Document:

Exhibit 10.3

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

PUBLIC HEALTH SERVICE

 

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT
 FOR EXTRAMURAL-PHS CLINICAL RESEARCH

 

This Agreement is based on the model Cooperative Research and Development Agreement (“CRADA”) adopted by the U.S. Public Health Service (“PHS”) Technology Transfer Policy Board for use by components of the National Institutes of Health (“NIH”), the Centers for Disease Control and Prevention (“CDC”), and the Food and Drug Administration (“FDA”), which are agencies of the PHS within the Department of Health and Human Services (“HHS”).

 

This Cover Page identifies the Parties to this CRADA:

 

The U.S. Department of Health and Human Services, as represented by 
 the National Cancer Institute
  an Institute, Center, or Division (hereinafter referred to as the “ICD”) of the 
  National Institutes of Health

 

and

 

BN ImmunoTherapeutics,
 hereinafter referred to as the “Collaborator”,
 having offices at 2425 Garcia Avenue, Mountain View, CA 94043,
 created and operating under the laws of Delaware

 

 

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

FOR EXTRAMURAL-PHS CLINICAL RESEARCH

 

Article 1.               Introduction

 

This CRADA between ICD and Collaborator will be effective when signed by the Parties, which are identified on both the Cover Page and the Signature Page (page 22).  The official contacts for the Parties are identified on the Contacts Information Page (page 23).  Publicly available information regarding this CRADA appears on the Summary Page (page 24).  The research and development activities that will be undertaken by ICD, ICD’s contractors or grantees, and Collaborator in the course of this CRADA are detailed in the Research Plan, attached as Appendix A. The staffing, funding, and materials contributions of the Parties are set forth in Appendix B. Any changes to the model CRADA are set forth in Appendix C.

 

Article 2.               Definitions

 

The terms listed in this Article will carry the meanings indicated throughout the CRADA. To the extent a definition of a term as provided in this Article is inconsistent with a corresponding definition in the applicable sections of either the United States Code (U.S.C.) or the Code of Federal Regulations (C.F.R.), the definition in the U.S.C. or C.F.R. will control.

 

“Adverse Drug Experience” or “ADE” means an Adverse Event associated with the use of the Test Article, that is, an event where there is a reasonable possibility that the Test Article may have caused the event (a relationship between the Test Article and the event cannot be ruled out), in accordance with the definitions of 21 C.F.R. Part 310, 305, or 312, or other applicable regulations.

 

“Adverse Event” or “AE” means any untoward medical occurrence in a Human Subject administered Test Article.  An AE does not necessarily have a causal relationship with the Test Article, that is, it can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the Test Article, whether or not it is related to it.  See FDA Good Clinical Practice Guideline (International Conference on Harmonisation (ICH) E6: “Good Clinical Practice: Consolidated Guidance, 62 Federal Register 25, 691 (1997)).

 

“Affiliate” means any corporation or other business entity controlled by, controlling, or under common control with Collaborator at any time during the term of the CRADA. For this purpose, “control” means direct or indirect beneficial ownership of at least fifty percent (50%) of the voting stock or at least fifty percent (50%) interest in the income of the corporation or other business entity.

 

“Annual Report” means the report of progress of an IND-associated investigation that the Sponsor must submit to the FDA within sixty (60) days of the anniversary of the effective date of the IND (pursuant to 21 C.F.R. § 312.33).

 

	
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“Background Invention” means an Invention conceived and first actually reduced to practice before the Effective Date.

 

“Clinical Data in ICD’s Possession and Control” means all Raw Data that ICD employees create directly; and all copies of Raw Data and Summary Data that ICD obtains from Clinical Investigators or contractors performing CRADA activities.

 

“Clinical Investigator” means, in accordance with 21 C.F.R. § 312.3, an individual who actually conducts a clinical investigation, that is, who directs the administration or dispensation of Test Article to a subject, and who assumes responsibility for studying Human Subjects, for recording and ensuring the integrity of research data, and for protecting the welfare and safety of Human Subjects.

 

“Clinical Research Site(s)” means the site(s) at which the Protocol(s) described in the Research Plan will be performed.

 

“Collaborator Materials” means all tangible materials not first produced in the performance of this CRADA that are owned or controlled by Collaborator and used in the performance of the Research Plan.  The term “Collaborator Materials” does not include “Test Article” (defined below).

 

“Confidential Information” means confidential scientific, business, financial information, or Identifiable Private Information provided that Confidential Information does not include:

 

(a)         information that is publicly known or that is available from public sources;

 

(b)         information that has been made available by its owner to others without a confidentiality obligation;

 

(c)          information that is already known by the receiving Party, or information that is independently created or compiled by the receiving Party without reference to or use of the provided information; or

 

(d)         information that relates to potential hazards or cautionary warnings associated with the production, handling, or use of the subject matter of the Research Plan.

 

“Cooperative Research and Development Agreement” or “CRADA” means this Agreement, entered into pursuant to the Federal Technology Transfer Act of 1986, as amended (15 U.S.C. §§ 3710a et seq.), and Executive Order 12591 of April 10, 1987.

 

“CRADA Data” means information developed by or on behalf of the Parties in the performance of the Research Plan, excluding Raw Data.

 

“CRADA Materials” means all tangible materials first produced in the performance of the Research Plan other than CRADA Data.

 

	
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“CRADA Principal Investigator(s)” or “CRADA PI(s)” means the person(s) designated by the Parties who will be responsible for the scientific and technical conduct of the Research Plan.

 

“CRADA Subject Invention” means any Invention of either or both Parties, conceived or first actually reduced to practice in the performance of the Research Plan.

 

“Drug Master File” or “DMF” is described in 21 C.F.R. Part 314.420.  A DMF is a submission to the FDA that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.

 

“Effective Date” means the date of the last signature of the Parties executing this Agreement.

 

“Government” means the Government of the United States of America.

 

“Human Subject” means, in accordance with the definition in 45 C.F.R. § 46.102(f), a living individual about whom an investigator conducting research obtains:

 

(a)         data through intervention or interaction with the individual; or

 

(b)         Identifiable Private Information.

 

“ICD Materials” means all tangible materials not first produced in the performance of this CRADA that are owned or controlled by ICD and used in the performance of the Research Plan.

 

“IND” means an “Investigational New Drug Application,” filed in accordance with 21 C.F.R. Part 312 under which clinical investigation of an experimental drug or biologic (Test Article) is performed in Human Subjects in the United States or intended to support a United States licensing action.

 

“Identifiable Private Information” or “IPI” about a Human Subject means private information from which the identity of the subject is or may readily be ascertained.  Regulations defining and governing this information include 45 C.F.R. Part 46 and 21 C.F.R. Part 50.

 

“Institutional Review Board” or “IRB” means, in accordance with 45 C.F.R. Part 46, 21 C.F.R. part 56, and other applicable regulations, an independent body comprising medical, scientific, and nonscientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of the Human Subjects involved in a study.

 

	
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“Invention” means any invention or discovery that is or may be patentable or otherwise protected under Title 35 of the United States Code, or any novel variety of plant which is or may be protectable under the Plant Variety Protection Act, 7 U.S.C. §§ 2321 et seq.

 

“Investigator’s Brochure” means, in accordance with the definition in 21 C.F.R. § 312.23(a)(5), a document containing information about the Test Article, including animal screening, preclinical toxicology, and detailed pharmaceutical data, including a description of possible risks and side effects to be anticipated on the basis of prior experience with the drug or related drugs, and precautions, such as additional monitoring, to be taken as part of the investigational use of the drug.

 

“Patent Application” means an application for patent protection for a CRADA Subject Invention with the United States Patent and Trademark Office (“U.S.P.T.O.”) or the corresponding patent-issuing authority of another nation.

 

“Patent” means any issued United States patent, any international counterpart(s), and any corresponding grant(s) by a non-U.S. government in place of a patent.

 

“Placebo” means an inactive substance identical in appearance to the material being tested that is used to distinguish between drug action and suggestive effect of the material under study.

 

“Protocol” means the formal, detailed description of a study to be performed as provided for in the Research Plan.  It describes the objective(s), design, methodology, statistical considerations, and organization of a trial.  For the purposes of this CRADA, the term, Protocol, for clinical research involving Human Subjects, includes any and all associated documents, including informed consent forms, to be provided to Human Subjects and potential participants in the study.

 

“Raw Data” means the primary quantitative and empirical data first collected from experiments and clinical trials conducted within the scope of this CRADA.

 

“Research Plan” means the statement in Appendix A of the respective research and development commitments of the Parties.  The Research Plan should describe the provisions for sponsoring the IND, clinical and safety monitoring, and data management.

 

“Sponsor” means, in accordance with the definition in 21 C.F.R. § 312.3, an organization or individual who assumes legal responsibility for supervising or overseeing clinical trials with Test Articles, and is sometimes referred to as the IND holder.

 

“Steering Committee” means the research and development team whose composition and responsibilities with regard to the research performed under this CRADA are described in Appendix A.

 

	
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“Summary Data” means any extract or summary of the Raw Data, generated either by or, on behalf of, ICD or by, or on behalf of, Collaborator.  Summary Data may include extracts or summaries that incorporate IPI.

 

“Test Article” means, in accordance with 21 C.F.R. § 50.3(j), any drug (including a biological product), medical device, food additive, color additive, electronic product, or any other article subject to regulation under the Federal Food, Drug, and Cosmetic Act that is intended for administration to humans or animals, including a drug or biologic as identified in the Research Plan and Appendix B, that is used within the scope of the Research Plan.  The Test Article may also be referred to as Investigational Agent, Study Material, or Study Product.

 

Article 3.               Cooperative Research and Development

 

3.1          Performance of Research and Development.  The research and development activities to be carried out under this CRADA will be performed by the Parties identified on the Cover Page, as well as ICD’s contractors or grantees as described in the Research Plan.  However, ICD’s contractors or grantees are not Parties to the CRADA, and this CRADA does not grant to Collaborator any rights to Inventions made by ICD’s contractors or grantees.  The CRADA PIs will be responsible for coordinating the scientific and technical conduct of this project on behalf of their employers.  Any Collaborator employees who will work at ICD facilities will be required to sign a Guest Researcher or Special Volunteer Agreement appropriately modified in view of the terms of this CRADA.

 

3.2          Research Plan.  The Parties recognize that the Research Plan describes the collaborative research and development activities they will undertake and that interim research goals set forth in the Research Plan are good faith guidelines.  Should events occur that require modification of these goals, then by mutual agreement the Parties can modify them through an amendment, according to Paragraph 13.6.

 

3.3          Use and Disposition of Collaborator Materials and ICD Materials.  The Parties agree to use Collaborator Materials and ICD Materials only in accordance with the Research Plan and Protocol(s), not to transfer these materials to third parties except in accordance with the Research Plan and Protocol(s) or as approved by the owning or providing Party, and, upon expiration or termination of the CRADA, to dispose of these materials as directed by the owning or providing Party.

 

3.4          Third-Party Rights in Collaborator’s CRADA Subject Inventions.  If Collaborator has received (or will receive) support of any kind from a third party in exchange for rights in any of Collaborator’s CRADA Subject Inventions, Collaborator agrees to ensure that its obligations to the third party are both consistent with Articles 6 through 8 and subordinate to Article 7 of this CRADA.

 

	
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3.5          Disclosures to ICD.  Prior to execution of this CRADA, Collaborator agrees to disclose to ICD all instances in which outstanding royalties are due under a PHS license agreement and in which Collaborator had a PHS license terminated in accordance with 37 C.F.R. § 404.10.  These disclosures will be treated as Confidential Information upon request by Collaborator in accordance with Paragraphs 2.4, 8.3, and 8.4.

 

3.6          Clinical Investigator Responsibilities.  The Clinical Investigator will be required to submit, or to arrange for submission of, each Protocol associated with this CRADA to all appropriate IRBs, and for ensuring that the IRBs are notified of the role of Collaborator in the research.  In addition to the Protocol all associated documents, including informational documents and advertisements, must be reviewed and approved by the appropriate IRB(s) before starting the research at each Clinical Research Site.  The research will be done in strict accordance with the Protocol(s) and no substantive changes in a finalized Protocol will be made unless mutually agreed upon, in writing, by the Parties.  Research will not commence (or will continue unchanged, if already in progress) until each substantive change to a Protocol, including those required by either the FDA or the IRB, has been integrated in a way acceptable to the Parties, submitted to the FDA (if applicable) and approved by the appropriate IRBs.

 

3.7          Investigational Applications.

 

3.7.1                     If an IND is required either ICD or Collaborator, as indicated in the Research Plan, will submit an IND and all Clinical Investigators must have completed registration documents on file (1572 forms).

 

3.7.2                     If ICD elects to file its own IND, Collaborator agrees to provide ICD background data and information necessary to support the IND. Collaborator further agrees to provide a letter of cross-reference to all pertinent regulatory filings sponsored by Collaborator.  Collaborator’s employees will be reasonably available to respond to inquiries from the FDA regarding information and data contained in the Collaborator’s IND, DMF, other filings, or other information and data provided to ICD by the Collaborator pursuant to this Article 3.  If ICD has provided information or data to assist Collaborator in its IND filing, ICD will provide a letter of cross reference to its IND and respond to inquiries related to information provided by ICD, as applicable.

 

3.7.3                     If Collaborator supplies Confidential Information to ICD in support of an IND filed by ICD, this information will be protected in accordance with the corresponding confidentiality provisions of Article 8.

 

3.7.4                     Collaborator may sponsor its own clinical trials and hold its own IND for studies performed outside the scope of this CRADA. These studies, however, should not adversely affect the ability to accomplish the goal of the Research Plan, for example, by competing for the same study population.  All data from those clinical trials are proprietary to Collaborator for purposes of this CRADA.

 

	
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3.8          Test Article Information and Supply.  Collaborator agrees to provide ICD without charge and on a schedule that will ensure adequate and timely performance of the research, a sufficient quantity of formulated and acceptably labeled, clinical-grade Test Article (and, as required by the Protocol(s), Placebo) to complete the clinical trial(s) agreed to and approved under this CRADA. Collaborator will provide a Certificate of Analysis to ICD for each lot of the Test Article provided.

 

3.9          Test Article Delivery and Usage.  Collaborator will ship the Test Article and, if required, Placebo to ICD or its designee in containers marked in accordance with 21 C.F.R. § 312.6.  ICD agrees that the Clinical Investigators will keep appropriate records and take reasonable steps to ensure that the Test Article is used in accordance with the Protocol(s) and applicable FDA regulations.  In addition, ICD agrees that the Test Article (and all Confidential Information supplied by Collaborator relating to the Test Article) will be used solely for the conduct of the CRADA research and development activities.  Furthermore, ICD agrees that no analysis or modification of the Test Article will be performed without Collaborator’s prior written consent.  At the completion of the Research Plan, any unused quantity of Test Article will be returned to Collaborator or disposed as directed by Collaborator.  Pharmacy contacts at ICD or its designee will be determined by ICD and communicated to Collaborator.

 

3.10        Monitoring.

 

3.10.1              The Sponsor or its designee will be primarily responsible for monitoring clinical sites and for assuring the quality of all clinical data, unless otherwise stated in the Research Plan.  Monitoring will comply with FDA Good Clinical Practice (International Conference on Harmonisation (ICH) E6: “Good Clinical Practice: Consolidated Guidance; 62 Federal Register 25, 691 (1997)).  The other Party may also perform quality assurance oversight.  The monitor will communicate significant Protocol violations and submit documentation of monitoring outcomes on Protocol insufficiencies to the other Party in a timely manner.

 

3.10.2              Subject to the restrictions in Article 8 concerning IPI, and with reasonable advance notice and at reasonable times, ICD will permit Collaborator or its designee(s) access to clinical site(s) to monitor the conduct of the research, as well as to audit source documents containing Raw Data, to the extent necessary to verify compliance with FDA Good Clinical Practice and the Protocol(s).

 

3.11        FDA Meetings/Communications.  All meetings with the FDA concerning any clinical trial within the scope of the Research Plan will be discussed by Collaborator and ICD in advance.  Each Party reserves the right to take part in setting the agenda for, to attend, and to participate in these meetings.  The Sponsor will provide the other Party with copies of FDA meeting minutes, all transmittal letters for IND submissions, IND safety reports, formal questions and responses that have been submitted to the FDA, Annual Reports, and official FDA correspondence, pertaining either to the INDs under this CRADA or to the Clinical Investigators on Protocols performed in accordance with the Research Plan, except to the extent that those documents contain the proprietary information of a third party or dissemination is prohibited by law.

 

	
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Article 4.               Reports

 

4.1          Interim Research and Development Reports.  The CRADA PIs should exchange information regularly, in writing.  This exchange may be accomplished through meeting minutes, detailed correspondence, circulation of draft manuscripts, Steering Committee reports, copies of Annual Reports and any other reports updating the progress of the CRADA research.  However, the Parties must exchange updated Investigator’s Brochure, formulation and preclinical data, and toxicology findings, as they become available.

 

4.2          Final Research and Development Reports.  The Parties will exchange final reports of their results within six (6) months after the expiration or termination of this CRADA. These reports will set forth the technical progress made; any publications arising from the research; and the existence of invention disclosures of potential CRADA Subject Inventions and/or any corresponding Patent Applications.

 

4.3          Fiscal Reports.  If Collaborator has agreed to provide funding to ICD under this CRADA and upon the request of Collaborator, then concurrent with the exchange of final research and development reports according to Paragraph 4.2, ICD will submit to Collaborator a statement of all costs incurred by ICD for the CRADA. If the CRADA has been terminated, ICD will specify any costs incurred before the date of termination for which ICD has not received funds from Collaborator, as well as for all reasonable termination costs including the cost of returning Collaborator property or removal of abandoned Collaborator property, for which Collaborator will be responsible.

 

4.4          Safety Reports.  In accordance with FDA requirements, the Sponsor will establish and maintain records and submit safety reports to the FDA, as required by 21 C.F.R. § 312.32 and 21 C.F.R. 812.150(b)(1), or other applicable regulations.  In the conduct of research under this CRADA, the Parties will comply with specific ICD guidelines and policies for reporting ADEs and AEs, as well as procedures specified in the Protocol(s).  The Sponsor must provide the other Party with copies of all Safety Reports concurrently with their submission to the FDA, and with any other information affecting the safety of Human Subjects in research conducted under this CRADA.

 

4.5          Annual Reports.  The Sponsor will provide the other Party a copy of the Annual Report concurrently with the submission of the Annual Report to the FDA. Annual Reports will be kept confidential in accordance with Article 8.

