Amendment No. 1 to Research Collaboration and License 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 10.9



Amendment No. 1 TO Research Collaboration and License Agreement

Between Tularik Inc. and Syntex (U.S.A.) Inc.



This Amendment No. 1 (this "Amendment") to the Research Collaboration

and License Agreement dated as of July 8, 1997 (the "Agreement") by and between

Syntex (U.S.A.) Inc., a Delaware corporation, through its Roche Bioscience

division, having offices at 3401 Hillview Avenue, Palo Alto, California 94304

("Roche Bioscience"), and Tularik Inc., a Delaware corporation having offices

at Two Corporate Drive, South San Francisco, California 94080 ("Tularik"), is

entered into as of December 19, 1997.



Whereas, the parties previously entered into the Agreement, which provided for a collaboration between Roche Bioscience and Tularik to discover proprietary Targets to use to identify proprietary compounds for development into Products;



Whereas, the Parties wish to clarify certain Sections of the Agreement relating to the disclosure of structural information on Validated Hits and the transferring of compounds between the Parties;



Whereas, the parties desire to modify Schedule B of the Agreement to clarify the universe of Tularik Background Patent Rights and Existing Third Party Agreements;



Whereas, in order to accomplish the foregoing, the parties have agreed to amend the Agreement in part;



Now, Therefore, in consideration of the premises and the mutual covenants and agreements expressed herein, and for other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, and intending to be legally bound, Tularik and Roche Bioscience hereby agree as follows:



1. Section 1 of the Agreement is hereby amended by adding the following Sections:



1.77 "Collaboration Medicinal Chemistry Program" means a program

for the chemical synthesis of structural analogs of a Validated Hit in

order to improve the biological properties of such Validated Hit towards a

Target as part of the Research Collaboration



1.78 "Primary Interest" means a small molecule that (i) is, at

the time of identification of such molecule as a Validated Hit, [ * ].





[ * ] = 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.







1.79 "Roche Medicinal Chemistry Program" means a program

conducted by or on behalf of Roche for the chemical synthesis of structural

analogs of a compound in order to improve the biological properties of such

compound, excluding [ * ].



1.80 "Screening Party" has the meaning set forth in Section 5.7.



1.81 "Transferring Party" has the meaning set forth in Section

5.7.



2. Section 5.5 is hereby amended to read in its entirety as set forth below:



5.5 Roche Bioscience Screening Library. The Roche Bioscience

Screening Library is not part of the Research Compound Library, but may, in

Roche Bioscience's sole discretion, be used in HTS against the Targets.

Except for the Roche Bioscience Screening License, Tularik shall have no

rights to compounds originating from the Roche Bioscience Screening Library

unless a Library Compound becomes a Development Compound under Section 5.2.

Roche Bioscience shall provide structural information on Validated Hits

from the Roche Bioscience Screening Library; [ * ]. Structural information

on compounds in the Roche Bioscience Screening Library that are not

Validated Hits shall [ * ]. Derivatives made as part of a Collaboration

Medicinal Chemistry Program from compounds originating from the Roche

Bioscience Screening Library shall be considered part of the Roche Compound

Library. The Roche Bioscience Screening Library shall be treated as Roche

Bioscience's Confidential Information. .



3. The penultimate sentence of Section 5.6 of the Agreement is hereby amended to read as follows:



Derivatives made as part of a Collaboration Medicinal Chemistry Program

from compounds originating from the Tularik Screening Library shall be

considered part of the Research Compound Library.



4. Article 5 of the Agreement is hereby amended by adding a new Section 5.7:



Section 5.7 Transfer of Compounds. If either party (the "Transferring

Party") transfers compounds to the other party (the "Screening Party")

pursuant to the screening licenses set forth in Section 12.2 below, the

Screening Party shall use such compounds solely in accordance with the

terms of this Agreement. Such use must be at the Screening Party's place

of business and in accordance with the Research Plan. Any unused quantities

of the compounds shall be returned to the Transferring Party no later than

the end of the Research Term or, upon written request by Transferring

Party, destroyed according to prescribed federal, state and local

guidelines, including any written instructions received from the

Transferring Party. THE TRANSFERRING PARTY DOES NOT MAKE ANY WARRANTY AS

TO THE IDENTITY, PURITY OR ACTIVITY OF THE COMPOUNDS. The Screening Party

shall bear all risk and liability for all harm arising from its use of the



5. Schedule B of the Agreement is hereby amended to read in its entirety as set forth on Schedule B hereto.





[ * ] = 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.







