or (iii) issue from any such applications subsequently filed on inventions made as of the Effective Date and (b) which Merck owns, controls or has a license to (with the right to sublicense), and (c) which relate to the development, manufacture, use or sale of the Products or the Program Assays.



1.24 "Merck Substances" shall mean those natural extracts, natural compounds and synthetic compounds which Merck owns or has the right to license or sublicense as of the





[ * ]= Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





Effective Date or from time to time during the Research Program, and which Merck has approved for screening under the Research Program.



1.25 "Merck Technology" shall mean, collectively, the Merck Patents and the Merck Know-How.



1.26 "NDA" (or "New Drug Application") shall mean a new drug application as defined by the U.S. FDA or the foreign equivalent in [ * ].



1.27 "Net Sales" shall mean, with respect to a Product, and on a country-by-country basis, the gross invoice price of all quantities of such Product sold by a party, its Affiliates or sublicensees to an independent third party after deducting, if not already deducted in the amount invoiced [ * ]. With respect to sales of combination products, which shall consist of Products combined with one or more additional active ingredients, Net Sales shall be calculated on the basis of the [ * ].



1.28 "New Target" and "New Target Assay" shall have the meanings assigned to each, respectively, in Section 2.3 hereof.



1.29 "Option Compound" shall mean a Program Substance (i) which as a result of screening activities under the Research Program, [ * ] and (iii) as to which Tularik has commenced and is proceeding with preliminary development activities within [ * ] after the expiration of the Research Term.



1.30 "Option Product" shall mean any pharmaceutical product which results during the Research Term [ * ], from research conducted with respect to an Option Compound. Each Option Product shall be deemed to include [ * ].



1.31 "Option Program" shall mean either the [ * ] Option Program or the [ * ] Option Program, as the case may be.



1.32 "Option Targets" shall mean those targets applicable to the [ * ] set forth on Appendix A hereto, or otherwise designated by a majority of the members of the entire Research Committee in writing.



1.33 "Original Agreement" shall mean the Collaboration and License Agreement dated as of December 22, 1993 by and between Tularik and Merck.





[ * ]= Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





1.34 "Products" shall mean, collectively, the Option Products and the Program Products.



1.35 "Program Assays" shall mean those assays relating to the Core Targets or the Option Targets which, as of the Effective Date and from time to time during the Research Term, each party respectively owns or has rights to (with a right to sublicense), as set forth and periodically updated on Appendix A hereto.



1.36 "Program Compound" shall mean a Program Substance which (i) as a result of screening activities under the Research Program, [ * ], (ii) [ * ] and (iii) is designated by the Research Committee for [ * ]. Program Compounds shall also include all Option Compounds within any Option Program as to which Merck has exercised the Merck Option.



1.37 "Program Know-How" shall mean all materials and information developed in the course of the Research Program.



1.38 "Program Patents" shall mean any and all patents, both foreign and domestic, which have not been held invalid or unenforceable by a court of competent jurisdiction from which no appeal has been or can be taken, including with out limitation, all substitutions, extensions, reissues, renewals, supplementary protection certificates and inventors' certificates which cover inventions or discoveries made in the course of the Research Program.



1.39 "Program Product" shall mean any pharmaceutical product which results during the Research Term [ * ] from research conducted with respect to a Program Compound. Each Program Product shall be deemed to include all indications, formulations, line extensions or modes of administration thereof.



1.40 "Program Substances" shall mean the Merck Substances and the Tularik Substances.



1.41 "Research Committee" shall mean that committee formed pursuant to Section 2.2 hereof.



1.42 "Research Management Committee" or "RMC" shall mean Merck's Research Management Committee.



1.43 "Research Program" shall mean the research program carried out by the parties in the Field during the Research Term pursuant to Article 2 hereof, as further described in Appendix B.



1.44 "Restricted Compound" shall mean any Program Compound or Option Compound which Merck has designated as restricted in accordance with Sections 2.1(c) hereof.





[ * ] =Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





1.45 "Third Party Screening Royalty" shall mean any royalty obligation owed by Tularik or Merck to any third party, for the screening or use of any Program Substance.



1.46 "Tularik Know-How" shall mean all materials and information that Tularik owns, controls or has a license to (with a right to sublicense) as of the Effective Date and from time to time during the Research Term, which arise outside the Research Program, but only insofar as any of the above are necessary or useful to the conduct of the activities carried out under the Research Program.