 

Article 5.               Staffing, Financial, and Materials Obligations

 

5.1          ICD and Collaborator Contributions.  The contributions of any staff, funds, materials, and equipment by the Parties are set forth in Appendix B. The Federal Technology Transfer Act of 1986, 15 U.S.C. § 3710a(d)(1) prohibits ICD from providing funds to Collaborator for any 

 

	
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research and development activities under this CRADA.

 

5.2          ICD Staffing.  No ICD employees will devote 100% of their effort or time to the research and development activities under this CRADA. ICD will not use funds provided by Collaborator under this CRADA for ICD personnel to pay the salary of any permanent ICD employee.  Although personnel hired by ICD using CRADA funds will focus principally on CRADA research and development activities, Collaborator acknowledges that these personnel may nonetheless make contributions to other research and development activities, and the activities will be outside the scope of this CRADA.

 

5.3          Collaborator Funding.  Collaborator acknowledges that Government funds received by Collaborator from an agency of the Department of Health and Human Services may not be used to fund ICD under this CRADA. If Collaborator has agreed to provide funds to ICD then the payment schedule appears in Appendix B and Collaborator will make payments according to that schedule.  If Collaborator fails to make any scheduled payment, ICD will not be obligated to perform any of the research and development activities specified herein or to take any other action required by this CRADA until the funds are received.  ICD will use these funds exclusively for the purposes of this CRADA. Each Party will maintain separate and distinct current accounts, records, and other evidence supporting its financial obligations under this CRADA and, upon written request, will provide the other Party a Fiscal Report according to Paragraph 4.3, which delineates all payments made and all obligated expenses, along with the Final Research Report described in Paragraph 4.2.

 

5.4          Capital Equipment.  Collaborator’s commitment, if any, to provide ICD with capital equipment to enable the research and development activities under the Research Plan appears in Appendix B. If Collaborator transfers to ICD the capital equipment or provides funds for ICD to purchase it, then ICD will own the equipment.  If Collaborator loans capital equipment to ICD for use during the CRADA, Collaborator will be responsible for paying all costs and fees associated with the transport, installation, maintenance, repair, removal, or disposal of the equipment, and ICD will not be liable for any damage to the equipment.

 

Article 6.               Intellectual Property

 

6.1          Ownership of CRADA Subject Inventions, CRADA Data, and CRADA Materials.  Subject to the Government license described in Paragraph 7.5, the sharing requirements of Paragraph 8.1 and the regulatory filing requirements of Paragraph 8.2, the producing Party will retain sole ownership of and title to all CRADA Subject Inventions, all copies of CRADA Data, and all CRADA Materials produced solely by its employee(s).  The Parties will own jointly all CRADA Subject Inventions invented jointly and all CRADA Materials developed jointly.  A PHS contractor’s or grantee’s rights in data it generates will not be affected by this CRADA.

 

6.2          Reporting.  The Parties will promptly report to each other in writing each CRADA Subject Invention reported by their respective personnel, and any Patent Applications filed thereon, resulting from the research and development activities conducted under this CRADA.

 

	
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Each Party will report all CRADA Subject Inventions to the other Party in sufficient detail to

 

determine inventorship, which will be determined in accordance with U.S. patent law.  These reports will be treated as Confidential Information in accordance with Article 8.  Formal reports will be made by and to the Patenting and Licensing Offices identified on the Contacts Information Page herein.

 

6.3          Filing of Patent Applications.  Each Party will make timely decisions regarding the filing of Patent Applications on the CRADA Subject Inventions made solely by its employee(s), and will notify the other Party in advance of filing.  Collaborator will have the first opportunity to file a Patent Application on joint CRADA Subject Inventions and will notify PHS of its decision within sixty (60) days of an Invention being reported or at least thirty (30) days before any patent filing deadline, whichever occurs sooner.  If Collaborator fails to notify PHS of its decision within that time period or notifies PHS of its decision not to file a Patent Application, then PHS has the right to file a Patent Application on the joint CRADA Subject Invention.  Neither Party will be obligated to file a Patent Application.  Collaborator will place the following statement in any Patent Application it files on a CRADA Subject Invention: “This invention was created in the performance of a Cooperative Research and Development Agreement with the [INSERT into Agency’s model as appropriate: National Institutes of Health, Food and Drug Administration, Centers for Disease Control and Prevention], an Agency of the Department of Health and Human Services.  The Government of the United States has certain rights in this invention.” If either Party files a Patent Application on a joint CRADA Subject Invention, then the filing Party will include a statement within the Patent Application that clearly identifies the Parties and states that the joint CRADA Subject Invention was made under this CRADA.

 

6.4          Patent Expenses.  Unless agreed otherwise, the Party filing a Patent Application will pay all preparation and filing expenses, prosecution fees, issuance fees, post issuance fees, patent maintenance fees, annuities, interference expenses, and attorneys’ fees for that Patent Application and any resulting Patent(s).  If a license to any CRADA Subject Invention is granted to Collaborator, then Collaborator will be responsible for all expenses and fees, past and future, in connection with the preparation, filing, prosecution, and maintenance of any Patent Applications and Patents claiming exclusively licensed CRADA Subject Inventions and will be responsible for a pro-rated share, divided equally among all licensees, of those expenses and fees for non-exclusively licensed CRADA Subject Inventions.  Collaborator may waive its exclusive option rights at any time, and incur no subsequent financial obligation for those Patent Application(s) or Patent(s).

 

6.5          Prosecution of Patent Applications.  The Party filing a Patent Application will provide the non-filing Party with a copy of any official communication relating to prosecution of the Patent Application within thirty (30) days of transmission of the communication.  Each Party will also provide the other Party with the power to inspect and make copies of all documents retained in the applicable Patent Application or Patent file.  The Parties agree to consult with

 

	
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each other regarding the prosecution of Patent Applications directed to joint CRADA Subject Inventions.  If Collaborator elects to file and prosecute Patent Applications on joint CRADA Subject Inventions, then Collaborator agrees to use the U.S.P.T.O. Customer Number Practice 

and/or grant PHS a power(s) of attorney (or equivalent) necessary to assure PHS access to its intellectual property rights in these Patent Applications.  PHS and Collaborator will cooperate with each other to obtain necessary signatures on Patent Applications, assignments, or other documents.

 

Article 7.               Licensing

 

7.1          Background Inventions.  Other than as specifically stated in this Article 7, nothing in this CRADA will be construed to grant any rights in one Party’s Background Invention(s) to the other Party, except to the extent necessary for the Parties to conduct the research and development activities described in the Research Plan.

 

7.2          Collaborator’s License Option to CRADA Subject Inventions.  With respect to Government rights to any CRADA Subject Invention made solely by an ICD employee(s) or made jointly by an ICD employee(s) and a Collaborator employee(s) for which a Patent Application was filed, PHS hereby grants to Collaborator an exclusive option to elect an exclusive or nonexclusive commercialization license.  The license will be substantially in the form of the appropriate model PHS license agreement and will fairly reflect the nature of the CRADA Subject Invention, the relative contributions of the Parties to the CRADA Subject Invention and the CRADA, a plan for the development and marketing of the CRADA Subject Invention, the risks incurred by Collaborator, and the costs of subsequent research and development needed to bring the CRADA Subject Invention to the marketplace.  The field of use of the license will not exceed the scope of the Research Plan.

 

7.3          Exercise of Collaborator’s License Option.  To exercise the option of Paragraph 7.2 Collaborator must submit a written notice to the PHS Patenting and Licensing Contact identified on the Contacts Information Page (and provide a copy to the ICD Contact for CRADA Notices) within three (3) months after either (i) Collaborator receives written notice from PHS that the Patent Application has been filed or (ii) the date on which Collaborator files the Patent Application.  The written notice exercising this option will include a completed “Application for License to Public Health Service Inventions” and will initiate a negotiation period that expires nine (9) months after the exercise of the option.  If PHS has not responded in writing to the last proposal by Collaborator within this nine (9) month period, the negotiation period will be extended to expire one (1) month after PHS so responds, during which month Collaborator may accept in writing the final license proposal of PHS. In the absence of Collaborator’s exercise of the option, or upon election of a nonexclusive license, PHS will be free to license the CRADA Subject Invention to others.  These time periods may be extended at the sole discretion of PHS upon good cause shown in writing by Collaborator.

 

7.4          Government License in ICD Sole CRADA Subject Inventions and Joint CRADA 

 

	
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Subject Inventions.  Pursuant to 15 U.S.C. § 3710a(b)(1)(A), for CRADA Subject Inventions owned solely by ICD or jointly by ICD and Collaborator, and licensed pursuant to the option of Paragraph 7.2, Collaborator grants to the Government a nonexclusive, nontransferable, irrevocable, paid-up license to practice the CRADA Subject Invention or have the CRADA 

Subject Invention practiced throughout the world by or on behalf of the Government.  In the exercise of this license, the Government will not publicly disclose trade secrets or commercial or financial information that is privileged or confidential within the meaning of 5 U.S.C. § 552(b)(4) or which would be considered privileged or confidential if it had been obtained from a non-federal party.

 

7.5          Government License in Collaborator Sole CRADA Subject Inventions.  Pursuant to 15 U.S.C. § 3710a(b)(2), for CRADA Subject Inventions made solely by an employee of Collaborator, Collaborator grants to the Government a nonexclusive, nontransferable, irrevocable, paid-up license to practice the CRADA Subject Invention or have the CRADA Subject Invention practiced throughout the world by or on behalf of the Government for research or other Government purposes.

 

7.6          Third Party License.  Pursuant to 15 U.S.C. § 3710a(b)(1)(B), if PHS grants Collaborator an exclusive license to a CRADA Subject Invention made solely by an ICD employee or jointly with a Collaborator employee, the Government will retain the right to require Collaborator to grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense to use the CRADA Subject Invention in Collaborator’s licensed field of use on terms that are reasonable under the circumstances; or, if Collaborator fails to grant a license, to grant a license itself.  The exercise of these rights by the Government will only be in exceptional circumstances and only if the Government determines (i) the action is necessary to meet health or safety needs that are not reasonably satisfied by Collaborator, (ii) the action is necessary to meet requirements for public use specified by federal regulations, and such requirements are not reasonably satisfied by Collaborator; or (iii) Collaborator has failed to comply with an agreement containing provisions described in 15 U.S.C. § 3710a(c)(4)(B).  The determination made by the Government under this Paragraph is subject to administrative appeal and judicial review under 35 U.S.C. § 203(2).

 

7.7          Third-Party Rights In ICD Sole CRADA Subject Inventions.  For a CRADA Subject Invention conceived prior to the Effective Date solely by an ICD employee that is first actually reduced to practice after the Effective Date in the performance of the Research Plan, the option offered to Collaborator in Paragraph 7.2 may be restricted if, prior to the Effective Date, PHS had filed a Patent Application and has either offered or granted a license in the CRADA Subject Invention to a third party.  Collaborator nonetheless retains the right to apply for a license to any such CRADA Subject Invention in accordance with the terms and procedures of 35 U.S.C. § 209 and 37 C.F.R. Part 404.

 

7.8          Joint CRADA Subject Inventions Not Exclusively Licensed by Collaborator.  If 

 

	
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Collaborator does not acquire an exclusive commercialization license in a joint CRADA Subject Invention in all fields of use then, for those fields of use not exclusively licensed to Collaborator, each Party will have the right to use the joint CRADA Subject Invention and to license its use to others, and each Party will cooperate with the other, as necessary, to fulfill international licensing requirements.  The Parties may agree to a joint licensing approach for any remaining fields of use.

 

Article 8.               Rights of Access and Publication

 

8.1          Right of Access to CRADA Data and CRADA Materials.  ICD and Collaborator agree to exchange all CRADA Data and to share all CRADA Materials.  If the CRADA is terminated, both Parties agree to provide CRADA Materials in quantities needed to complete the Research Plan.  Such provision will occur before the termination date of the CRADA or sooner, if required by the Research Plan.  If Collaborator possesses any human biological specimens from clinical trials under the CRADA, the specimens must be handled as described in the Protocol or as otherwise directed by ICD before the termination date of the CRADA.

 

8.2          Use of CRADA Data and CRADA Materials.  The Parties will be free to utilize CRADA Data and CRADA Materials internally for their own purposes, consistent with their obligations under this CRADA. ICD may share CRADA Data or CRADA Materials with any contractors, grantees, or agents it has engaged to conduct the CRADA research and development activities, provided the obligations of this Article 8.2 are simultaneously conveyed.  Collaborator may share CRADA Data or CRADA Materials with any contractors, Affiliates, or agents it has engaged to conduct the CRADA research and development activities, provided the obligations of this Article 8.2 are simultaneously conveyed.

 

8.2.1       CRADA Data.

 

Collaborator and ICD will use reasonable efforts to keep CRADA Data confidential until published or until corresponding Patent Applications are filed.  To the extent permitted by law, each Party will have the right to use any and all CRADA Data in and for any regulatory filing by or on behalf of the Party.

 

8.2.2       CRADA Materials.

 

Collaborator and ICD will use reasonable efforts to keep descriptions of CRADA Materials confidential until published or until corresponding Patent Applications are filed.  Collaborator acknowledges that the basic research mission of PHS includes sharing with third parties for further research those research resources made in whole or in part with NIH funding.  Consistent with this mission and the tenets articulated in “Sharing of Biomedical Research Resources: Principles and Guidelines for Recipients of NIH Research Grants and Contracts,” December 1999, available at http://ott.od.nih.gov/NewPages/RTguide_final.html, following publication either Party may make available to third parties for further research those CRADA Materials made jointly by both PHS and Collaborator.  

 

	
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Notwithstanding the above, if those joint CRADA Materials are the subject of a pending Patent Application or a Patent, or were created using a patent-pending or patented material or technology, the Parties may agree to restrict distribution or freely distribute them.  Either Party may distribute those CRADA Materials made solely by the other Party only upon written consent from that other Party or that other Party’s designee.

 

8.3          Confidential Information.  Each Party agrees to limit its disclosure of Confidential Information to the amount necessary to carry out the Research Plan, and will place a confidentiality notice on all this information.  A Party orally disclosing Confidential Information to the other Party will summarize the disclosure in writing and provide it to the other Party within fifteen (15) days of the disclosure.  Each Party receiving Confidential Information agrees to use it only for the purposes described in the Research Plan.  Either Party may object to the designation of information as Confidential Information by the other Party.

 

8.4          Protection of Confidential Information.  Confidential Information will not be disclosed, copied, reproduced or otherwise made available to any other person or entity without the consent of the owning or providing Party except as required by a court or administrative body of competent jurisdiction, or federal law or regulation.  Each Party agrees to use reasonable efforts to maintain the confidentiality of Confidential Information, which will in no instance be less effort than the Party uses to protect its own Confidential Information.  Each Party agrees that a Party receiving Confidential Information will not be liable for the disclosure of that portion of the Confidential Information which, after notice to and consultation with the disclosing Party, the receiving Party determines may not be lawfully withheld, provided the disclosing Party has been given a reasonable opportunity to seek a court order to enjoin disclosure.

 

8.5          Human Subject Protection.  The research to be conducted under this CRADA involves Human Subjects or human tissues within the meaning of 45 C.F.R. Part 46, and all research to be performed under this CRADA will conform to applicable federal laws and regulations.  Additional information is available from the HHS Office for Human Research Protections (http://www.hhs.gov/ohrp/).

 

8.6          Duration of Confidentiality Obligation.  The obligation to maintain the confidentiality of Confidential Information will expire at the earlier of the date when the information is no longer Confidential Information as defined in Paragraph 2.4 or three (3) years after the expiration or termination date of this CRADA, except for IPI, for which the obligation to maintain confidentiality will extend indefinitely.  Collaborator may request an extension to this term when necessary to protect Confidential Information relating to products not yet commercialized.

 

8.7          Publication.  The Parties are encouraged to make publicly available the results of their research and development activities.  Before either Party submits a paper or abstract for publication or otherwise intends to publicly disclose information about a CRADA Subject Invention, CRADA Data, or CRADA Materials, the other Party will have thirty (30) days to review proposed manuscripts and three (3) days to review proposed abstracts to assure that

 

	
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Confidential Information is protected.  Either Party may request in writing that the proposed publication or other disclosure be delayed for up to thirty (30) additional days as necessary to file a Patent Application.

 

8.8          Clinical Investigators’ Research and Development Activities.  Although this CRADA does not grant to Collaborator any rights to Inventions made or Raw Data generated by ICD’s contractors or grantees, as they are not parties to this CRADA, ICD agrees that:

 

8.8.1       Subject to the other provisions of Article 8 of this CRADA, ICD will maintain, to the extent permitted by law, all Clinical Data in ICD’s Possession and Control as Confidential Information, and make them available to Collaborator for its own use and for exclusive use in obtaining regulatory approval for the commercial marketing of Test Article and related CRADA Subject Inventions.

 

8.8.2       With regard to Collaborator’s Confidential Information, ICD will require the Clinical Investigators to agree to confidentiality provisions at least as restrictive as those provided in this CRADA and to Collaborator’s use of data in accordance with Paragraph 8.8.1 for obtaining regulatory approval for marketing Test Article.

 

8.8.3       If Collaborator wants access to Raw Data or any other data in the possession of the Clinical Investigators working with Test Article, Collaborator must first contact the CRADA PI. Collaborator will bear any costs associated with Raw Data provided in formats customized for Collaborator.

 

8.8.4       Collaborator’s right to access Clinical Data in ICD’s Possession and Control under Paragraph 8.8 is dependent upon Collaborator’s continued development and commercialization of Investigational Agent.  If Collaborator fails to continue development or commercialization of Investigational Agent without the transfer of its development efforts to another party within ninety (90) days of discontinuation, ICD has the right to make Clinical Data in ICD’s Possession and Control available to a third party.

 

Article 9.               Representations and Warranties

 

9.1          Representations of ICD.  ICD hereby represents to Collaborator that:

 

9.1.1       ICD has the requisite power and authority to enter into this CRADA and to perform according to its terms, and that ICD’s official signing this CRADA has authority to do so.

 

9.1.2       To the best of its knowledge and belief, neither ICD nor any of its personnel involved in this CRADA is presently subject to debarment or suspension by any agency of the Government which would directly affect its performance of the CRADA. Should ICD or any of its personnel involved in this CRADA be debarred or suspended during the term of this CRADA, ICD will notify Collaborator within thirty (30) days of receipt of final notice.