6. Capitalized terms used herein but not otherwise defined herein shall have the respective meanings assigned to such terms in the Agreement.



7. Except as expressly modified by this Amendment, all of the terms and conditions of the Agreement shall remain in full force and effect.



8. This Amendment may be executed in two or more counterparts, each of which shall be deemed an original but all of which shall be considered one and the same instrument.



In Witness Whereof, the parties have executed, or caused their duly authorized officer or representative to execute, this Amendment as of October __, 1997.



Tularik Inc.



By: /s/ David V. Goeddel

---------------------------------------- Name: David V. Goeddel, Ph.D. Title: President and Chief Executive Officer



Syntex (U.S.A.) Inc., through its Roche Bioscience division





By: /s/ James N. Woody

---------------------------------------- Name: James N. Woody, M.D., Ph.D. Title: President





[ * ] = 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.







Schedule B



TULARIK BACKGROUND PATENT RIGHTS AND EXISTING THIRD PARTY



[ * ]



[ * ]



[ * ]



[ * ]



[ * ]



[ * ]



[ * ]



[ * ]



[ * ]





[ * ]





[ * ] = 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 10.9



Research Collaboration and License Agreement



This Research Collaboration and License Agreement is entered into on July 8, 1997 (the "Effective Date"), by and between Syntex (U.S.A.) Inc., a Delaware corporation, through its Roche Bioscience division, having offices at 3401 Hillview Avenue, Palo Alto, California 94304 ("Roche Bioscience"), and Tularik Inc., a Delaware corporation having offices at Two Corporate Drive, South San Francisco, California 94080 ("Tularik"). Roche Bioscience and Tularik may be referred to herein as a "Party" or, collectively, as "Parties."



Whereas, Tularik is a recognized leader in conducting research in inflammatory pathways with assays available or under development for certain key targets.



Whereas, Roche Bioscience wishes to collaborate with Tularik to discover proprietary Targets to use to identify proprietary compounds for development into Products.



Now, Therefore, the Parties agree as follows:



1. Definitions



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



1.1 "Additional Indications" means a medical condition that is not included within the definition of Roche Bioscience Indication or Tularik Indication.



1.2 "Adjusted Gross Sales" means the amount of gross sales invoiced by a Developing Party, its Affiliates (which, with respect to Roche Bioscience, shall include Genentech for purposes of this Section 1.2 only), or sublicensees for a Product to Third Parties less deductions of returns (including withdrawals and recalls), rebates (price reductions, including Medicaid and similar types of rebates, e.g. chargebacks), volume (quantity) discounts, discounts granted at the time of invoicing, sales taxes and other taxes (other than income taxes), all to the extent directly linked to and included in the gross sales amount as computed on a product by product basis for the countries concerned.



1.3 "Affiliate" means a business entity that owns, is owned by or is under common ownership with a Party. For the purposes of this definition, the term "owns" (including, with correlative meanings, the terms "owned by" and "under common ownership with") as used with respect to any Party, shall mean the possession (directly or indirectly) of more than fifty percent (50%) of the outstanding voting securities of a corporation or comparable equity interest in any other type of entity; provided, however, in any country where the local law does not permit foreign equity participation of at least fifty percent (50%), then an "Affiliate" includes any business entity in which a Party owns the maximum percentage of outstanding stock or voting rights permitted by local law and of which such Party exercises practical control of the management of such entity's operations with respect to a Product; provided, further, however, Genentech, Inc., with offices located at One DNA Way, South San Francisco, California, 94080,





[ * ] = 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.





shall not be considered an Affiliate of Roche Bioscience (other than for purposes of Section 1.2 only) unless a duly authorized officer of Roche Bioscience notifies Tularik in writing that Genentech shall be deemed an Affiliate.