1.47 "Tularik Patents" shall mean any and all patents, both foreign and domestic, which have not been held invalid or unenforceable by a court of competent jurisdiction from which no appeal has been or can be taken, including without limitation all substitutions, extensions, reissues, renewals, supplementary protection certificates and inventors' certificates, (a) which (i) are issued as of the Effective Date, or (ii) subsequently issue from applications (including divisionals, continuations and continuations-in-part) pending as of the Effective Date, or (iii) issue from any such applications subsequently filed on inventions made as of the Effective Date, (b) which Tularik owns, controls or has a license to (with the right to sublicense), and (c) which relate to the development, manufacture, use and sale of the Products or the Program Assays.



1.48 "Tularik Substances" shall mean those natural extracts, natural compounds and synthetic compounds which Tularik owns or has the right to license or sublicense as of the Effective Date or from time to time during the Research Program, and which Tularik has approved for screening under the Research Program.



1.49 "Tularik Technology" means, collectively, the Tularik Patents and the Tularik Know-How.



RESEARCH PROGRAM



2.1 Research Program. Tularik and Merck will conduct the Research Program under the direction of the Research Committee. During the Research Term, Tularik shall [ * ] the Research Program, including management of the Program. Tularik shall appoint [ * ] to manage the Research Program. Tularik acknowledges that the involvement of [ * ] in the Research Program is critical to the success of the Research Program. Merck acknowledges that [ * ] will [ * ]. The parties intend that the work of [ * ] relating to his employment responsibilities at the [ * ], shall not be utilized in the Research Program; provided, however, that [ * ]. Merck shall have the right to approve all changes in the management of the Research Program, in its sole discretion.



(a) Provision of Program Substances. Merck shall provide the Merck Substances in coded form, and Tularik shall provide the Tularik Substances, for use in the





[ * ]= Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





Research Program, in accordance with Appendix B. It is understood that neither party shall have an obligation to provide any particular amounts or types of Substances. Each Merck or Tularik Substance that does not possess Anti-Viral Activity will be returned to Merck or Tularik, as the case may be, and will cease to be subject to the terms of this Agreement.



(b) Screening Activities. During the Research Term, each party shall respectively make all Program Assays available for the Research Program. In the event that either party develops or acquires new Program Assays during the Research Term, such party shall promptly inform the Research Committee of the existence of such Program Assay. Unless otherwise directed by the Research Committee, Tularik shall conduct all screening of the Program Substances. To the extent practicable, the Program Substances shall be screened contemporaneously in Program Assays for both the Core Targets and Option Targets. Tularik shall notify Merck promptly when a Program Substance demonstrates Anti-Viral Activity in a Core Target or Option Target. Any Program Substance which does not demonstrate Anti-Viral Activity in a Core Target or Option Target shall be returned to the party which supplied such Program Substance, and shall not be included further under the terms of the Agreement.



(c) [ * ] Compounds. Within [ * ] of the date Merck receives all material data indicating whether or not a Merck Substance has reacted positively in a Program Assay for a Core Target or an Option Target, Merck shall [ * ], upon which occurrence [ * ]. In the event that Merck [ * ], the Research Committee shall commence evaluation of such Merck Substance, or Tularik shall be free to conduct further research, in the case of a Merck Substance [ * ], subject to the terms and conditions of this Agreement. Merck will [ * ], as the case may be, for which such [ * ] without the agreement of Tularik. It is understood that there are [ * ].



2.2 Research Committee.



(a) Formation of Research Committee. The Research Committee shall consist of six (6) members, Merck and Tularik each to appoint and substitute as necessary from time to time three (3) members of such Committee. Each member shall have appropriate technical credentials and knowledge and ongoing familiarity with the Research Program. The Chairperson of the Research Committee shall be one of the Merck-appointed members. Except as otherwise provided in Sections 1.6, 1.8 and 1.32, all decisions of the Research Committee shall be unanimous.



(b) Meetings of Research Committee. The Research Committee shall meet quarterly, at such times as shall be mutually agreed upon by the parties. The location of such meetings shall alternate between sites designated by Tularik and sites designated by Merck.