 

	
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9.2          Representations and Warranties of Collaborator.  Collaborator hereby represents and warrants to ICD that:

 

9.2.1       Collaborator has the requisite power and authority to enter into this CRADA and to perform according to its terms, and that Collaborator’s official signing this CRADA has authority to do so.

 

9.2.2       Neither Collaborator nor any of its personnel involved in this CRADA, including Affiliates, agents, and contractors are presently subject to debarment or suspension by any agency of the Government.  Should Collaborator or any of its personnel involved in this CRADA be debarred or suspended during the term of this CRADA, Collaborator will notify ICD within thirty (30) days of receipt of final notice.

 

9.2.3       Subject to Paragraph 12.3, and if and to the extent Collaborator has agreed to provide funding under Appendix B, Collaborator is financially able to satisfy these obligations in a timely manner.

 

9.2.4       The Test Article provided has been produced in accordance with the FDA’s current Good Manufacturing Practice set out in 21 C.F.R. §§ 210-211, and ICH QA7, and meets the specifications cited in the Certificate of Analysis and Investigator’s Brochure provided.

 

Article 10.            Expiration and Termination

 

10.1        Expiration.  This CRADA will expire on the last date of the term set forth on the Summary Page.  In no case will the term of this CRADA extend beyond the term indicated on the Summary Page unless it is extended in writing in accordance with Paragraph 13.6.

 

10.2        Termination by Mutual Consent.  ICD and Collaborator may terminate this CRADA at any time by mutual written consent.

 

10.3        Unilateral Termination.  Either ICD or Collaborator may unilaterally terminate this CRADA at any time by providing written notice at least sixty (60) days before the desired termination date.  ICD may, at its option, retain funds transferred to ICD before unilateral termination by Collaborator for use in completing the Research Plan.  If Collaborator terminates this Agreement before the completion of all approved or active Protocol(s), then Collaborator will supply enough Test Article (and Placebo, if applicable) to complete these Protocol(s) unless termination is for safety concerns.

 

10.4        Funding for ICD Personnel.  If Collaborator has agreed to provide funding for ICD personnel and this CRADA is mutually or unilaterally terminated by Collaborator before its expiration, then Collaborator agrees that funds for that purpose will be available to ICD for a

 

	
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period of six (6) months after the termination date or until the expiration date of the CRADA, whichever occurs sooner.  If there are insufficient funds to cover this expense, Collaborator agrees to pay the difference.

 

10.5        New Commitments.  Neither Party will incur new expenses related to this CRADA after expiration, mutual termination, or a notice of a unilateral termination and will, to the extent feasible, cancel all outstanding commitments and contracts by the termination date.  Collaborator acknowledges that ICD will have the authority to retain and expend any funds for up to one (1) year subsequent to the expiration or termination date to cover any unpaid costs obligated during the term of the CRADA in undertaking the research and development activities set forth in the Research Plan.

 

10.6        Collaborator Failure to Continue Development.  If Collaborator suspends development of the Test Article without the transfer of its active development efforts, assets, and obligations to a third party within ninety (90) days of discontinuation, Collaborator agrees that ICD may continue developing the Test Article.  In that event, the following will apply:

 

10.6.1     Collaborator agrees to transfer to ICD all information necessary to enable ICD to contract for the manufacture of the Test Article and, unless abandoned for reasons relating to safety as determined by the data safety monitoring board, to provide the Test Article (and Placebo, if any) in Collaborator’s inventory to ICD.

 

10.6.2     Further, Collaborator hereby grants to ICD a nonexclusive, irrevocable, world-wide, paid-up license to practice, or have practiced for or on behalf of the Government, any Background Invention that Collaborator may currently have or will obtain on the Test Article, its manufacture, or on any method of using the Test Article for the indication(s) described in the Research Plan, including the right to sublicense to third parties.

 

Article 11.            Disputes

 

11.1        Settlement.  Any dispute arising under this CRADA which is not disposed of by agreement of the CRADA Principal Investigators will be submitted jointly to the signatories of this CRADA. If the signatories, or their designees, are unable to jointly resolve the dispute within thirty (30) days after notification thereof, the Assistant Secretary for Health (or his/her designee or successor) will propose a resolution.  Nothing in this Paragraph will prevent any Party from pursuing any additional administrative remedies that may be available and, after exhaustion of such administrative remedies, pursuing all available judicial remedies.

 

11.2        Continuation of Work.  Pending the resolution of any dispute or claim pursuant to this Article 11, the Parties agree that performance of all obligations will be pursued diligently.

 

	
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Article 12.            Liability

 

12.1        NO WARRANTIES. EXCEPT AS SPECIFICALLY STATED IN ARTICLE 9, THE PARTIES MAKE NO EXPRESS OR IMPLIED WARRANTY AS TO ANY MATTER WHATSOEVER, INCLUDING THE CONDITIONS OF THE RESEARCH OR ANY INVENTION OR MATERIAL, WHETHER TANGIBLE OR INTANGIBLE, MADE OR DEVELOPED UNDER OR OUTSIDE THE SCOPE OF THIS CRADA, OR THE OWNERSHIP, MERCHANTABILITY, OR FITNESS FOR A PARTICULAR PURPOSE OF THE RESEARCH OR ANY INVENTION OR MATERIAL, OR THAT A TECHNOLOGY UTILIZED BY A PARTY IN THE PERFORMANCE OF THE RESEARCH PLAN DOES NOT INFRINGE ANY THIRD-PARTY PATENT RIGHTS.

 

12.2        Indemnification and Liability.  Collaborator agrees to hold the Government harmless and to indemnify the Government for all liabilities, demands, damages, expenses and losses arising out of the use by Collaborator for any purpose of the CRADA Data, CRADA Materials or CRADA Subject Inventions produced in whole or part by ICD employees under this CRADA, unless due to the negligence or willful misconduct of ICD, its employees, or agents.  The Government has no statutory authority to indemnify Collaborator.  Each Party otherwise will be liable for any claims or damages it incurs in connection with this CRADA, except that ICD, as an agency of the Government, assumes liability only to the extent provided under the Federal Tort Claims Act , 28 U.S.C. Chapter 171.

 

12.3        Force Majeure.  Neither Party will be liable for any unforeseeable event beyond its reasonable control and not caused by its own fault or negligence, which causes the Party to be unable to perform its obligations under this CRADA, and which it has been unable to overcome by the exercise of due diligence.  If a force majeure event occurs, the Party unable to perform will promptly notify the other Party.  It will use its best efforts to resume performance as quickly as possible and will suspend performance only for such period of time as is necessary as a result of the force majeure event.

 

Article 13.            Miscellaneous

 

13.1        Governing Law.  The construction, validity, performance and effect of this CRADA will be governed by U.S. federal law, as applied by the federal courts in the District of Columbia.  If any provision in this CRADA conflicts with or is inconsistent with any U.S. federal law or regulation, then the U.S. federal law or regulation will preempt that provision.

 

13.2        Compliance with Law.  ICD and Collaborator agree that they will comply with, and advise any contractors, grantees, or agents they have engaged to conduct the CRADA research and development activities to comply with, all applicable Executive Orders, statutes, and HHS regulations relating to research on human subjects (45 C.F.R. Part 46, 21 C.F.R. Parts 50 and 56) and relating to the appropriate care and use of laboratory animals (7 U.S.C. §§ 2131 et seq.; 9 C.F.R. Part 1, Subchapter A).  ICD and Collaborator will advise any contractors, grantees, or agents they have engaged to conduct clinical trials for this CRADA that they must comply with all applicable federal regulations for the protection of Human Subjects, which may include the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part

 

	
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164.  Collaborator agrees to ensure that its employees, contractors, and agents who might have access to a “select agent or toxin” (as that term is defined in 42 C.F.R. §§ 73.4-73.5) transferred from ICD is properly licensed to receive the “select agent or toxin.”

 

13.3        Waivers.  None of the provisions of this CRADA will be considered waived by any Party unless a waiver is given in writing to the other Party.  The failure of a Party to insist upon strict performance of any of the terms and conditions hereof, or failure or delay to exercise any rights provided herein or by law, will not be deemed a waiver of any rights of any Party.

 

13.4        Headings.  Titles and headings of the articles and paragraphs of this CRADA are for convenient reference only, do not form a part of this CRADA, and will in no way affect its interpretation.

 

13.5        Severability.  The illegality or invalidity of any provisions of this CRADA will not impair, affect, or invalidate the other provisions of this CRADA.

 

13.6        Amendments.  Minor modifications to the Research Plan may be made by the mutual written consent of the CRADA Principal Investigators.  Substantial changes to the CRADA, extensions of the term, or any changes to Appendix C will become effective only upon a written amendment signed by the signatories to this CRADA or by their representatives duly authorized to execute an amendment.  A change will be considered substantial if it directly expands the range of the potential CRADA Subject Inventions, alters the scope or field of any license option governed by Article 7, or requires a significant increase in the contribution of resources by either Party.

 

13.7        Assignment.  Neither this CRADA nor any rights or obligations of any Party hereunder will be assigned or otherwise transferred by either Party without the prior written consent of the other Party.  This CRADA will be binding upon and inure to the benefit of the Parties and their respective successors and permitted assigns.

 

13.8        Notices.  All notices pertaining to or required by this CRADA will be in writing, signed by an authorized representative of the notifying Party, and delivered by first class, registered, or certified mail, or by an express/overnight commercial delivery service, prepaid and properly addressed to the other Party at the address designated on the Contacts Information Page, or to any other address designated in writing by the other Party.  Notices will be considered timely if received on or before the established deadline date or sent on or before the deadline date as verifiable by U.S. Postal Service postmark or dated receipt from a commercial carrier.  Notices regarding the exercise of license options will be made pursuant to Paragraph 7.3.  Either Party may change its address by notice given to the other Party in the manner set forth above.

 

13.9        Independent Contractors.  The relationship of the Parties to this CRADA is that of independent contractors and not agents of each other or joint venturers or partners.  Each Party will maintain sole and exclusive control over its personnel and operations.

 

	
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13.10      Use of Name; Press Releases.  By entering into this CRADA, the Government does not directly or indirectly endorse any product or service that is or will be provided, whether directly or indirectly related to either this CRADA or to any patent or other intellectual-property license or agreement that implements this CRADA by Collaborator, its successors, assignees, or licensees.  Collaborator will not in any way state or imply that the Government or any of its organizational units or employees endorses any product or services.  Each Party agrees to provide proposed press releases that reference or rely upon the work under this CRADA to the other Party for review and comment at least five (5) business days before publication.  Either Party may disclose the Title and Abstract of the CRADA to the public without the approval of the other Party.

 

13.11      Reasonable Consent.  Whenever a Party’s consent or permission is required under this CRADA, its consent or permission will not be unreasonably withheld.

 

13.12      Export Controls.  Collaborator agrees to comply with U.S. export law and regulations.  If Collaborator has a need to transfer any CRADA Materials made in whole or in part by ICD, or ICD Materials, or ICD’s Confidential Information to a person located in a country other than the United States, to an Affiliate organized under the laws of a country other than the United States, or to an employee of Collaborator in the United States who is not a citizen or permanent resident of the United States, Collaborator will acquire any and all necessary export licenses and other appropriate authorizations.

 

13.13      Entire Agreement.  This CRADA constitutes the entire agreement between the Parties concerning the subject matter of this CRADA and supersedes any prior understanding or written or oral agreement.

 

13.14      Survivability.  The provisions of Paragraphs 3.3, 3.4, 3.8, 4.2, 4.3, 5.3, 5.4, 6.1-9.2, 10.3-10.6, 11.1, 11.2, 12.1-12.3, 13.1-13.3, 13.7, 13.10 and 13.14 will survive the expiration or early termination of this CRADA.

 

SIGNATURES BEGIN ON THE NEXT PAGE

 

 

	
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SIGNATURE PAGE

 

ACCEPTED AND AGREED

 

BY EXECUTING THIS AGREEMENT, EACH PARTY REPRESENTS THAT ALL STATEMENTS MADE HEREIN ARE TRUE, COMPLETE, AND ACCURATE TO THE BEST OF ITS KNOWLEDGE. COLLABORATOR ACKNOWLEDGES THAT IT MAY BE SUBJECT TO CRIMINAL, CIVIL, OR ADMINISTRATIVE PENALTIES FOR KNOWINGLY MAKING A FALSE, FICTITIOUS, OR FRAUDULENT STATEMENT OR CLAIM.

 

	
FOR ICD:
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
08/01/08
    
	
[***]
    	
 
    	
Date
    
	
Deputy Director, NCI
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
FOR COLLABORATOR:
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
08/12/08
    
	
[***]
    	
 
    	
Date
    
	
Title: President and   Chief Executive Officer
    	
 
    	
 
    

 

	
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CONTACTS INFORMATION PAGE

 

	
CRADA Notices
    
	
 
    	
 
    
	
For ICD:
    	
For Collaborator:
    
	
 
    	
 
    
	
Technology Transfer   Center
    	
[***]
    
	
National Cancer   Institute
    	
President and CEO
    
	
6120 Executive Blvd.,   Suite 450
    	
BN ImmunoTherapeutics, Inc.
    
	
Rockville, MD   20852-7181
    	
2425 Garcia Avenue
    
	
Phone: 301-496-0477
    	
Mountain View, CA 94043
    
	
Fax: 301-402-2117
    	
Tel: [***]
    
	
 
    	
Fax: [***]
    
	
 
    
	
Patenting and Licensing
    
	
 
    	
 
    
	
For ICD:
    	
For Collaborator (if   separate from above):
    
	
 
    	
 
    
	
Division Director,   Division of Technology
    	
[***]
    
	
Development and   Transfer
    	
President and CEO
    
	
NIH Office of   Technology Transfer
    	
BN   ImmunoTherapeutics, Inc.
    
	
6011 Executive   Boulevard, Suite 3252425
    	
Garcia Avenue
    
	
Rockville, Maryland   20852-3804
    	
Mountain View, CA 94043
    
	
Tel: 301-496-7057
    	
Tel: [***]
    
	
Fax: 301-402-0220
    	
Fax: [***]
    
	
 
    
	
Delivery of Materials Identified In Appendix B (if   any)
    
	
 
    	
 
    
	
For ICD:
    	
For Collaborator:
    
	
 
    	
 
    
	
Dr. [***]
    	
[***]
    
	
10 Center Drive, MSC   1750
    	
Senior Director,   Clinical Operations
    
	
Building 10, Room 8B09
    	
BN   ImmunoTherapeutics, Inc.
    
	
Bethesda, MD 20892
    	
2425 Garcia Avenue
    
	
Phone: [***]
    	
Mountain View, CA 94043
    
	
Fax: [***]
    	
Tel: [***]
    
	
Email: [***]
    	
Fax: [***]
    
	
 
    	
Email: [***]
    

 

	
ICD Project Officer for Extramural Investigators
    
	
 
    	
 
    
	
Name:
    	
[***],   Ph.D.
    
	
Branch:
    	
NCI, DCTD, CTEP
    
	
Address:
    	
6130 Executive Blvd.,   Suite 7108, Rockville, MD 20852, Phone: [***]
    

 

	
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SUMMARY PAGE

 

EITHER PARTY MAY, WITHOUT FURTHER CONSULTATION OR PERMISSION,

RELEASE THIS SUMMARY PAGE TO THE PUBLIC.

 

	
TITLE OF CRADA: The Development of Recombinant Poxviruses   as Vaccine Immunotherapies for the Treatment and/or Prevention of Human   Prostate Cancer
    
	
 
    	
 
    
	
PHS [ICD] Component:
    	
National Cancer   Institute
    
	
ICD CRADA Principal   Investigator:
    	
Jeffrey Schlom, Ph.D.
    
	
 
    	
 
    
	
Collaborator:
    	
BN ImmunoTherapeutics
    
	
Collaborator CRADA   Principal Investigator:
    	
Reiner Laus, M.D.
    
	
Term of CRADA:
    	
five (5) years   from the Effective Date
    

 

ABSTRACT OF THE RESEARCH PLAN:

 

BN ImmunoTherapeutics, Inc. and the National Cancer Institute, National Institutes of Health, will collaborate under a Cooperative Research and Development Agreement on the preclinical and clinical development of recombinant poxviruses expressing tumor-associated antigens as potential vaccines for the prevention and/or treatment of human prostate cancer.

 

	
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PUBLIC HEALTH SERVICE

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

FOR EXTRAMURAL-PHS CLINICAL RESEARCH

 

APPENDIX A

 

RESEARCH PLAN

 

TITLE OF CRADA

The Development of Recombinant Poxviruses As Vaccine Immunotherapies for the 
 Treatment and/or Prevention of Human Prostate Cancer

 

NCI, NIH Principal Investigator

Jeffrey Schlom, Ph.D.

Laboratory of Tumor Immunology and Biology (LTIB), Center for Cancer Research
 (CCR), National Cancer Institute (NCI)

 

Collaborator Principal Investigator

Reiner Laus, M.D.

BN ImmunoTherapeutics, Inc. (BNIT)

 

Term of CRADA

Five (5) years from the Effective Date.

 

GOAL OF THIS CRADA

 

The principal goal of this CRADA is to develop recombinant poxviruses as vaccines that can be used for the therapy and/or prevention of human prostate cancer.The scope of this CRADA including any in vitro and in vivo testing conducted by Dr. Jeffrey Schlom’s laboratory is strictly limited to the development of recombinant poxviruses encoding for prostate-associated antigens, cytokines, and/or immunostimulatory molecules as vaccine immunotherapies for the treatment and prevention of prostate cancer.

 

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GLOSSARY of TERMS

 

Vaccinia: Vaccinia is the poxvirus that has been used in the smallpox eradication program. It is not the smallpox virus, but a virus originally derived from cowpox. Many genes can be inserted into vaccinia and other poxviruses. When this occurs, it is then termed a recombinant virus (e.g., rV- for recombinant vaccinia). Vaccinia is a replication competent virus and has been used as the primary (first) vaccination in diversified prime and boost vaccine regimens in both pre-clinical and clinical studies.

 

Fowlpox: Fowlpox is replication incompetent in mammalian cells. Many genes can be

 

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inserted into fowlpox. When this occurs, it is then termed a recombinant fowlpox (rF-). Recombinant fowlpox has been used as multiple booster vaccinations in diversified prime and boost vaccine regimens. Fowlpox appears to be very safe and is a member of the Avipox family.

 

MVA: MVA stands for modified vaccinia Ankara.