1.4 "Agreement" means the present agreement together with all appendices and schedules, including the Research Plan.



1.5 "Application" has the meaning set forth in Section 11.3.2.



1.6 "Compound Libraries" means the Roche Bioscience Screening Library, the Tularik Screening Library, and the Research Compound Library.



1.7 "Confidential Information" means, subject to the limitations contained in Section 13.2, all information and materials received by either Party from the other Party pursuant to this Agreement, including but not limited to the information disclosed pursuant to Sections 6.3.2, 6.3.3, and 6.3.4.



1.8 "Cover" (including variations thereof such as "Covered, "Coverage", or "Covering) means that the making, having made, using, offering for sale, selling or importing of a particular product would infringe a Valid Claim of an issued patent in the absence of rights under such patent. The determination of whether a product is Covered by particular patent rights shall be made on a country by country basis.



1.9 "Developing Party" means the Party whom the Research Management Committee designates to develop a Research Compound into a Product as provided in Section 5.2.



1.10 "Development Compound" means a Roche Bioscience Compound or a Tularik Compound.



1.11 "Effective Date" has the meaning set forth in the first paragraph hereof.



1.12 "Entry into Portfolio" means the date upon which [ * ].



1.13 "FDA" means the United States Food and Drug Administration.



1.14 "Field" means research, development and commercialization of [ * ], for use in the treatment of Roche Bioscience Indications, Tularik Indications or Additional Indications.



1.15 "Filing Party" has the meaning set forth in Section 11.3.1.



1.16 "First Commercial Sale" of a Product shall mean the first sale for use or consumption of such Product in a country after required marketing and pricing approval has been granted by the governing health regulatory authority of such country.



1.17 "First Right of Negotiation" has the meaning set forth in Section 7.1.





[ * ] = 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.





1.18 "FTE" means one full time-equivalent research employee.



1.19 "HTS" means high throughput screening.



1.20 "IND" means an Investigational New Drug application as defined in the rules and regulations of the FDA.



1.21 "Independent Research" has the meaning set forth in Section 2.5.2.



1.22 "Invention" means any possibly patentable discovery or invention made during the course of the Research Collaboration and within the scope of the Research Plan. Determination of inventorship shall be made in accordance with the patent laws of the United States of America.



1.23 "Inventing Party" means the Party having made an Invention.



1.24 "Joint Inventions" has the meaning set forth in Section 11.1.



1.25 "Joint Patent" means a Patent claiming a Joint Invention.



1.26 "Library Compound" means a compound from a Roche Bioscience Screening Library or a Tularik Screening Library.



1.27 "Licensee" has the meaning set forth in Section 7.2.



1.28 "Major Market" means [ * ].



1.29 "NDA" means a New Drug Application filed pursuant to the requirements of the FDA or the equivalent application in any other country.



1.30 "Net Sales" means the amount calculated by [ * ].



1.31 "Offer" has the meaning set forth in Section 7.2.



1.32 "Officers" has the meaning set forth in Section 2.5.3.



1.33 "Patent" means (a) patents (including inventors certificates) that include one or more Valid Claims, including without limitation any substitution, extension (including supplemental protection certificate), registration, confirmation, reissue, reexamination or renewal





[ * ] = 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.





thereof and (b) pending applications, including provisional applications, continuations, divisionals, and continuations-in-part of any of the foregoing.



1.34 "Patent Management" has the meaning set forth in Section 11.3.1.



1.35 "Patent Costs" means the fees and expenses paid to outside legal counsel and other Third Parties, and filing, prosecution and maintenance expenses, incurred in connection with the establishment and maintenance of Patent Rights.



1.36 "Patent Rights" means all rights under Patents.