(c) Responsibilities of the Research Committee. The Research Committee shall carry out the following responsibilities during the Research Term and, with respect to Option Compounds which continue to be subject to the Merck Option, for [ * ]: (1) defining the yearly research objectives, (2) determining whether a Program Substance has Anti-Viral Activity,





[ * ]= Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





(3) coordinating activities required to carry out the Research Program, (4) periodically revising the Research Program, (5) monitoring progress of the Research Program and (6) making recommendations regarding further pre-IND development of Program Compounds and Option Compounds.



2.3 New Target Assays. In the event that Tularik develops any new screening assays relating to any disease in the Field other than the Core Targets and the Option Targets (each, a "New Target Assay" and "New Target," respectively) during the Research Term, Tularik hereby agrees to promptly disclose to Merck the existence of each New Target Assay. Merck shall have the right to [ * ] for the identification and/or development of compounds relating to such New Target by delivering to Tularik within [ * ] of Tularik's disclosure of the New Target Assay, [ * ]. Upon receipt by Tularik of [ * ] relating to the New Target. [ * ].



2.4 Term and Termination of Research Program. The Research Program shall be carried out for a period commencing on the Effective Date and ending on December 31, 1999 (the "Research Term"), which Research Term may be extended at Merck's option for additional one (1)-year periods; provided, however, that any such extension shall be made upon [ * ] prior written notice to Tularik. Anything in the foregoing sentence to the contrary notwithstanding, Merck may terminate the Research Term upon [ * ] written notice given to Tularik any time after December 31, 1998. In the event of any such termination, payments under Section 5.1(b) shall be prorated to fund the Research Program to the effective date of such termination. After expiration or termination of the Research Term, Tularik may, in its sole discretion, screen Merck Compounds at Merck's request, at fees and upon terms to be mutually agreed upon by the parties at such time.



DEVELOPMENT AND COMMERCIALIZATION OF OPTION PRODUCTS



3.1 Tularik Development of Option Compounds. Tularik shall have the right, but not the obligation, to conduct research and development and to commercialize all Option Compounds, subject only to the Merck Option.



3.2 Tularik to Keep Merck Informed. Tularik shall provide Merck with semi-annual reports of its progress in developing each Option Compound for which Merck may be entitled to exercise the Merck Option in such reasonable detail as shall be necessary and appropriate to permit Merck to determine whether it wishes to exercise the Merck Option.



3.3 Merck Option.



(a) Merck Option. Merck may give Tularik written notice of its intention to conduct research and development activities with respect to an Option Program at any time, but





[ * ]= Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





not later than the expiration of [ * ] following the Exercise Date relating to such Option Program. Upon exercising the Merck Option by giving such notice in such manner, all Option Compounds within such Option Program shall become Program Compounds for all purposes of this Agreement. Upon exercise by Merck of the Merck Option, Tularik will [ * ] for which the Merck Option has been exercised or [ * ].



(b) Other Option Programs. Notwithstanding any exercise by Merck of the Merck Option with respect to an Option Program, [ * ] relating to [ * ] and [ * ] for which the Merck Option has not been exercised, subject to Section 3.3(a) above.



(c) Reimbursement. Merck shall reimburse Tularik for the reasonable costs and expenses incurred by Tularik relating to studies and preliminary development conducted on any Option Program as to which Merck exercises the Merck Option. Such cost reimbursement shall be on a basis of [ * ], which reimbursement shall include the items listed on Exhibit C hereto. Merck will also reimburse Tularik for any additional outside expenses that it approves at the time of such reimbursement, as necessary and appropriate.



3.4 Tularik Request for Exercise of Merck Option. Tularik shall notify Merck that the Merck Option has become exercisable with respect to an Option Program by submission to Merck of Exercise Data on the Exercise Date. In no event shall Merck be obligated to consider exercise of the Merck Option with respect to such Option Program unless Exercise Data for such Option Program shall have been submitted to Merck. In the event Merck shall not exercise the Merck Option with respect to such Option Program within [ * ] following the Exercise Date, the Merck Option shall expire with respect to such Option Program. Following such expiration: (i) [ * ]; (ii) Tularik shall [ * ]; and (iii) Tularik may [ * ].



EXTRA-FIELD INDICATIONS



4.1 Extra-Field Indications. The parties acknowledge that the Program Compounds and Option Compounds may prove to have applications for indications outside the Field. Subject to the provisions of this Article 4, Merck shall have the [ * ] and Tularik shall ha ...