 

TRICOM: TRICOM is a triad of T-cell costimulatory molecules consisting of the following human T-cell costimulatory molecule genes: B7.1, ICAM-l and LFA-3. TRICOM was developed at NCI in the LTIB. TRICOM has been shown to activate T cells more than the additive effect of each costimulatory molecule when used individually.   A T-cell costimulatory molecule is necessary for the enhanced activation of human T cells, which are believed to be the primary cell type responsible for vaccine-mediated anti-tumor activity. The NCI has demonstrated that the addition of all three of these genes, i.e., TRICOM, into recombinant vaccinia and fowlpox results in enhanced activation of T cells. This has been shown in both murine and human systems in vitro and in murine systems in vivo. It also appears to be the case in clinical trials.

 

PSA: PSA (prostate-specific antigen) is a tumor-associated antigen expressed in prostate cancer and normal prostate tissue. PSA is also expressed in some other carcinomas. The LTIB has developed a PSA agonist construct, which is a modified form of the PSA gene to make it more immunogenic. The PROSTVAC construct contains the entire PSA gene with the PSA agonist epitope.

 

PROSTVAC (also called Investigational Agent): PROSTVAC consists of rV-PSA/TRICOM and rF-PSA/TRICOM, which are used in a prime and boost vaccine strategy. The PSA gene contains the agonist epitope.

 

rF-GM-CSF: rF-GM-CSF is a recombinant fowlpox expressing the human GM-CSF (granulocyte macrophage colony stimulating factor) gene. It has been demonstrated in preclinical studies to enhance the recruitment of dendritic cells to regional nodes of the vaccine site.

 

INTRODUCTION

 

Dr. Jeffrey Schlom and his colleagues at the LTIB, NCI have developed a number of replication competent and replication defective poxvirus-based vectors containing transgenes for tumor-associated antigens (TAAs) as vaccine immunotherapies for the treatment and prevention of human cancers, including prostate cancer.  They have also developed a number of preclinical models and vaccine strategies to investigate the therapeutic benefits of these vaccines against cancer.  In these approaches, TAAs which are primarily expressed in human tumor cells and not expressed or minimally expressed in normal tissues have been employed to generate a tumor-associated immune response that results in tumor destruction.

 

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The LTIB has extensive experience in preclinical models in the analysis of immune responses directed against a range of TAAs. They have the demonstrated ability to analyze a range of immune cell subsets, including CD4, CD8, Natural Killer (NK), and regulatory T cells.  The LTIB also has extensive experience in the following:

(A) The development and use of animal models to analyze both the immune response and the therapeutic efficacy of cancer vaccines.  They have developed animal models in which the tumors express self antigens so that one can assess the ability of a vaccine to break immune tolerance.  They have also developed animal models involving subcutaneous tumors, lung metastasis, orthotopic renal cell cancers, and spontaneous mammary carcinomas.

(B) The design and evaluation of vaccine combination therapy regimens, including the use of vaccines with chemotherapeutic agents, small molecule targeted therapeutics, monoclonal antibodies, external beam radiation, chelated radionuclides, and cytokines.

(C) The modification of human TAAs to enhance their immunogenicity and in the development of subsequent agonist epitopes of those TAAs.

(D) The analysis of human TAAs for their ability to activate human T-cell responses in vitro.

(E) The planning and carrying out of clinical trials involving cancer vaccines as monotherapy or in combination therapies for a range of human cancers.

(F) The analysis of immune responses of patients both prior to and post-vaccination.

 

BN ImmunoTherapeutics, Inc. (BNIT) has extensive experience in developing poxviral vaccines for cancer immunotherapy.  Their core technology is a proprietary recombinant poxvirus-based platform, Modified Vaccinia Ankara BN (MVA-BN®), which they are developing as an immunotherapy for breast, prostate, and other cancers.  BNIT is a subsidiary of Bavarian Nordic (BN).  BN has a dedicated research and development facility in Martinsried, Germany, where recombinant poxviruses are generated and produced for research use. Small scale manufacturing of research grade lots is provided by the facility at Martinsried. Initial 1000 dose lots have been completed for dozens of viral constructs to date. The site has produced multiple recombinant poxviruses encoding infectious disease antigens, and in conjunction with BNIT, multiple tumor antigen-expressing viruses. HIV nef, HIV polytope, and HIV multiantigen, Dengue, Japanese encephalitis, measles, and RSV viral vaccines have been constructed and manufactured. In conjunction with BNIT, Her2 and PAP/PSA double antigen expressing recombinant viruses have been developed. BNIT has also begun to construct additional vectors with immunomodulatory inserts.

 

BN also has a clinical scale cGMP facility in Berlin that produces vaccine for clinical trials. The facility has been in operation since 2002, and has produced over 14 lots of clinical trial grade material. The facility produces clinical trial lots at intermediate scale (100s to 1000s of doses) with cGMP compliant processes that are similar and scalable to commercial scale. Current commercial scale manufacturing is operational at the Kvistgaard, Denmark facility. The facility has the capability of producing 30 million doses/year.

 

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BACKGROUND

 

Historical Background

 

Under a now terminated CRADA [***] there was significant progress in the development of new recombinant poxviral vectors, preclinical evaluation of those vectors in murine in vitro and in vivo models, and in human in vitro models. These preclinical studies led to several Phase 1 and Phase 2 clinical studies, several of which showed evidence of clinical benefit in patients with a range of human carcinomas. Much progress was also made in (a) the identification and evaluation of prostate-associated antigens including human prostate-specific antigen (PSA) and the development of agonist epitopes to those antigens, which would render them more immunogenic, and (b) the identification of which T cell costimulatory molecules and combinations of those molecules best enhanced T cell responses. As a consequence of these studies, it was shown that the insertion of transgenes for a triad of the T cell costimulatory molecules B7.1, ICAM-1 and LFA-3 (designated TRICOM) into poxvirus vectors gave optimal effects; this was shown in preclinical studies to enhance immune responses and anti-tumor activity. As a consequence of these preclinical studies, clinical trials were initiated to evaluate the efficacy of vectors containing the transgene for a tumor-associated antigen, i.e., PSA, and the transgenes for either one, two or three T cell costimulatory molecules.

 

The enormous progress in both preclinical and clinical studies using the poxvirus vaccine technology is demonstrated in the 47 publications of preclinical studies in peer-review journals and the 12 clinical studies in peer-review journals that resulted from these collaborative activities (see References).

 

An overview of some of the published clinical results employing the recombinant poxvirus vaccines in patients with prostate cancer is as follows:

 

In a Phase 1 study in prostate cancer patients, rV-PSA was administered to 33 patients with biochemical progression after local therapy or with metastatic disease. PSA levels in 13/33 men became stable for at least 6 months post-vaccination. Nine patients remained stable for 11—25 months and six remained progression free with stable PSA. At the time of the publication, several patients remained without evidence of clinical progression for up to 21 months.

 

An NCI-sponsored ECOG randomized Phase 2 trial was then carried out using two different PSA pox vectors in different prime/boost regimens: rV-PSA(V) and/or rF-PSA(F) in patients (n = 64) with biochemical progression after local therapy for prostate cancer. At the 2-year follow-up, median time to PSA and/or clinical progression was 9.2 months in the FFFF cohort, 9.0 months in the FFFV cohort, and 18 months in the VFFF cohort.

 

The NCI then completed studies with a diversified prime-boost strategy involving priming with rV-PSA + rV-B7.1 followed by rF-PSA booster vaccinations.  In the first trial, 28

 

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patients with metastatic androgen independent prostate cancer (AIPC) were randomized to receive vaccine alone or vaccine plus weekly docetaxel. Patients on the vaccine arm alone were allowed to cross over to receive docetaxel at time of progression. After vaccine, median progression-free survival on docetaxel was 6.1 months compared with a progression-free survival of 3.7 months with the same docetaxel regimen and patient population at the same institution.

 

In another Phase 2 trial at the NCI, 42 patients with nonmetastatic AIPC and rising serum PSA were randomized to receive either vaccine (rV-PSA/B7.1 prime and rF-PSA boosts) or nilutamide, an androgen-receptor antagonist (ARA). After 6 months, patients with a rising PSA were allowed to “cross over” and receive a combination of both therapies. Median time to treatment failure was similar in the vaccine (9.9 months) and ARA (7.6 months) arms. However, for the patients who first received vaccine and then went on to receive vaccine plus ARA, time to treatment failure was 13.9 months from the time of initiation of ARA, and the time to treatment failure from the initiation of any therapy was 25.9 months. Of the initial randomized population (n = 21/cohort), for those patients who received nilutamide first (nilutamide alone or nilutamide then vaccine), 5-year overall survival was 38%, vs. a median overall survival of 59% for those patients who received vaccine first (vaccine alone or nilutamide plus vaccine).

 

The NCI then developed rV- and rF- vectors containing the transgenes for PSA and three human costimulatory molecules (B7.1, ICAM-1 and LFA-3, designated TRICOM). PSA-TRICOM was well tolerated in a Phase 1 study. Recent Phase 2 trials in patients with metastatic and locally advanced prostate cancer have shown clinical responses and drops in serum PSA. A sponsored multi-center randomized Phase 2 study in 125 patients with metastatic androgen-independent asymptomatic prostate cancer did not meet its primary endpoint of progression-free survival. However, patients’ overall survival data are currently being accumulated, with provocative results. Median overall survival thus far is 16.3 months for the control cohort (wild-type vector) (n = 41) vs. 24.4 months for those patients receiving PSA-TRICOM vaccines (n = 84). A recently completed NCI Phase 2 trial with PSA-TRICOM vaccines in prostate cancer patients with metastatic disease also demonstrated clinical responses and evidence of increased survival.

 

So therefore, the promising clinical results from these studies encourages the establishment of a new CRADA to allow for the continual development and manufacture of PROSTVAC and other poxvirus-based prostate cancer vaccines.

 

WORK SCOPE

 

Contributions of NCI and BNIT

 

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Contributions of NCI

 

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DESCRIPTION OF THE CONTRIBUTIONS AND RESPONSIBILITIES OF THE PARTIES

 

CONTRIBUTIONS OF BNIT AND LTIB

 

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CONTRIBUTIONS OF LTIB, NCI

 

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CONTRIBUTIONS OF DCTD, CTEP, NCI

 

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CONTRIBUTIONS OF BNIT

 

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DESCRIPTION OF RELATED NCI-BNIT AGREEMENTS AND INTELLECTUAL PROPERTY OF THE PARTIES

 

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PATENTS/PATENT APPLICATIONS

 

BNIT patent rights

 

Below is a representative listing of patents and patent applications of BN which relate to the research under this CRADA.

 

1)   U.S. Patent No. 6,440,422, entitled “Recombinant MVA Virus And The Use Thereof.” Inventors: Sutter et al.

 

2)   PCT Application No. PCT/EP03/05045, entitled “Intergenic Regions As Insertion Sites In The Genome Of Modified Vaccinia Virus Ankara (MVA).”  Inventors: Howley et al.

 

3)   U.S. Patent No. 6,761,893, entitled “Modified Vaccinia Ankara Virus Variant.”  Inventors: Chaplin et al.

 

4)   U.S. Patent No. 6,682,742, entitled “Vector for Integration of Heterologous Sequences Into Poxviral Genomes.”  Inventors: Wintersperger et al.

 

5)   U.S. Patent No. 6,682,743, entitled “Altered Strain Of The Modified Vaccinia Virus Ankara (MVA).”  Inventor: Anton Mayr

 

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6)   U.S. Patent No. 6,924,137, entitled “Method For Virus Propagation.” Inventors: Howley et al.

 

7)   U.S. Patent No. 7,094,412, entitled “Poxvirus Containing Formulations And Process For Preparing Stable Poxvirus Containing Compositions.” Inventors: Howley et al.

 

8)   U.S. Patent No. 7,056,723, entitled “Method For The Recovery And Purification Of Poxviruses From Infected Cells.” Inventors: Heller et al.

 

9)   PCT Patent Application No. PCT/EP03/09704, entitled “Method For The Cultivation Of Primary Cells And For The Amplification Of Viruses Under Serum Free Conditions.” Inventors: Rathe et al.

 

10) U.S. Provisional Patent Application No. 60/924,413, entitled “Affinity-Purification of Vaccinia Virus and Recombinant Vaccinia Virus-Based Vaccines.”

 

11) PCT Patent Application No. PCT/US2007/021436, entitled “Methods for treating cancer with MVA.” Inventors: Delcayre et al.

 

12) U.S. Provisional Patent Application No. 60/960,893, entitled “Use Of MVA To Treat Prostate Cancer.”

 

NCI Patent Applications

 

A Federal Register notice was advertised on November 15, 2007, announcing the NIH’s intent to grant an exclusive license to BNIT.  The prospective exclusive license territory is worldwide and the field of use is limited to the development of therapies for prostatic diseases.  For the avoidance of doubt, said delivery formulation specifically excludes canary poxvirus vectors, NYVAC, eukaryotic expression vectors, aqueous-based delivery formulations and recombinant yeast.  The following patents and patent applications are in the prospective exclusive license:

 

1.                                      U.S. Patent No. 6,946,133 issued September 20, 2005 and U.S. Patent Application No.11/606, 929 filed December 1, 2006, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-062-1996/0], entitled “PROSTATE SPECIFIC ANTIGEN OLIGO-EPITOPE PEPTIDE.” Inventors: Jeffrey Schlom, Kwang Y. Tsang, and Sam Zaremba.

 

2.                                      U.S. Patent Application Nos. 60/334,669 and 10/497,003 filed November 30, 2001 and August 24, 2004, respectively, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-124-2001/0,1], entitled “PEPTIDE AGONISTS OF PROSTATE-SPECIFIC ANTIGEN, AND USES THEREFOR.”  Inventors: Jeffrey Schlom and Kwong Y. Tsang.

 

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3.             U.S. Patent No. 6,165, 460 issued December 26, 2000 and U.S. Patent Application No. 09/693,121 filed October 20, 2000, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No E-200-1990/4], entitled “GENERATION OF IMMUNE RESPONSES TO PROSTATE SPECIFIC ANTIGEN (PSA).” Inventors: Jeffrey Schlom and Dennis L. Panicali.

 

The following list of NIH patents and patent applications are also contained within this prospective license on a non-exclusive basis:

 

1.                                      U.S. Patent No. 6,969,609 issued November 29, 2005; U.S. Patent No. 7,211,432 issued May 1, 2007; U.S. Patent Application No. 11/723,666 filed March 21, 2007; as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-256-1998/0].

 

2.                                      U.S. Patent Application Nos. 08/686,280 filed July 25, 1996 and 08/686,281 filed July 25, 1996 as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-259-1994/3, 4].

 

3.                                      U.S. Patent Nos. 6,893,869, 6,548,068 and 6,045,802 issued May 17, 2005, April 15, 2003 and April  4, 2000 respectively, as well as issued and pending foreign counterparts [HHS Ref. Nos. E-260-1994/1-US-03, US-02, US-01]; and U.S. Patent. Application No. 11/090,686 filed March 8, 2005 [HHS Ref. No E-260-1994/1-US-04].

 

4.                                      U.S. Patent Application Nos. 60/211,717 and 10/297,168 filed June 15, 2000 and August 16, 2003 respectively, as well as all continuations, divisionals, and foreign counterparts [HHS Ref. No. E-187-2000/0].

 

5.                                      U.S. Patent Application Nos. 60/448,591 and 10/543,944 filed February 20, 2003 and February 20, 2004 respectively, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-028-2007/0].

 

6.                                      U.S. Patent No. 6,699,475 issued March 2, 2004, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-134-2007/0].

 

7.                                      U.S. Patent No. 5,093,258 issued March 3, 1992, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-135-2007/0].

 

8.                                      U.S. Patent Application No. 07/205,189 filed June 10, 1988, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-136-2007].

 

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9.                                      U.S. Patent Application No. 60/625,321 filed November 5, 2004, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-138-2007].

 

10.                               U.S. Patent Application No. 07/340,052 filed April 18, 1989, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-147-2007].

 

REFERENCES

 

Prior LTIB, NCI published studies involving recombinant poxviruses

 

Preclinical:

 

Mostböck S, Vidal S, Schlom J, and Sabzevari H. Enhanced levels of costimulation lead to reduced effector/memory CD8+ T cell functionality. J. Immunol. 179:3524-3534, 2007.

 

Kudo-Saito C, Garnett CT, Wansley EK, Schlom J, and Hodge JW. Intratumoral delivery of vector mediated IL-2 in combination with vaccine results in enhanced T-cell avidity and anti-tumor activity. Cancer Immunol. Immunother. 56:1897-1910, 2007.

 

Chakraborty M, Schlom J, and Hodge JW. The combined activation of positive costimulatory signals with modulation of a negative costimulatory signal for the enhancement of vaccine mediated T-cell responses.Cancer Immunol. Immunother. 56:1471-1484, 2007.

 

Kudo-Saito C, Wansley EK, Gruys ME, Wiltrout R, Schlom J and Hodge J. Combination therapy of an orthotopic renal cell carcinoma model employing intratumoral vector-mediated costimulation and systemic IL-2. Clin. Cancer Res. 13:1936-1946, 2007.

 

Palena C, Foon KA, Panicali D, Yafal AG, Chinsangaram J, Hodge JW, Schlom J, and Tsang KY. A potential approach to immunotherapy of chronic lymphocytic leukemia (CLL): enhanced immunogenicity of CLL cells via infection with vectors encoding for multiple costimulatory molecules. Blood 106:3515-3523, 2005.

 

Yang S, Hodge JW, Grosenbach DW, and Schlom J. Vaccines with enhanced costimulation maintain high avidity memory CTL. J. Immunol. 175:3715-3723, 2005.

 

Yang S, Tsang KY, and Schlom J. Induction of higher avidity human CTL by vector-mediated enhanced costimulation of antigen-presenting cells. Clin Cancer Res. 11:5603-5615, 2005.

 

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Kudo-Saito C, Schlom J, Camphausen K, Coleman CN, and Hodge JW. The requirement of multimodal therapy (vaccine, local tumor radiation, and reduction of suppressor cells) to eliminate established tumors. Clin Cancer Res. 11:4533-4544, 2005.

 

Hodge JW, Chakraborty M, Kudo-Saito C, Garnett CT, and Schlom J. Multiple costimulatory modalities enhance CTL avidity. J. Immunol. 174:5994-6004, 2005.

 

Kudo-Saito C, Schlom J, and Hodge JW. Induction of an antigen cascade by diversified subcutaneous/                      intratumoral vaccination is associated with antitumor responses. Clin. Cancer Res. 11:2416-2426, 2005.