1.37 "Pathways" means the [ * ], as described on Exhibit A, and any additional pathways added to this Agreement upon the written agreement of the Parties.



1.38 "Phase I" means that portion of the clinical development program which generally provides for the first introduction into humans of a product with the primary purpose of determining safety, metabolism and pharmacokinetic properties and clinical pharmacology of the product, as more precisely defined by the rules and regulations of the FDA and corresponding rules and regulations in other countries.



1.39 "Phase II" means that portion of the clinical development program which provides for the initial trials of a product on a limited number of patients for the primary purpose of evaluating safety, dose ranging and efficacy in the proposed therapeutic indication, as more precisely defined by the rules and regulations of the FDA and corresponding rules and regulations in other countries.



1.40 "Phase III" means that portion of the clinical development program which provides for the continued trials of a product on sufficient numbers of patients to establish the safety and efficacy of a product for the desired claims and indications, as more precisely defined by the rules and regulations of the FDA and corresponding rules and regulations in other countries. Any trial designed to support a NDA without further clinical studies will be considered a Phase III trial for purposes of this Agreement.



1.41 "Product" means any product incorporating a Development Compound, in any formulation, designed for treatment of a Roche Bioscience Indication, Tularik Indication or an Additional Indication, delivered by any route of administration.



1.42 "Research Collaboration" means the research conducted by the parties during the Research Term pursuant to the Research Plan and this Agreement.



1.43 "Research Compound" means any analog or other derivative compound, including a peptidomimetic, that has been synthesized or acquired pursuant to the Research Plan or at the direction of the Officers as provided in Section 2.5, and is based upon any Validated Hit.





[ * ] = 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.





1.44 "Research Compound Library" means all Research Compounds.



1.45 "Research Plan" has the meaning set forth in Section 4.1.



1.46 "Research Term" has the meaning set forth in Section 6.1.



1.47 "Responsible Party" means the Party responsible for Patent Management.



1.48 "Right of First Refusal" has the meaning set forth in Section 7.2.



1.49 "RMC or Research Management Committee" has the meaning set forth in Section 3.1.



1.50 "Roche" means Roche Bioscience together with its Affiliates.



1.51 "Roche Bioscience Compound" means a small molecule from any of the Compound Libraries which the Research Management Committee designates as a "Roche Bioscience Compound" pursuant to Section 5.2 or which Roche Bioscience designates as a "Roche Bioscience Compound" pursuant to Section 6.3.2.



1.52 "Roche Bioscience Indications" means [ * ].



1.53 "Roche Bioscience Invention(s)" has the meaning set forth in Section 11.1.



1.54 "Roche Bioscience Patent" means a Patent claiming a Roche Bioscience Invention.



1.55 "Roche Bioscience Screening Library" means the library consisting of compounds that have been synthesized or acquired by or on behalf of either Roche Bioscience or its Affiliates either (a) prior to the Effective Date or (b) during the Research Term or the applicable Tail Period, if any, but independent of the Research Collaboration.



1.56 "Roche Bioscience Screening License" has the meaning set forth in Section 12.2.2.



1.57 "Royalty Receiving Party" has the meaning set forth in Section 10.1.



1.58 "Royalty Term" means, in the case of any Product, in any country, the period of time commencing on the First Commercial Sale of such Product and ending upon the later of (a) ten (10) years from the date of First Commercial Sale of such Product in such country or (b) the expiration of the last to expire of the Patent Rights Covering such Product in such country. Royalty Term shall be determined on a Product by Product, country by country basis.





[ * ] = 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.





1.59 "Scientifically Reasonable and Diligent Efforts" means, unless the Parties agree otherwise, those efforts consistent with the exercise of prudent scientific and business judgment, as applied to other products of similar scientific and commercial potential within the relevant product lines of the Developing Party and its Affiliates.



1.60 [ * ]



1.61 "Substantial Competition" means market penetration in a country with respect to a Product by one or more Third Parties with a product [ * ].



1.62 "Tail Period" has the meaning set forth in Section 6.3.2.



1.63 "Target" means an [ * ] and is either (a) listed as an included target on Exhibit A or (b) discovered by one or both Parties as part of the Research Collaboration (excluding any molecule that is subject to prior rights of any Third Party under an agreement with either Party at the time it is discovered, which agreement is either listed on Exhibit 2 or is subject to the provisions of Section 2.5) or (c) licensed by either Party during the Research Collaboration pursuant to Section 2.5.



1.64 "Target Information" has the meaning set forth in Section 2.4.



1.65 "Third Party" means any entity other than Tularik or Roche Bioscience or an Affiliate of Tularik or Roche Bioscience.



1.66 "Third Party Technology" has the meaning set forth in Section 2.5.2.



1.67 "Tularik Background Patent Rights" means all rights under Patents existing as of the Effective Date that Tularik owns or to which it has a license (with rights to sublicense as provided herein) and which relate to the Field, and which Patents are set forth on Schedule B.



1.68 "Tularik Compound(s)" means a small molecule from any of the Compound Libraries which the Research Management Committee designates as a "Tularik Compound" pursuant to Section 5.2 or which Tularik designates as a "Tularik Compound" pursuant to Section 6.3.2.



1.69 "Tularik Indications" means [ * ].



1.70 "Tularik Invention" has the meaning set forth in Section 11.1.



1.71 "Tularik Patent" means a Patent claiming a Tularik Invention.





[ * ] = 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.





1.72 "Tularik Screening Library" means the library consisting of compounds that have been synthesized or acquired by or on behalf of either Tularik or its Affiliates either (a) prior to the Effective Date or (b) during the Research Term or the applicable Tail Period, if any, but independent of the Research Collaboration.



1.73 " Tularik Screening License" has the meaning set forth in Section 12.2.1.



1.74 "Valid Claim" means a claim of an issued patent which claim has not lapsed, expired, been canceled or become abandoned and has not been declared invalid by an unreversed and unappealable decision or judgment of a court or other appropriate body of competent jurisdiction, and which has not been admitted to be invalid or unenforceable through reissue or disclaimer.



1.75 "Validated Hit" means a small molecule that has shown activity against a Target in primary screening as part of the Research Collaboration.



2. Research Collaboration



2.1 Scope of Research Collaboration. The Research Collaboration will focus on Targets in the Pathways, both in finding new proprietary Targets as well as with respect to Targets identified by Tularik prior to the Effective Date, and the use of Targets for HTS assay development to discover proprietary drug leads. The Research Collaboration will initially focus on elucidating proprietary drug discovery Targets in the Pathways and is anticipated to be restricted to proprietary Targets in the Pathways. Roche Bioscience and Tularik shall conduct the Research Collaboration on a collaborative basis with the goal of identifying Research Compounds that are suitable for development into Products for commercialization. The Research Collaboration is intended to be flexible to allow for pursuit of unforeseen opportunities in the area of inflammation biology involving the Targets and the Pathways.



2.2 New Targets. If a Target is discovered as part of the Research Collaboration, the Party discovering such new Target shall notify the Research Management Committee. At the next Research Management Committee meeting, the parties shall discuss such new Target. If the Research Management Committee decides that the new Target should be included in the Research Collaboration, then Roche Bioscience shall disclose whether the Target is under investigation by another Roche research site. If the new Target is not under investigation by Roche at such time, such new Target shall be included in the Research Collaboration. If the new Target is under investigation by Roche at such time, Roche Bioscience shall notify Tularik in writing within sixty (60) days of such Research Management Committee meeting whether Roche Bioscience shall (a) exclude such Target from the Research Collaboration and the definition of "Target" or (b) include such Target in the Research Collaboration. If the Research Management Committee or Roche Bioscience elects to exclude such Target from the Research Collaboration, then each Party may pursue HTS, development and commercialization activities against such Target outside of the Research Collaboration subject to any proprietary rights of the other Party (including its Affiliates) or any Third Party; provided, however, that the Party that did not discover such Target shall not use any information developed during the Research Collaboration with respect to such Target; and ...