 

Tsang K-Y, Palena C, Yokokawa J, Arlen PM, Gulley JL, Mazzara GP, Gritz L, Gómez Yafal A, Ogueta S, Greenhalgh P, Manson K, Panicali D, and Schlom J. Analyses of recombinant vaccinia and fowlpox vaccine vectors expressing transgenes for two human tumor antigens and three human costimulatory molecules. Clin. Cancer Res. 11:1597-1607, 2005.

 

Reali E, Canter D, Zeytin H, Schlom J, Greiner JW. Comparative studies of avipox-GM-CSF versus recombinant GM-CSF protein as immune adjuvants with different vaccine platforms. Vaccine 23: 2909-2921, 2005.

 

Slavin-Chiorini DC, Catalfamo M, Kudo-Saito C, Hodge JW, Schlom J, and Sabzevari H. Amplification of the lytic potential of effector/memory CD8+ cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy. Cancer Gene Ther. 11:665-680, 2004.

 

Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, and Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine mediated T-cell killing. Cancer Res. 64:4328-4337, 2004.

 

Zeytin HE, Patel AC, Rogers CJ, Canter D, Hursting SD, Schlom J, and Greiner JW. Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (Celecoxib) elicits anti-tumor immunity and long-term survival in CEA.Tg/Min mice. Cancer Res. 64:3668-3678, 2004.

 

Palena C, Zhu M-Z, Schlom J, and Tsang K-Y. Human B cells that hyperexpress a triad of costimulatory molecules via avipoxvector infection: an alternative source of efficient antigen-presenting cells. Blood 104:192-199, 2004.

 

Kudo-Saito C, Schlom J, and Hodge JW. Intratumoral vaccination and diversified subcutaneous/intratumoral vaccination with recombinant poxviruses encoding a tumor antigen and multiple costimulatory molecules. Clin. Cancer Res. 10:1090-1099, 2004.

 

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Hodge JW, Poole DJ, Aarts WM, Gomez Yafal A, Gritz L, and Schlom J. Modified vaccinia virus ankara recombinants are as potent as vaccinia recombinants in diversified prime and boost vaccine regimens to elicit therapeutic antitumor responses. Cancer Res. 63:7942-7949, 2003.

 

Arlen PM, Gulley JL, Palena C, Marshall J, Schlom J, and Tsang K-Y. A novel ELISPOT assay to enhance detection of antigen-specific T cells employing antigen-presenting cells expressing vector-driven human B7-1. J. Immunol. Meth. 279:183-192, 2003.

 

Grosenbach DW, Schlom J, Gritz L, Yafal AG, and Hodge JW. A recombinant vector expressing transgenes for four T-cell costimulatory molecules (OX40L, B7-1, ICAM-1, LFA-3) induces sustained CD4+ and CD8+ T-cell activation, protection from apoptosis and enhanced cytokine production. Cell. Immunol. 222:45-57, 2003.

 

Hodge JW, Grosenbach DW, Aarts Wm, Poole DJ, and Schlom J. Vaccine therapy of established tumors in the absence of autoimmunity. Clin. Cancer Res. 9:1837-1849, 2003.

 

Greiner J, Zeytin H, Anver MR, and Schlom J. Vaccine-based therapy directed against carcinoembryonic antigen demonstrates antitumor activity on spontaneous intestinal tumors in the absence of autoimmunity. Cancer Res. 62:6944-6951, 2002.

 

Tatari-Calerone Z, Semnani RT, Nutman, TB, Schlom J, and Sabzevari H. Acquisition of CD80 by human T cells at early states of activation: functional involvement of CD80 acquisition in T-cell to T-cell interaction. J. Immunol. 169:6162-6169, 2002.

 

Aarts WM, Schlom J, and Hodge JW. Vector-based vaccine/cytokine combination therapy to enhance induction of immune responses to a self-antigen and anti-tumor activity. Cancer Res. 62:5770-5777, 2002.

 

Terasawa H, Tsang Kwong-Yok, Gulley J, Arlen P, and Schlom J. Identification and characterization of a human agonist CTL epitope of human prostate-specific antigen. Clin. Cancer Res. 8: 41-53, 2002.

 

Shankar P, Schlom J, and Hodge JW. Enhanced activation of Rhesus T cells by vectors encoding a triad of costimulatory molecules (B7-1, ICAM-1, LFA-3). Vaccine 20: 744-755, 2001.

 

Tsang KY, Zhu MZ, Even J, Gulley J, Arlen P, and Schlom J. The infection of human dendritic cells with recombinant avipox vectors expressing a costimulatory molecule transgene (CD80) to enhance the activation of antigen-specific cytolytic T cells. Cancer Res. 61: 7568-7576, 2001.

 

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Zhu MZ, Terasawa H, Gulley J, Panicali D, Arlen P, Schlom J, and Tsang KY.  Enhanced activation of human T cells via avipox vector-mediated hyperexpression of a triad of costimulatory molecules in human dendritic cells. Cancer Res. 61: 3725-3734, 2001.

 

Hodge JW, Grosenbach DW, Rad AN, Giuliano M, Sabzevari H, and Schlom J. Enhancing the potency of peptide-pulsed antigen presenting cells by vector-driven hyperexpression of a triad of costimulatory molecules. Vaccine 19: 3552-3567, 2001.

 

Grosenbach DW, Barrientos JC, Schlom J, and Hodge JW.  Synergy of vaccine strategies to amplify antigen-specific immune responses and anti-tumor effects. Cancer Res. 61: 4497-4505, 2001.

 

Sabzevari H, Kantor J, Jaigirdar A, Tagaya Y, Naramura M, Hodge JW, Bernon J, and Schlom J. Acquisition of CD 80 (B7-1) by T cells. J. Immunol. 166: 2505-2513, 2001.

 

Kass E, Panicali DL, Mazzara G, Schlom J, and Greiner, JW. Granulocyte/macrophage colony-stimulating factor produced by recombinant avian poxviruses enriches the regional lymph nodes with antigen-presenting cells and acts as an immunoadjuvant. Cancer Res. 61: 206-214, 2001.

 

Arlen P, Tsang KY, Marshall JL, Chen A, Steinberg SM, Poole D, Horan Hand P, Schlom J, and Hamilton JM. The use of a rapid ELISPOT assay to analyze peptide-specific immune responses in carcinoma patients to peptide vs. recombinant poxvirus vaccines. Cancer Immunol. Immunother. 49: 517-529, 2000.

 

Hodge JW, Rad AN, Grosenbach DW, Sabzevari H, Yafal AG, Gritz L, and Schlom J. Enhanced activation of T cells by dendritic cells engineered to hyperexpress a triad of costimulatory molecules. J. Natl. Cancer Inst. 92: 1228-1239, 2000.

 

Kass E, Parker J, Schlom J, and Greiner JW. Comparative studies of the effects of recombinant GM-CSF and GM-CSF administered via a poxvirus to enhance the concentration of antigen presenting cells in regional lymph nodes. Cytokine 12: 960-971, 2000.

 

Freund YR, Mirsalis JC, Fairchild DG, Brune J, Hokama LA, Schindler-Horvat J, Tomaszewski JE, Hodge JW, Schlom J, Kantor JA, Tyson CA, and Donohue SJ. Vaccination with a recombinant vaccinia vaccine containing the B7-1 co-stimulatory molecule causes no significant toxicity and enhances T cell-mediated cytotoxicity. Int. J. Cancer 85: 508-517, 2000.

 

Hodge JW, Sabzevari H, Yafal AG, Gritz L, Lorenz MGO, and Schlom J. A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res. 59: 5800-5807, 1999.

 

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Hodge JW and Schlom J. Comparative studies of a retrovirus versus a poxvirus vector in whole-tumor-cell vaccines. Cancer Res. 59: 5106-5111, 1999.

 

Tsang KY, Zhu MZ, Nieroda CA, Correale P, Zaremba S, Hamilton JM, Cole D, Lam C, and Schlom J. Phenotypic stability of a cytotoxic T-cell line directed against an immuno-dominant epitope of human carcinoembryonic antigen. Clin. Cancer Res. 3: 2439-2449, 1997.

 

McLaughlin JP, Abrams S, Kantor J, Schlom J, and Greiner JW. Immunization with a syngeneic tumor infected with recombinant vaccinia virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) induces tumor regression and long-lasting systemic immunity. J. Immunother. 20: 449-459, 1997.

 

Hodge JW, McLaughlin JP, Kantor JA, and Schlom J. Diversified prime and boost protocols using recombinant vaccinia virus and recombinant nonreplicating avian pox virus to enhance T-cell immunity and antitumor responses. Vaccine 15: 759-768, 1997.

 

Akagi J, Hodge JW, McLaughlin JP, Gritz L, Panicali D, Kufe D, Schlom J, and Kantor J. Therapeutic antitumor response after immunization with an admixture of recombinant vaccinia viruses expressing a modified MUC1 gene and the murine T-cell costimulatory molecule B7. J. Immunother. 20: 38-47, 1997.

 

McLaughlin JP, Schlom J, Kantor JA, and Greiner J. Improved immunotherapy of a recombinant CEA vaccinia vaccine when given in combination with Interleukin-2. Cancer Res. 56: 2361-2367, 1996.

 

Hodge JW, McLaughlin JP, Abrams S, Shupert WL, Schlom J, and Kantor JA. Admixture of a recombinant vaccinia virus containing the gene for the costimulatory molecule B7 and a recombinant vaccinia virus containing a tumor associated antigen gene results in enhanced specific T-cell responses and antitumor immunity. Cancer Res. 55: 3598-3603, 1995.

 

Hodge JW, Donohue SJ, Levine BS, Wheeler CW, Panicali D, Schlom J, and Kantor JA. A recombinant vaccinia virus expressing human prostate-specific antigen (PSA): Safety and immunogenicity in a nonhuman primate. Int. J. Cancer 63: 231-237, 1995.

 

Karr JF, Kantor JA, Horan Hand P, Eggensperger DL, and Schlom J. Presence of prostate-specific antigen (PSA) gene in primates and the expression of recombinant human PSA in a transfected murine cell line. Cancer Res. 55: 2455-2462, 1995.

 

Hodge JW, Abrams S, Schlom J, and Kantor J. Induction of antitumor immunity by

 

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recombinant vaccinia viruses expressing B7-1 or B7-2 costimulatory molecules. Cancer Res. 54: 5552-5555, 1994.

 

Clinical:

 

Schlom J, Arlen PM, and Gulley JL. Cancer vaccines:  moving beyond current paradigms. Clin. Cancer Res. 13:3776-3782, 2007.

 

Arlen PM, Skarupa L, Pazdur M, Seetharam M, Tsang KY, Grosenbach DW, Feldman J, Poole DJ, Litzinger M, Steinberg SM, Jones E, Chen C, Marte J, Parnes H, Wright J, Dahut W, Schlom J, and Gulley JL. Clinical safety of a viral vector-based prostate cancer vaccine strategy. J. Urol. 178: 1515-1520, 2007

 

Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, Beetham P, Tsang KY, Grosenbach DW, Feldman J, Steinberg SM, Jones E, Chen C, Marte J, Schlom J, and Dahut W. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen independent prostate cancer. Clin Cancer Res 12:1260-1269, 2006.

 

Kaufman HL, Cohen S, Cheung K, DeRaffele, Mitcham J, Moroziewicz D, Schlom J, and Hesdorffer C. Local delivery of vaccinia virus expressing multiple costimulatory molecules for the treatment of established tumors. Human Gene Ther. 17:239-244, 2006.

 

Arlen PM, Gulley JL, Todd N, Lieberman R, Steinberg SM, Morin S, Bastian A, Marte J, Tsang K-Y, Beetham P, Grosenbach DW, Schlom J, and Dahut W. Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer. J. Urol. 174:539-546, 2005.

 

Gulley JL, Arlen PM, Bastian A, Morin S, Marte J, Beetham P, Tsang K-Y, Yokokawa J, Hodge JW, Ménard C, Coleman CN, Camphausen K, Sullivan F, Steinberg SM, Schlom J, and Dahut W. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin. Cancer Res. 11:3353-3362, 2005.

 

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Kaufman HL, Wang W, Manola J, DiPaola RS, Ko YJ, Sweeny C, Whiteside TL, Schlom J, Wilding G, Weiner LM.  Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897):  A trial of the eastern cooperative oncology group.  J. Clin. Oncol.  22: 2122-2132, 2004.

 

Marshall J, Gulley JL, Arlen PM, Beetham PK, Tsang KY, Slack R, Hodge JW, Doren S, Grosenbach DW, Hwang J, Fox E, Odogwa L, Park S, Panicali D, Schlom J. A phase I study of sequential vaccinations with fowlpox-CEA(6D)-TRICOM (B7-1/ICAM-1/LFA-3) alone and sequentially with vaccinia-CEA(6D)-TRICOM, with and without GM-CSF, in patients with CEA-expressing carcinomas. J. Clin. Oncol. 23:720-731, 2005.

 

Gulley J, Chen AP, Dahut W, Arlen PM, Bastian A, Steinberg SM, Tsang K, Panicali D, Poole D, Schlom J, and Hamilton JM. A Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer. The Prostate 53:109-117, 2002.

 

Marshall JL, Hoyer RJ, Toomey MA, Faraguna K, Chang P, Richmond E, Pedicano JE, Gehan E, Peck RA, Arlen P, Tsang KY, and Schlom J. Phase I study in advanced cancer patients of a diversified prime and boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J. Clin. Oncol. 18: 3964-3973, 2000.

 

Eder JP, Kantoff PW, Roper K, Xu G, Bubley GJ, Boyden J, Oh WK, Horzempa ML, Arlen P, Tsang A, Panicali D, Schlom J, and Kufe DW. A phase I trial of a recombinant vaccinia virus expressing prostate specific antigen in advanced prostate cancer. Clin. Cancer Res. 6: 1632-1638, 2000.

 

Tsang KY, Zaremba S, Nieroda CA, Zhu MZ, Hamilton JM, and Schlom J. Generation of human cytotoxic T cells specific for human carcinoembryonic antigen epitopes from patients immunized with recombinant vaccinia vaccine. J. Natl. Cancer Inst. 87: 982-990, 1995.

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

APPENDIX B

 

STAFFING, FUNDING AND MATERIALS/EQUIPMENT CONTRIBUTIONS
 OF THE PARTIES

 

Staffing Contributions:

 

ICD will provide scientific staff and other support necessary to conduct the research and other activities described in the Research Plan.  ICD’s scientific staff will include ICD’s CRADA Principal Investigator and technical staff.

 

ICD estimates that [***] person-years of effort per year will be required to complete the CRADA research.

 

Collaborator will provide scientific staff and other support necessary to conduct the research and other activities described in the Research Plan.  Collaborator’s scientific staff will include Collaborator’s Principal Investigator and technical staff.

 

Collaborator estimates that [***] person-years of effort per year will be required to complete the CRADA research.

 

Funding Contributions:

 

Collaborator agrees to provide funds in the amount of $[***] per year of the CRADA to ICD.  CRADA funds shall be used in support of this CRADA for technical, statistical, and administrative support for the research, including but not limited to:  (a) reagents, supplies, equipment, and other materials associated with experiments related to the CRADA; (b) salaries for nonpermanent employees; and (c) travel for CRADA-related activities.  Collaborator will provide funds in equal annual installments of $[***].  The first installment will be due within thirty (30) days of the Effective Date.  Each subsequent installment will be due within thirty (30) days of each anniversary of the Effective Date.  Collaborator agrees that ICD can allocate the funding between the various categories in support of the CRADA research as ICD’s CRADA PI sees fit.

 

CRADA PAYMENTS:

 

Collaborator will make payments by check as provided below.  Collaborator will make checks payable to the NCI, will reference the CRADA number and title on each check , and will send checks via trackable mail or courier to:

 

CRADA Funds Coordinator

National Cancer Institute

Technology Transfer Center

6120 Executive Blvd., Suite 450

Rockville, MD  20852-7181

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

CRADA Travel Payments:

 

Travel arrangements for all Government staff will be made in accordance with the Federal Travel Rules and Regulations, whether arranged by ICD and funded using either appropriated funds or CRADA funds, or arranged and funded directly by Collaborator.

 

Clinical Data Collection Support:

 

CTEP/DCTD utilizes the contract services of two companies for assistance in the monitoring of DCTD-sponsored clinical trials. Collaborator will be responsible for making arrangements directly with the appropriate DCTD contractors to receive reports from DCTD-sponsored trials. This will include quarterly reports, Adverse Event reports and summary reports. The contractor for the Phase 2 and 3 studies will provide these reports electronically in a format compatible with Collaborator’s database at a cost of $[***] per year, payable directly to the contractor.  The NCI Phase 1 contractor will also provide reports directly to Collaborator. Contact information for each of the DCTD contractors will be provided as needed. Any arrangement which involves the collection of more than the summarized data (Summary Data) provided annually to the DCTD will be at the expense of the Collaborator.

 

Collaborator may make only reasonable requests for access to Clinical Data and Results and Raw Data or any other information that is in the possession of extramural investigators.  The information will be provided according to a mutually agreed upon plan between the NCI, the Collaborator, and the investigator(s), and only in accordance with the guidelines and policies of the responsible Data Monitoring Committee.  Collaborator will be responsible for the costs associated with any unusually burdensome requests, such as a request that the data be provided in a format which is different than that normally collected. Should Collaborator choose to review copies of patient research records, such a review will be at Collaborator expense and occur after agreement and notification of the investigators by NCI and only after all patient identifiers have been removed.

 

Support for IB Preparation, Distribution, IND and IND Amendments:

 

CTEP/DCTD utilizes the contract services of two companies for assistance in the distribution of the IND, IND amendments and Investigator Brochures (IBs) for DCTD-sponsored clinical trials. Collaborator will be responsible for the costs associated with providing copies of the IBs to NCI registered investigators participating in clinical trials which are part of this CRADA, as well as the costs associated with the receipt of the IND and IND amendments. Collaborator will make arrangements directly with each DCTD contractor and will be invoiced directly by the contractor as described below.

 

The payments will be as follows:

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

IB Preparation (if performed by ICD):

 

Collaborator will be responsible for the costs associated with the preparation and updating of the IB. Collaborator will make arrangements directly with the DCTD contractor.

 

IB distribution:

 

Collaborator will be invoiced annually for the costs associated with IB distribution and payment will be expected within 30 days of receipt of each invoice. Collaborator agrees to provide funds for distribution of all IBs.  Typical costs, which are subject to change for the distribution of 10 IBs is $[***], $[***] for [***] IBs, and $[***] for [***] IBs.

 

IND amendments:

 

Collaborator will be invoiced quarterly for the costs associated with preparing, submitting, and distributing copies of IND Amendments to the Collaborator, and payment will be expected within 30 days of receipt of each invoice. Collaborator agrees to provide funds for all IND amendments. The costs, which are subject to change, will be as follows:

 

1.             IND Amendment (volume up to 100 pages): $[***]

2.             IND Amendment (amendment volume exceeding 100 pages): $[***]

3.             IND:  $[***]

 

Materials/Equipment Contributions:

 

ICD will provide the following ICD Materials, information and data to Collaborator:

 

[***]

 

[***]

 

[***]

 

[***]

 

B-3

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

[***]

 

[***]

 

[***]

 

[***]

 

[***]

 

[***]

 

[***]

 

[***]

 

[***]

 

[***]

 

[***]

 

[***]

 

B-4

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

[***]

 

[***]

 

[***]

 

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CONFIDENTIAL
    	
NCI — BN   ImmunoTherapeutics CRADA #2377
    

 

PUBLIC HEALTH SERVICE

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

FOR EXTRAMURAL-PHS CLINICAL RESEARCH

 

APPENDIX C

 

MODIFICATIONS TO THE MODEL EXTRAMURAL-PHS CLINICAL CRADA
 (Additions are indicated by underline, deletions by strike-out)

 

Amend or add the following definitions in Article 2:

 

“Confidential Information” means confidential scientific, business, financial information, or Identifiable Private Information provided that Confidential Information does not include:

 

(a)           information that is publicly known or that is available from public sources;

 

(b)                                 information that has been made available by its owner to others without a confidentiality obligation;

 

(c)                                  information that is already known by the receiving Party, or information that is independently created or compiled by the receiving Party without reference to or use of the provided information; or

 

(d)                                 information that relates to potential hazards or cautionary warnings associated with the production, handling, or use of the subject matter of the Research Plan.

 

The Parties agree that Collaborator’s Confidential Information includes information provided by Affiliates of Collaborator, including Bavarian Nordic A/S and Bavarian Nordic GmbH.

 

“Contract” means a Funding Agreement that is a research and development mechanism that provides that the contractor perform for the benefit of the Government, with an expectation of completion of the stated research goals and the delivery of a report, data, materials or other product. Generally, Contracts are administered under the Federal Acquisition Regulations (FAR) codified at Title 48 C.F.R., Chapter 1 or the Health Services Acquisition Regulations (HSAR) codified at Title 48 C.F.R., Chapter 3.

 

Cooperative Research and Development Agreement” or “CRADA” means this Agreement, entered into pursuant to the Federal Technology Transfer Act of 1986, as amended (15 U.S.C. §§ 3710a et seq.), and Executive Order 12591 of April 10, 1987.  For purposes of clarity and avoidance of disputes, the Parties agree that this Agreement is not a Contract, Cooperative Agreement, Funding Agreement or Grant.

 

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“Cooperative Agreement” means a Funding Agreement that is a species of a Grant, whereby the funding Federal agency intends to be substantially involved in carrying out the research program.

 

“CRADA Data” means information developed by or on behalf of the Parties in during the performance of the Research Plan, including  Summary Data and Clinical Data in ICD’s Possession and Control, but excluding Raw Data (that is not otherwise Clinical Data in ICD’s Possession and Control).

 

“CTA” means Clinical Trial Agreement.

 

“CTEP” means the Cancer Therapy Evaluation Program, DCTD, NCI, a program within NCI which plans, assesses and coordinates all aspects of clinical trials including extramural clinical research programs, internal resources, treatment methods and effectiveness, and compilation and exchange of data.

 

“DTP” means Developmental Therapeutics Program, DCTD, NCI, the program within the NCI which coordinates pre-clinical development of agents to be evaluated in DCTD-sponsored clinical trials.

 

“DCTD” means Division of Cancer Treatment and Diagnosis, NCI.

 

“FDA” means U.S. Food and Drug Administration.

 

“Funding Agreement” means a Contract, Grant, or Cooperative Agreement entered into between a Federal agency and another party for the performance of experimental, developmental or research work funded in whole or in part by the Federal Government.

 

“Grant” means a Funding Agreement that is an award of financial assistance which may be provided for support of basic research in a specific field of interest to the funding Federal agency.

 

“Multi-Party Data” means clinical data from clinical studies sponsored by NCI pursuant to CTAs or CRADAs, where such data are collected under protocols involving combinations of investigational agents from more than one CTA or CRADA collaborator.

 

“Protocol Review Committee” (or “PRC”) means the CTEP/DCTD committee that reviews and approves studies involving NCI investigational agents and/or activities supported by NCI.

 

“Test Article” means, in accordance with 21 C.F.R. § 50.3(j), any drug (including a biological product), medical device, food additive, color additive, electronic product, or any other article subject to regulation under the Federal Food, Drug, and Cosmetic Act that is intended for administration to humans or animals, including a drug or biologic as identified in the Research

 

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Plan and Appendix B, that is used within the scope of the Research Plan.  The Test Article may also be referred to as Investigational Agent, Study Material, or Study Product. is further characterized below as “Investigational Agent”, “PROSTVAC VF”, CRADA Materials or “Research Agent”, depending on the regulatory stage of Test Article in the product development process.

 

Under this Agreement, the Test Article to be studied in clinical trials pursuant to the Research Plan is also referred to as the “Investigational Agent.”  The Investigational Agent is PROSTVAC VF, a vaccine for the treatment of prostate cancer comprised of the combination of (i) PSA/TRICOM in a recombinant vaccinia virus vector and (ii) PSA/TRICOM in a recombinant fowlpox vector.

 

Under this Agreement, the Test Article to be studied in pre-clinical studies (not in humans) is referred to as the “Research Agent.”  The Research Agent is recombinant pox virus based prostate cancer vaccines and is also CRADA Materials.  In the event that, during the term of this CRADA, the parties mutually agree to advance one or more Research Agents to clinical trials in Human Subjects, the parties will negotiate in good faith appropriate amendments to this CRADA.

 

For purposes of clarity, the parties agree that the Investigational Agent does not include MVA-BN® or any agent proprietary to a third party in a Multi Party study pursuant to Article 8.9. Test Article as defined above is not CRADA Materials.

 

Amend Article 3.1

 

3.1          Performance of Research and Development.  The research and development activities to be carried out under this CRADA will be performed by the Parties in accordance with the Research Plan identified on the Cover Page, as well as and by ICD’s contractors or grantees as described in the Research Plan.  However, ICD’s contractors or grantees are not Parties to the CRADA, and this CRADA does not grant to Collaborator any rights to Inventions made by ICD’s contractors or grantees.  Notwithstanding the forgoing, ICD will include provisions granting Collaborator those rights described in CTEP’s Intellectual Property Option to Collaborators in each Funding Agreement for clinical studies conducted by an extramural Clinical Investigator(web site: http://ctep.cancer.gov/industry). The CRADA PIs will be responsible for coordinating the scientific and technical conduct of this project on behalf of their employers.  Any Collaborator employees who will work at ICD facilities will be required to sign a Guest Researcher or Special Volunteer Agreement appropriately modified in view of the terms of this CRADA.

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

Amend Article 3.3

 

3.3          Use and Disposition of Collaborator Materials and ICD Materials.  Except as otherwise provided in this Section 3.3, Tthe Parties agree to use Collaborator Materials, Test Articles, and ICD Materials only in accordance with the Research Plan and Protocol(s), not to transfer these materials to any third parties except in accordance with the Research Plan and Protocol(s) or as approved by the owning or providing Party, and, upon expiration or earlier termination of this CRADA, to dispose of these materials as directed by the owning or providing Party.

 

Notwithstanding the foregoing, within [***] following the Effective Date, ICD will execute a Notification of Change in Sponsorship, related FDA 1571 Forms, and any other documents required by law to transfer to Collaborator sponsorship of the following for the clinical development and commercialization of Licensed Products and Licensed Processes in the Licensed Field of Use, as those terms are defined in the Patent License Agreement — Exclusive License between PHS and Collaborator (HHS Ref. No. A-332-2007) executed contemporaneously with this CRADA (the “Patent License”):

 

1.              BB-MF 10428 PROSTVAC-VF, Serial #0077; and

2.              BB-MF 5537 (PROSTVAC), 6670 (PROSTVAC), 7421 (rF-PSA); 7646 (PROSTVAC).

 

In the event of the termination of the Patent License prior to the expiration of its term, Collaborator will execute a Notification of Change in Sponsorship, related FDA 1571 Forms, and any other documents required by law to transfer to ICD sponsorship of the INDs and DMFs.

 

Further notwithstanding the foregoing, ICD hereby grants to Collaborator (and its Affiliates, sub-licensees and contractors), and Collaborator accepts a non-exclusive, worldwide, royalty-free license in and to the PROSTVAC Materials (as defined below) to research, develop, make, have made, and use the PROSTVAC Materials. The foregoing license shall not include the right to distribute or sell the PROSTVAC Materials alone to any third party (except for permitted distribution to Affiliates, sub-licensees and contractors) and shall terminate in the event of the termination of the Patent License prior to the expiration of its term.  For the avoidance of doubt, the restriction on the distribution/sale of PROSTVAC Materials alone does not apply to vaccines used in the treatment of prostatic disease, or Licensed Products or Licensed Processes where PROSTVAC Materials are used in combination with Collaborator Materials.  Upon expiration of the Patent License, on a country-by-country basis, the license provided in this paragraph shall be irrevocable.  The foregoing license is predicated on the execution of the Patent License currently under negotiation between Collaborator and NIH (HHS Ref. No. A-332-2007).

 

In addition, until the expiration or earlier termination of this CRADA, ICD shall not transfer any aliquots of the PROSTVAC seed banks, aliquots of PROSTVAC master cell cultures, or any information specific to PROSTVAC to any third party, except for research purposes, in

 

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accordance with the Research Plan and related protocols.  The Parties acknowledge that ICD can share with third parties poxvirus manufacturing know-how in the possession of ICD at the initiation of the CRADA.

 

On and after the expiration or earlier termination of this CRADA and until the expiration or earlier termination of the Patent License, any transfer by ICD to a third party of any aliquots of the PROSTVAC seed banks, aliquots of  PROSTVAC master cell cultures, or any information specific to PROSTVAC shall be for research purposes only. ICD will insure that any transferee is informed of and agrees to the foregoing restrictions.  For purposes of this paragraph, the PROSTVAC seed banks, PROSTVAC master cell cultures or information specific to PROSTVAC means those materials and  information referred to in Appendix B at items 2(a) — (d)) and 3(d), with the exclusion of poxvirus manufacturing know-how, in each case under the heading “Materials/Equipment Contributions.”

 

For purposes of clarity and avoidance of disputes, the rights granted herein to the INDs and the PROSTVAC Materials shall not terminate upon the expiration or earlier termination of this CRADA.

 

“PROSTVAC Materials” means the materials and information listed in Appendix B, Materials/Equipment Contributions, sections 2 and 3 as those sections describe ICD Materials being supplied under the CRADA.

 

Promptly following the Effective Date, the Parties will work diligently to transfer the PROSTVAC Materials to Collaborator.

 

The Parties acknowledge that there may be materials or information related to PROSTVAC in addition to that listed in Appendix B which is necessary or useful for the research, development or commercialization of Licensed Products or Licensed Processes.  In that event, upon request of Collaborator, ICD and Collaborator will work together in good faith to provide such materials or information or access thereto to Collaborator, including executing documents of authorization or permission, and such additional materials or information shall be deemed to be PROSTVAC Materials hereunder.

 

Amend Article 3.6

 

3.6          Clinical Investigator Responsibilities.  The Clinical Investigator will be required to submit, or to arrange for submission of, each Protocol associated with under this CRADA for the study of the Investigational Agent in Human Subjects to all appropriate IRBs, and for ensuring that the IRBs are notified of the role of Collaborator in the research.  In addition to the Protocol all associated documents, including informational documents and advertisements, must be reviewed and approved by the appropriate IRB(s) before starting the research at each Clinical Research Site.  The research will be done in strict accordance with the Protocol(s) and no

 

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substantive changes in a finalized Protocol will be made unless mutually agreed upon, in writing, by the Parties.  Research will not commence (or will continue unchanged, if already in progress) until each substantive change to a Protocol, including those required by either the FDA or the IRB, has been integrated in a way acceptable to the Parties, submitted to the FDA (if applicable) and approved by the appropriate IRBs.

 

Amend Article 3.7

 

3.7          Investigational New Drug Applications.

 

3.7.1       If an IND is required either ICD or Collaborator, DCTD, NCI, as indicated in the Research Plan, will prepare and submit an IND, sponsor clinical trials that are subject to this CRADA, and all Clinical Investigators participating in DCTD-sponsored clinical trials must have completed registration documents on file (1572 forms) with CTEP.

 

3.7.2       If ICD elects to file its own IND, To support the DCTD IND, Collaborator agrees to provide ICD DCTD with background data and information necessary to support the IND, either directly or by right of cross reference as provided in the next sentence.  Collaborator further agrees to provide a letter of cross-reference to all pertinent regulatory filings including an IND(s) and/or DMF(s) sponsored by Collaborator.  Collaborator’s employees will be reasonably available to respond to inquiries from the FDA regarding information and data contained in the Collaborator’s IND, DMF, other filings, or other information and data provided to ICD DCTD by the Collaborator pursuant to this Article 3.7.  If ICD DCTD has provided information or data to assist Collaborator in its IND filing, ICD DCTD will provide a letter of cross reference to its IND and respond to inquiries related to information provided by ICD DCTD, as applicable.

 

3.7.3       If Collaborator supplies Confidential Information to ICD DCTD in support of an IND filed by ICD DCTD, this information will be protected in accordance with the corresponding confidentiality provisions of Article 8.

 

3.7.4       Collaborator or NCI may sponsor its own clinical trials and hold its own IND for studies which may be performed within or outside the scope of this CRADA and the Research Plan.  Collaborator and ICD shall use reasonable efforts to coordinate the ICD-sponsored studies under this CRADA and the Collaborator-sponsored studies so that these studies do not These studies, however, should not adversely affect the ability to accomplish the goal of the Research Plan or Collaborator’s clinical development plans, for example, by competing for the same study population.  All data from the those clinical trials or studies conducted outside of the scope of the CRADA by Collaborator are

 

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proprietary to Collaborator for purposes of this CRADA.  Collaborator and NCI mutually agree to notify the other party in advance of the initiation by Collaborator or NCI of any clinical study outside of the scope of the CRADA which involves Investigational Agent.

 

3.7.5    In the event that Canadian institutions are participating on DCTD-sponsored clinical trials, Collaborator will need to assist in the submission of the regulatory documents to the Canadian Health Products and Food Branch to allow for such participation. This may include a letter of cross-reference to an existing Clinical Trials Application (CTA) or a DMF, including supporting documentation on the production of the Investigational Agent. The forms and procedures for preparing Canadian CTAs are available at http://www.hc-sc.gc.ca/hpfb-dgpsa/index_e.html.

 

Amend Article 3.8

 

3.8          Research Agent and Test Article Information and Supply.  Collaborator agrees to provide ICD DCTD without charge and on a schedule that will ensure adequate and timely performance of the research, a sufficient quantity of formulated and acceptably labeled, clinical-grade Test Article (and, as required by the Protocol(s), Placebo) to complete the clinical trial(s) agreed to and approved under this CRADA and, as agreed in the Research Plan, a sufficient quantity of Research Agent to complete preclinical studies agreed to and approved under this CRADA.  Collaborator will provide a Certificate of Analysis to ICD DCTD for each lot of the Test Article Investigational Agent provided.  It is understood that DCTD shall take responsibility for and reasonable steps to maintain appropriate records and assure appropriate supply, handling, storage, distribution and usage of these materials in accordance with the terms of this Agreement, the Protocol(s) and any applicable laws and regulations relating thereto.  Notwithstanding the foregoing, ICD acknowledges that Collaborator will be required to develop an appropriate manufacturing process, test such process, and qualify an appropriate manufacturing facility, all as required by the FDA and cGMP, before the manufacture of cGMP Investigational Agent for provision to DCTD can commence, and that the development of an appropriate manufacturing process depends upon the receipt of manufacturing-related information in the possession of ICD.

 

Collaborator agrees to supply sufficient inventory to ensure adequate and timely supply of Investigational Agent for mutually agreed upon Protocol(s). DCTD will provide updated forecasts of amounts of Investigational Agent anticipated for ongoing and anticipated studies.  Collaborator further agrees to provide draft Investigational Agent labels to the NCI Pharmaceutical Management Branch (PMB) for review and agrees to reasonable labeling revisions to comply with DCTD label guidelines.  NCI NSC (National Service Center) numbers will be required to be on the label of Investigational Agent for all DCTD-sponsored clinical trials.

 

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Furthermore, Collaborator agrees to provide without charge Investigational Agent or unformulated analytical grade Investigational Agent or metabolites, if available, to DCTD to supply to NCI investigators for the development of mutually agreed upon analytical assays, ancillary correlative studies and non-clinical studies conducted in conjunction with DCTD-sponsored  protocols.

 

Collaborator agrees to allow Investigational Agent and Research Agent, as provided in the Research Plan, to be distributed to NCI investigators for mutually agreeable non-clinical studies as set forth in the Research Plan designed to enhance the basic understanding and development of Test Articles.  These will include non-clinical studies designed to support clinical trials in pediatric patients; non-clinical combination studies to provide data in support of a clinical trial and other pertinent requests.  All NCI investigators will sign Material Transfer Agreements (MTAs) that acknowledge the proprietary nature of the Test Articles to Collaborator and with respect to Investigational Agent and Research Agents include intellectual property and publication provisions consistent with those in this Agreement and CTEP’s Intellectual Property Option to Collaborator for clinical trials (web site: http://ctep.cancer.gov/industry).

 

Collaborator agrees to provide Investigational Agent and Research Agent to DCTD for DCTD to conduct mutually agreed upon pre-clinical studies (“DCTD Pre-clinical Studies”) as described in the Research Plan aimed at enhancing the understanding of the mechanism of action of Investigational Agent and its targets and optimizing its clinical development program.  DCTD’s work may also include such activities as the development of assays to detect target modulation, biomarker studies, and pharmacodynamic analyses performed in conjunction with the NCI-sponsored clinical studies.  In accordance with this Agreement, DCTD will update Collaborator regarding progress and findings to help ensure optimal designs and avoid duplication. DCTD will inform Collaborator prior to the execution of any DCTD Pre-clinical Studies involving  Investigational Agent or Research Agents.  Collaborator may, at their discretion, provide comment on any of the planned studies. Manuscripts and presentations related to these studies will be handled in accordance with Article 8.7 of this CRADA.

 

The Parties shall agree upon the Party to take the lead in preparing the Investigator’s Brochure (IB) for Investigational Agent.  The Party that does not prepare the IB shall provide the other Party with information in its possession as reasonably requested by the preparing party to support the preparation of   the IB and all subsequent revisions/editions. If DCTD prepares the IB, Collaborator will also be responsible for the costs associated with the preparation of the IB as detailed in Appendix B.  In addition to being filed to the DCTD IND, the IB will be on file in the PMB and will be distributed to all investigators participating on a clinical trial using the Investigational Agent.  Distribution will be accompanied by a statement about the confidentiality of the document and it is anticipated that distribution will be electronic.   All electronic distribution will be done using Adobe Acrobat PDF.  Any IB received by the PMB that is not in this format will be converted before distribution.  Hard copy IBs should be sent to IB Coordinator, Pharmaceutical Management Branch, CTEP, DCTD, NCI, 6130 Executive Blvd, Room 7149, Rockville, MD 20852.  Electronic versions should be emailed to the IB Coordinator 

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

at IBCoordinator@mail.nih.gov.

 

Amend Article 3.9

 

3.9          Test Article Investigational Agent Delivery and Usage.  Collaborator will ship the Test Article Investigational Agent and, if required, Placebo to ICD NCI or its designee in containers marked in accordance with 21 C.F.R. § 312.6.  Any Investigational Agent sent to the NCI Clinical Repository shall be sent from a U.S. facility and not directly from the foreign manufacturer. In other words, the Collaborator will be responsible for importing/shipping of the materials from the foreign manufacturer to their U.S. facility, then to the NCI Clinical Repository.   NCI agrees and will assure that appropriate records of Test Articles are kept and will take reasonable steps to ensure the Investigational Agent is used in accordance with the applicable protocols and FDA regulations.  ICD agrees that the Clinical Investigators will keep appropriate records and take reasonable steps to ensure that the Test Article Investigational Agent is used in accordance with the Protocol(s) and applicable FDA regulations.  In addition, ICD NCI agrees that all Clinical and DCTD Investigators will agree that the Test Article Investigational Agent and Research Agent (and all Confidential Information supplied by Collaborator relating to the Test Article Investigational Agent and Research Agent) will be used solely for the conduct of the CRADA research and development activities.  Furthermore, ICD NCI agrees that no analysis or modification of the Test Article Investigational Agent or Research Agent will be performed without Collaborator’s prior written consent.  At the completion of the Research Plan or when an Investigational Agent or Research Agent supply is no longer suitable for clinical or preclinical use, NCI will assure that any unused quantity of Test Article Investigational Agent and Research Agent will be returned to Collaborator at Collaborator’s expense or disposed of as directed by Collaborator at Collaborator’s expense.  Pharmacy contacts at ICD or its designee will be determined by ICD and communicated to Collaborator. The contact person for NCI will be [***] and the Collaborator contact will be [***]

 

Amend Article 3.10

 

3.10        Monitoring.

 

3.10.1     The Sponsor or its designee DCTD, NCI will be primarily responsible for monitoring clinical sites and for assuring the quality of all clinical data, unless otherwise stated in the Research Plan. Monitoring will comply with FDA Good Clinical Practice (international Conference on Harmonisation (ICH) E6:  Good Clinical Practice:  Consolidated Guidance; 62 Federal Register 25, 691 (1997)). the DCTD guidelines as described on the CTEP website at: http://ctep.cancer.gov/monitoring/index.html. The other Party may also perform quality assurance oversight.  The monitor will communicate significant Protocol violations and submit documentation of monitoring outcomes on Protocol

 

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insufficiencies to the other Party in a timely manner.

 

3.10.2     Subject to the restrictions in Article 8 concerning IPI, and with reasonable advance notice and at reasonable times, ICD DCTD will permit Collaborator or its designee(s) access to laboratories and clinical site(s) to monitor the conduct of the research, as well as.  Collaborator may also make arrangements with DCTD to audit source documents containing Raw Data, at Collaborator’s expense, to the extent necessary to verify compliance with FDA Good Laboratory Practices and Good Clinical Practice, and the Protocol(s).

 

Amend Article 3.11

 

3.11        FDA Meetings/Communications.  All formal meetings with the FDA concerning any clinical trial within the scope of the Research Plan will be discussed by Collaborator and ICD in advance.  Each Party reserves the right to take part in setting the agenda for, to attend, and to participate in these meetings.  The Sponsor will provide the other Party with copies of FDA meeting minutes, all transmittal letters for IND submissions, IND safety reports, formal questions and responses that have been submitted to the FDA, Annual Reports, and official FDA correspondence, pertaining either to the INDs under this CRADA or to the Clinical Investigators on Protocols performed in accordance with the Research Plan, except to the extent that those documents contain the proprietary information of a third party or dissemination is prohibited by law.

 

Add a new Article 3.12 as follows:

 

3.12        Steering Committee and CRADA Research.  The Parties agree to establish a Steering Committee comprising at least the CRADA Principal Investigators to conduct and monitor the proposed and ongoing clinical studies and non-clinical research of the Investigational Agent and Research Agents in accordance with the CRADA Research Plan.  Members of the Steering Committee shall continue to remain employed by their respective employers under their respective terms of employment.

 

The Steering Committee will meet at least once each six months on a mutually-agreeable date and time, and may meet more often as necessary to monitor the ongoing clinical studies and non-clinical research conducted pursuant to the Research Plan.   A meeting of the Steering Committee may be initiated by the Principal Investigator for either party on written notice which will include a proposed agenda for the meeting. The agenda for each meeting will include a report on the status and results to date for each active clinical trial or non-clinical research study.  The Steering Committee will endeavor to make all decisions by consensus.

 

The non clinical and clinical development of Investigational Agent and Research Agents under the CRADA Research Plan shall be a collaborative undertaking by Collaborator and NCI.

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

Details of this development beyond those set forth in the CRADA Research Plan shall be formulated and/or discussed in Steering Committee meeting(s) before implementation of large-scale or resource intensive clinical studies.  The clinical development plans formulated by the Steering Committee shall be implemented either intramurally at the NCI or extramurally under NCI-sponsored Funding Agreements.

 

Additional CRADA information, including Steering Committee meeting reports, Protocol Review Committee records, clinical trial protocols, Institutional Review Board approval information, IND and general regulatory information, and non-clinical and clinical data in NCI’s possession and control shall remain on file with NCI and available for review and, as appropriate under this CRADA, for copying by Collaborator.  ICD agrees to provide copies of any CRADA Data reasonably requested by Collaborator to support any Collaborator regulatory filing in any jurisdiction and to provide Collaborator with a right of cross reference to any IND sponsored by DCTD under this CRADA.

 

Add a new Article 3.13 as follows:

 

3.13        Clinical Protocols.  Clinical protocol Letters of Intent (LOI) or concepts for each study within the scope of the CRADA Research Plan will be solicited by CTEP from selected intramural and extramural Clinical Investigators. Clinical protocols from each DCTD- and Collaborator-approved LOI or concept will describe in detail the research to be conducted at each center and must be submitted to the Protocol Review Committee (PRC) for review and approval prior to implementation.  Each clinical protocol received by NCI will be forwarded electronically to Collaborator for review and comment approximately two weeks before it is reviewed by the PRC.  Comments from Collaborator received by CTEP before the PRC meeting will be discussed by the PRC, will be given due consideration, and will be incorporated into the protocol, absent good cause.  Comments from either Collaborator or the CTEP staff that are agreed upon in the PRC meeting will be formatted as a consensus review, which is returned to the Clinical Investigator for necessary and/or suggested changes before the protocol can be given final approval and submitted to the FDA.  A copy of the final approved protocol will be forwarded to Collaborator within 24 to 48 hours of its submission to the FDA.

 

Amend Article 4.2

 

4.2          Final Research and Development Reports. ICD and Collaborator will share CRADA Data as it is developed pursuant to the Research Plan, and will provide final reports of the results of non-clinical studies within [***] of the completion of the study and final reports of the results of clinical trials within [***] of the completion of the trial if available. Collaborator may contract directly with the extramural Clinical Investigator for preparation of a final report if no publication is provided.  The Parties will exchange final reports of their results within [***] after the expiration or termination of this CRADA.  These reports will set forth the technical progress made; any publications arising from the research; and the existence of invention disclosures of potential CRADA Subject Inventions and/or any corresponding

 

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Patent Applications.  Abstracts and publications provided to CTEP by investigators and further provided by CTEP to Collaborator will fulfill this final report obligation. Source documents from clinical studies under this CRADA containing Raw Data in the possession of either Party shall be made available to the other Party upon reasonable request for review and, as appropriate under this CRADA, for copying.

 

Amend Article 4.3

 

4.3          Fiscal Reports.  If Collaborator has agreed to provide funding to ICD under this CRADA and upon the request of Collaborator, ICD will submit to Collaborator a statement of all costs incurred by ICD for the CRADA then concurrent with the exchange of final research and development reports according to Paragraph 4.2.  If the CRADA has been terminated, ICD will specify any costs incurred before the date of termination for which ICD has not received funds from Collaborator, as well as for all reasonable termination costs including the cost of returning Collaborator property or removal of abandoned Collaborator property, for which Collaborator will be responsible.

 

Amend Article 4.4

 

4.4          Safety Reports.  In accordance with FDA requirements, the Sponsor will establish and maintain records and submit safety reports to the FDA, as required by 21 C.F.R. § 312.32 and 21 C.F.R. 812.150(b)(1), or other applicable regulations.  In the conduct of research under this CRADA, the Parties will comply with specific ICD guidelines and policies for reporting ADEs and AEs, as well as procedures specified in the Protocol(s).  The Sponsor must provide the other Party with copies of all Safety Reports concurrently with their submission to the FDA, and with any other information affecting the safety of Human Subjects in research conducted under this CRADA.  DCTD shall report all serious and/or unexpected Adverse Events to FDA in accordance with the reporting obligations of 21 CFR 312.32 and will, within 24 to 48 hours of notification to FDA, forward all such reports to Collaborator.  All other Adverse Event reports received by DCTD shall be reported to the FDA consistent with 21 CFR 312.32 and 312.33.  In the event that Collaborator informs the FDA of any serious and/or unexpected Adverse Events related to clinical trials of the Investigational Agent, Collaborator must notify the NCI at the same time by sending the reports to CTEPSupportAE@tech-res.com.  NCI will then notify the Clinical Investigator(s) conducting studies under DCTD-sponsored protocols, if appropriate.

 

Amend Article 4.5

 

4.5          Annual Reports.  The Sponsor DCTD will provide the other Party Collaborator a copy of the Annual Report concurrently with the submission of the Annual Report to the FDA.  Annual Reports will be kept confidential in accordance with Article 8.  Collaborator will provide DCTD with a copy of its Annual Report to the FDA if Collaborator is sponsoring studies of Investigational Agent under its own IND.

 

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Amend Article 6.1

 

6.1          Ownership of CRADA Subject Inventions, CRADA Data, and CRADA Materials.  Subject to the Government license described in Paragraph 7.5, the sharing requirements of Paragraph 8.1 and the regulatory filing requirements of Paragraph 8.2, the producing Party will retain sole ownership of and title to all CRADA Subject Inventions, all copies of CRADA Data, and all CRADA Materials produced solely by its employee(s).  The Parties will own jointly all CRADA Subject Inventions invented jointly and all CRADA Materials developed jointly.  A PHS contractor’s or grantee’s rights in data it generates will not be affected by this CRADA; provided, however, that ICD will use its reasonable efforts to require each such contractor or grantee to share such data with and permit use of such data by Collaborator in accordance with the terms of this CRADA.

 

Amend Article 6.3

 

6.3          Filing of Patent Applications.  Each Party will make timely decisions regarding the filing of Patent Applications on the CRADA Subject Inventions made solely by its employee(s), and will notify the other Party in advance of filing.  Collaborator will have the first opportunity to file a Patent Application on joint CRADA Subject Inventions and will notify PHS of its decision within sixty (60) days of an Invention being reported or at least thirty (30) days before any patent filing deadline, whichever occurs sooner.  If Collaborator fails to notify PHS of its decision within that time period or notifies PHS of its decision not to file a Patent Application, then PHS has the right to file a Patent Application on the joint CRADA Subject Invention.  Neither Party will be obligated to file a Patent Application; provided, however, that at the written request of Collaborator and at Collaborator’s sole cost and expense, Collaborator may request for ICD to file a Patent Application on any CRADA Subject Invention made solely by ICD employee(s).  Collaborator will place the following statement in any Patent Application it files on a CRADA Subject Invention:  “This invention was created in the performance of a Cooperative Research and Development Agreement with the National Institutes of Health, an Agency of the Department of Health and Human Services.  The Government of the United States has certain rights in this invention.”  If either Party files a Patent Application on a joint CRADA Subject Invention, then the filing Party will include a statement within the Patent Application that clearly identifies the Parties and states that the joint CRADA Subject Invention was made under this CRADA.

 

Amend Article 7.2

 

7.2          Collaborator’s License Option to CRADA Subject Inventions.  With respect to Government rights to any CRADA Subject Invention made solely by an ICD employee(s) or made jointly by an ICD employee(s) and a Collaborator employee(s) for which a Patent Application was filed, PHS hereby grants to Collaborator an exclusive option to elect an exclusive, or co-exclusive, if applicable, or nonexclusive commercialization license.  The option to elect a co-exclusive license shall apply when a CRADA Subject Invention is also a CRADA

 

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Subject Invention under another CRADA resulting from mutually agreed upon studies as described in Article 8.9 and the field of use of this co-exclusive license shall be to the use of the combination of the Investigational Agent with another agent(s) commensurate with the scope of the Research Plan.  The license will be substantially in the form of the appropriate model PHS license agreement and will fairly reflect the nature of the CRADA Subject Invention, the relative contributions of the Parties to the CRADA Subject Invention and the CRADA, a plan for the development and marketing of the CRADA Subject Invention, the risks incurred by Collaborator, and the costs of subsequent research and development needed to bring the CRADA Subject Invention to the marketplace.  The field of use of the license will not exceed the scope of the Research Plan.

 

Amend Article 7.3

 

7.3          Exercise of Collaborator’s License Option.  To exercise the option of Paragraph 7.2 Collaborator must submit a written notice to the PHS Patenting and Licensing Contact identified on the Contacts Information Page (and provide a copy to the ICD Contact for CRADA Notices) within three (3) months after either (i) Collaborator receives written notice from PHS that the Patent Application has been filed or (ii) the date on which Collaborator files the Patent Application.  The written notice exercising this option will include a completed “Application for License to Public Health Service Inventions” and will initiate a negotiation period that expires nine (9) months after the exercise of the option.  If PHS has not responded in writing to the last proposal by Collaborator within this nine (9) month period, the negotiation period will be extended to expire one (1) month after PHS so responds, during which month Collaborator may accept in writing the final license proposal of PHS.  In the absence of Collaborator’s exercise of the option, or upon election of a nonexclusive license, PHS will be free to license the CRADA Subject Invention to others.  These time periods may be extended at the sole discretion of PHS upon good cause shown in writing by Collaborator.

 

Amend Article 7.6

 

7.6          Third Party License.  Pursuant to 15 U.S.C. § 3710a(b)(1)(B), if PHS grants Collaborator an exclusive, or co-exclusive license to a CRADA Subject Invention made solely by an ICD employee or jointly with a Collaborator employee, the Government will retain the right to require Collaborator to grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense to use the CRADA Subject Invention in Collaborator’s licensed field of use on terms that are reasonable under the circumstances; or, if Collaborator fails to grant a license, to grant a license itself.  The exercise of these rights by the Government will only be in exceptional circumstances and only if the Government determines (i) the action is necessary to meet health or safety needs that are not reasonably satisfied by Collaborator, (ii) the action is necessary to meet requirements for public use specified by federal regulations, and such requirements are not reasonably satisfied by Collaborator; or (iii) Collaborator has failed to comply with an agreement containing provisions described in 15 U.S.C. § 3710a(c)(4)(B).  The determination made by the Government under this Paragraph is subject to administrative appeal

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

and judicial review under 35 U.S.C. § 203(2).

 

Amend Article 8.1

 

8.1          Right of Access to CRADA Data and CRADA Materials.  ICD and Collaborator agree to exchange all CRADA Data and to share all CRADA Materials.  If the CRADA is terminated  pursuant to Sections 10.2 or 10.3, both Parties agree to provide CRADA Materials in quantities needed to complete the Research Plan; provided, however, that either Party’s obligation shall be limited to supplying quantities of CRADA Materials sufficient to complete activities under the Research Plan for the first [***] following termination of the CRADA.  Such provision will occur before the termination date of the CRADA or sooner, if required by the Research Plan.  If Collaborator possesses any human biological specimens from clinical trials under the CRADA, the specimens must be handled as described in the Protocol or as otherwise directed by ICD before the termination date of the CRADA.

 

Amend Article 8.2

 

8.2          Use of CRADA Data and CRADA Materials.  The Parties will be free to utilize CRADA Data and CRADA Materials internally for their own purposes, consistent with their obligations under this CRADA.  ICD may share CRADA Data or CRADA Materials with any contractors, grantees, or agents it has engaged to conduct the CRADA research and development activities, provided the obligations of this Article 8.2 are simultaneously conveyed. Collaborator may use CRADA Data, Raw Data, and CRADA Materials for the research, development and commercialization of products and may share CRADA Data, Raw Data or CRADA Materials with its Affiliates and development partners and with any contractors Affiliates, or agents it has engaged to conduct the CRADA research and development activities, provided the obligations of this Article 8.2 are simultaneously conveyed.

 

Amend Article 8.6

 

8.6          Duration of Confidentiality Obligation.  The obligation to maintain the confidentiality of Confidential Information will expire at the earlier of the date when the information is no longer Confidential Information as defined in Paragraph 2.4 Article 2 or three (3) years after the expiration or termination date of this CRADA, except for IPI, for which the obligation to maintain confidentiality will extend indefinitely, and manufacturing know how and information related to poxvirus-based cancer vaccine process development for which the obligation to maintain confidentiality shall extend until such information is no longer Confidential Information.  Collaborator may request an extension to this term when necessary to protect Confidential Information relating to products not yet commercialized.

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

Amend Article 8.7

 

8.7          Publication.  The Parties are encouraged to make publicly available the results of their research and development activities.  Before either Party Collaborator or NCI CCR investigator(s) submits a paper or abstract for publication or otherwise intends to publicly disclose information about a CRADA Subject Invention, CRADA Data, or CRADA Materials, the other Party will have thirty (30) days to review proposed manuscripts and three (3) business  days to review proposed abstracts to assure that Confidential Information is protected.  Either Party may request in writing that the a proposed publication or other disclosure be delayed for up to thirty (30) additional days as necessary to file a Patent Application.  Manuscripts to be submitted for publication by NCI non-CCR investigators will be sent to NCI’s Regulatory Affairs Branch [***] for forwarding to Collaborator for review as soon as they are received and in compliance with the timelines outlined above, to allow for preservation of U.S. or foreign patent rights. In addition, NCI non-CCR investigators will provide all manuscripts and abstracts to NCI’s Regulatory Affairs Branch [***] at the same time they provide them to Collaborator. Abstracts to be presented by NCI investigators will be sent to NCI’s Regulatory Affairs Branch [***] for forwarding to Collaborator as soon as they are received, preferably no less than [***].

 

Amend Article 8.8

 

8.8          Clinical Investigators’ Research and Development Activities.  In pursuing the development of  Investigational Agent and Research Agents pursuant to this CRADA, NCI may utilize contractors and extramural investigators that are not NCI employees for part or all of the completion of this Research Plan, which may cover non-clinical and clinical studies.  Participation in DCTD-sponsored clinical trials by these investigators shall be determined after competitive solicitation and review of Protocol Letters of Intent (LOIs) and study protocols by CTEP, NCI.  All Funding Agreements, for the conduct of extramural clinical trials will include CTEP’s Intellectual Property Option to Collaborator, Terms of Award Addition, offering Collaborator first rights of negotiation to extramural inventions (web site: http://ctep.cancer.gov/industry).  Although this CRADA does not grant to Collaborator any rights to Inventions made or Raw Data generated by ICD’s NCI’s contractors or grantees, as they are not parties to this CRADA, ICD NCI agrees that:

 

8.8.1       Subject to the other provisions of Article 8 of this CRADA, ICD NCI will maintain, to the extent permitted by law, all Clinical Data in ICD’s NCI’s Possession and Control as Confidential Information, and make them available to Collaborator for its own use and for exclusive use in obtaining regulatory approval for the commercial marketing of Test Article Investigational Agent and related CRADA Subject Inventions.  Similarly, NCI will also maintain, to the extent permitted by law, all data generated in non-clinical studies that are in NCI’s possession and control as Confidential Information in accordance with Article 8.2.1, and make them available to Collaborator for its own use and for use in obtaining regulatory approval for the commercial marketing of  Test

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

Articles and related CRADA Subject Inventions.  Collaborator will not publish any such data provided under the CRADA without NCI’s permission.  Accordingly, said data shall not be transferable by Collaborator to any third party, except to Collaborator Affiliates and development partners, without the written permission of the NCI. Following NCI’s permission, the third party shall enter into a Confidential Disclosure Agreement with the NCI and Collaborator, if requested by NCI, before any data can be transferred. The Parties agree that the forgoing restrictions on publication do not apply to data submitted in connection with any regulatory filing by Collaborator.

 

8.8.2       With regard to Collaborator’s or its Affiliate(s)’ Confidential Information, ICD NCI will require the Clinical Investigators to agree to confidentiality provisions at least as restrictive as those provided in this CRADA and to Collaborator’s use of data in accordance with Paragraph 8.8.1 for obtaining regulatory approval for marketing Test Articles.

 

8.8.3 If Collaborator wants access to Raw Data or any other data in the possession of the Clinical Investigators working with Test Article Investigational Agent under a Funding Agreement or other agreements, Collaborator must first contact the CRADA PI [***].  Subsequent to authorization by RAB, Collaborator may directly contact the Clinical Investigators.  Collaborator will bear any costs associated with Raw Data provided in formats customized for Collaborator, which costs will be paid by Collaborator directly to the Clinical Investigators.

 

8.8.4 Collaborator’s right to access Clinical Data in ICD’s NCI’s Possession and Control under Paragraph 8.8 is dependent upon Collaborator’s continued development and commercialization of Investigational Agent.  If Collaborator fails to continue development or commercialization of Investigational Agent without the transfer of its development efforts to another party within ninety (90) days of discontinuation, ICD NCI has the right to make Clinical Data in ICD’s NCI’s Possession and Control available to a third party.

 

Add a new Article 8.9 as follows:

 

8.9          Multi-Party Data Rights. For clinical protocol(s) where Investigational Agent is used in combination with another investigational agent supplied to NCI pursuant to a CTA or CRADA between NCI and an entity not a Party to this CRADA [hereinafter referred to as “Third Party”], the access and use of Multi-Party Data by the Collaborator and Third Party shall be co-exclusive as follows:

 

8.9.1       NCI will provide both Collaborator and Third Party with notice regarding the existence and nature of the agreements governing their collaborations with NIH, the

 

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design of the proposed combination protocol(s), and the existence of any obligations that might restrict NCI’s participation in the proposed combination protocols.

 

8.9.2       Collaborator shall agree to permit use of the Multi-Party Data from these trials by Third Party to the extent necessary to allow Third Party to develop, obtain regulatory approval for, or commercialize its own investigational agent(s).  However, this provision will not apply unless Third Party also agrees to Collaborator’s reciprocal use of Multi-Party Data.

 

8.9.3       Collaborator and Third Party must agree in writing prior to the commencement of the combination trial(s) that each will use the Multi-Party Data solely for the development, regulatory approval, and commercialization of its own investigational agent(s).

 

Add a new Article 8.10 as follows:

 

8.10        Access, review and receipt of Identifiable Private Information. Collaborator access to and review of Identifiable Private Information shall be only for on-site quality auditing. Collaborator will receive Identifiable Private Information only if necessary for purposes of satisfying FDA or other health authorities’ reporting requirements, and for internal research purposes, directly related to obtaining regulatory approval of Investigational Agent.  Collaborator is prohibited from access, review, receipt, or use of such information for other purposes.  All IRB approved protocols and informed consent documents related to this research project will clearly describe this practice.  If the Collaborator will have access to Identifiable Private Information, the protocol and the informed consent must clearly state (i) the existence of the Collaborator; (ii) the Collaborator’s access to Identifiable Private Information, if any; and (iii) the extent to which confidentiality will be maintained.  For clinical protocol(s) involving a third party, the other party’s access, review, receipt, or use of Identifiable Private Information shall be subject to the same limitations as described in this Article 8.10.

 

Amend Article 9.1.2

 

9.1.2                     To the best of its knowledge and belief, neither ICD nor any of its personnel involved in this CRADA is presently subject to debarment or suspension by any agency of the Government which would directly affect its performance of the CRADA.  Should ICD or receive notice that any of its personnel or Clinical Investigators, contractors or grantees involved in this CRADA may be debarred or suspended during the term of this CRADA, ICD will notify Collaborator within thirty (30) days of receipt of such final notice.

 

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Amend Article 9.2.2

 

9.2.2                     To the best of its knowledge and belief, Nneither Collaborator nor any of its personnel involved in this CRADA, including Affiliates, agents, and contractors are presently subject to debarment or suspension by any agency of the Government.  Should Collaborator receive notice that it or any of its personnel involved in this CRADA may be debarred or suspended during the term of this CRADA, Collaborator will notify ICD within thirty (30) days of receipt of such notice.

 

9.2.4                     The Test Article Investigational Agent provided has been produced in accordance with the FDA’s current Good Manufacturing Practice set out in 21 C.F.R. §§ 210-211, and ICH QA7, and meets the specifications cited in the Certificate of Analysis and the information supplied by Collaborator for the Investigator’s Brochure provided.

 

Amend Article 10.3

 

10.3                        Unilateral Termination.  Either ICD or Collaborator may unilaterally terminate this CRADA at any time by providing written notice at least sixty (60) days before the desired termination date.  ICD may, at its option, retain funds transferred to ICD before unilateral termination by Collaborator for use in completing the Research Plan.  If Collaborator terminates this Agreement before the completion of all approved or active Protocol(s), then Collaborator will supply enough Test Article (and Placebo, if applicable) to complete these Protocol(s) unless termination is for safety concerns.  In the event of termination of the CRADA prior to the expiration date, or upon expiration of the CRADA, Collaborator will continue to provide cross reference letters to its DMFs and/or INDs in order to enable ICD to complete the studies approved, initiated or active.

 

Amend Article 10.6

 

10.6        Collaborator Failure to Continue Development.  If Collaborator suspends development of the Test Article Investigational Agent without the transfer of its active development efforts, assets, and obligations to a third party within ninety (90) days of discontinuation, Collaborator agrees that ICD may continue developing the Test Article Investigational Agent.  In that event, the following will apply:

 

10.6.1     Collaborator agrees to transfer to ICD all information necessary to enable ICD to contract for the manufacture of the Test Article Investigational Agent and, unless abandoned for reasons relating to safety as determined by the data safety monitoring board, to provide the Test Article Investigational Agent (and Placebo, if any) in Collaborator’s inventory to ICD  In addition, Collaborator will cause to be manufactured or arrange for an independent contractor to manufacture and provide Investigational

 

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Agent to NCI in sufficient quantity to complete (i) the preclinical and clinical studies of Investigational Agent then planned or (ii) for the preclinical and clinical studies then planned for the two years following such discontinuation, whichever is lesser.

 

10.6.2     Further, Collaborator hereby grants to ICD a nonexclusive, irrevocable, world-wide, paid-up license to practice, or have practiced for or on behalf of the Government, any Background Invention that Collaborator may currently have or will obtain on the Test Article Investigational Agent, its manufacture, or on any method of using the Test Article Investigational Agent for the indication(s) described in the Research Plan, including the right to sublicense to third parties

 

Amend Article 12.2

 

12.2        Indemnification and Liability.  Collaborator agrees to hold the Government harmless and to indemnify the Government for all liabilities, demands, damages, expenses and losses arising out of the use by Collaborator for any purpose of the CRADA Data, CRADA Materials or CRADA Subject Inventions produced in whole or part by ICD employees under this CRADA, unless due to breach of this Agreement or the negligence or willful misconduct of ICD, its employees, or agents.  The Government has no statutory authority to indemnify Collaborator.  Each Party otherwise will be liable for any claims or damages it incurs in connection with this CRADA, except that ICD, as an agency of the Government, assumes liability only to the extent provided under the Federal Tort Claims Act , 28 U.S.C. Chapter 171.

 

Amend Article 13.9

 

13.9        Independent Contractors.  The relationship of the Parties to this CRADA is that of independent contractors and not agents of each other or joint venturers or partners.  Each Party will maintain sole and exclusive control over its personnel and operations.  If Collaborator elects to perform any portion of the Research Plan through a contractor or consultant, Collaborator agrees to incorporate into such contract all provisions necessary to ensure that the work of such contractor or consultants is governed by the terms of the CRADA, including, but not limited to a provision for the assignment of inventions of the contractor or consultant to the Collaborator.

 

Amend Article 13.10

 

13.10      Use of Name; Press Releases.  By entering into this CRADA, the Government does not directly or indirectly endorse any product or service that is or will be provided, whether directly or indirectly related to either this CRADA or to any patent or other intellectual-property license or agreement that implements this CRADA by Collaborator, its successors, assignees, or licensees.  Collaborator will not in any way state or imply that the Government or any of its organizational units or employees endorses any product or services.  Each Party agrees to provide proposed press releases that reference or rely upon the work under this CRADA to the other Party for review and comment at least five (5) business days before publication or such

 

C-20

 

shorter period as may be required by law or the rules of any securities exchange.  Either Party may disclose the Title and Abstract of the CRADA to the public without the approval of the other Party.

 

Amend Article 13.12

 

13.12      Export Controls.  Collaborator agrees to comply with U.S. export law and regulations, including 21 U.S.C. 382 and 21 CFR Part 312.110.  If Collaborator has a need to transfer any CRADA Materials made in whole or in part by ICD, or ICD Materials, or ICD’s Confidential Information to a person located in a country other than the United States, to an Affiliate organized under the laws of a country other than the United States, or to an employee of Collaborator in the United States who is not a citizen or permanent resident of the United States, Collaborator will acquire any and all necessary export licenses and other appropriate authorizations.

 

Amend Article 13.14

 

13.14      Survivability.  The provisions of Paragraphs 3.3, 3.4, 3.8, 4.2, 4.3, 4.4, 5.3, 5.4, 6.1-9.2, 10.3-10.6, 11.1, 11.2, 12.1-12.3, 13.1-13.3, 13.7, 13.10 and 13.14 will survive the expiration or early termination of this CRADA.

 

C-21

 

	
CONFIDENTIAL
    	
 
    	
NCI — BN   ImmunoTherapeutics
    
	
 
    	
 
    	
Amendment #1 to CRADA   #02377
    

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

Amendment #1 to
 Cooperative Research and Development Agreement #02377

 

“The Development of Recombinant Poxviruses As Vaccine
 Immunotherapies for the Treatment and/or Prevention of Human
 Prostate Cancer”

 

The purpose of this amendment is to change certain terms of the above-referenced Cooperative Research and Development Agreement (CRADA). These changes are reflected below, and except for these changes, all other provisions of the original CRADA remain in full force and effect.

 

The Parties agree as follows:

 

1.  The term of the CRADA is extended for five (5) years from August 12, 2013 to August 12, 2018.

 

2.  Article 7.8 is deleted in its entirety.

 

3.  The name of the Collaborator Principal Investigator is changed to James Breitmeyer, M.D., Ph.D.

 

4.  Article 10.5 is modified to read as follows where strikeout indicates deletions and underline indicates additions:

 

10.5        New Commitments.  Neither Party will incur new expenses related to this CRADA after expiration, mutual termination, or a notice of a unilateral termination and will, to the extent feasible, cancel all outstanding commitments and contracts by the termination date. Collaborator acknowledges that IC will have the authority to retain and expend any funds for up to [***] subsequent to the expiration or termination date to cover any unpaid costs obligated during the term of the CRADA in undertaking the research and development activities set forth in the Research Plan and for ongoing CRADA-related expenses that arise after the expiration or termination date, such as vaccine stability testing, managing or analyzing CRADA Data and CRADA Materials, continuing ongoing clinical trials, and conducting follow-up observations of Human Subjects treated under the CRADA, such that the authority to make these expenditures will survive the CRADA.

 

1

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

ACCEPTED AND AGREED TO:

 

	
For the National Cancer   Institute
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
6/25/13
    
	
[***]
    	
 
    	
Date
    
	
 
    	
 
    	
 
    
	
Deputy Director for   Clinical and Translational
    	
 
    	
 
    
	
Research, NCI
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
For Collaborator:
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
28 May 2013
    
	
Name:
    	
[***]
    	
 
    	
Date
    
	
Title:
    	
President, BN   Immunotherapeutics, Inc.
    	
 
    	
 
    

 

2

 

Amendment #2 to
 Cooperative Research and Development Agreement #02377

 

“The Development of Recombinant Poxviruses As Vaccine Immunotherapies 
 for the Treatment and/or Prevention of Human Prostate Cancer”

 

The purpose of this amendment is to change certain terms of the above-referenced Cooperative Research and Development Agreement (CRADA).  These changes are reflected below, and except for these changes, all other provisions of the original CRADA, as amended by Amendment #1 on June 21, 2013, remain in full force and effect.

 

The Parties agree as follows:

 

1.  Article 8.2 is modified to read as follows where underline indicates additions:

 

8.2                               Use of CRADA Data and CRADA Materials.  The Parties will be free to utilize CRADA Data and CRADA Materials internally for their own purposes, consistent with their obligations under this CRADA.  ICD may share CRADA Data or CRADA Materials with any contractors, grantees, or agents it has engaged to conduct the CRADA research and development activities, provided the obligations of this Article 8.2 are simultaneously conveyed.  Collaborator may use CRADA Data, Raw Data, and CRADA Materials for the research, development and commercialization of products and may share CRADA Data, Raw Data or CRADA Materials with its Affiliates and development partners and with any contractors or agents it has engaged to conduct the CRADA research and development activities, provided the obligations of this Article 8.2 are simultaneously conveyed.  Consistent with the obligations in this CRADA, including Articles 8.5 and 8.10, Collaborator shall have the exclusive right to use CRADA Data, Raw Data, and CRADA Materials for the commercial development (including in all regulatory filings seeking marketing approval for a new indication (e.g., NDAs and sNDAs)) and commercialization of therapies for prostatic diseases pursuant to the Licensed Field of Use under, and to conduct the activities permitted by, the PHS Exclusive Patent License Agreement #L-149- 2008/0 and amended in a first amendment #L-149-2008/1 and a second amendment #L-149-2008/2.  For the avoidance of doubt, “commercial development” refers to all the pre-marketing approval activities needed to commercialize a product, and any IND filings made by ICD will be considered for research purposes and not commercial development. “Commercialization” refers to all the post-marketing approval activities connected with launching, marketing, promoting, advertising, selling and/or distributing a product.

 

2.  At1icle 8.2.1 is modified to read as follows where underline indicates additions:

 

8.2.1                     CRADA Data.  Collaborator and ICD will use reasonable efforts to keep CRADA Data and Raw Data confidential until published or until corresponding Patent Applications are filed.  To the extent permitted by law, either Party will

 

1

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

have the right to use any and all CRADA Data and Raw Data in and for any regulatory filing by or on behalf of the Patty. provided. however. That Collaborator shall have the exclusive right to use CRADA Data and Raw Data in regulatory filings for approvals and other commercial purposes for PSA-Tricom (Prostvac®).

 

3.  Article 10.3 is modified to read as follows where underline indicates additions:

 

10.3                        Unilateral Termination.  Either ICD or Collaborator may unilaterally terminate this CRADA at any time by providing written notice at least sixty (60) days before the desired termination date.  ICD shall provide a copy of any such notice to any third party previously designated in writing by Collaborator to receive such notices at the same time as ICD provides such notice to Collaborator.  ICD may, at its option, retain funds transferred to ICD before unilateral termination by Collaborator for use in completing the Research Plan.  If Collaborator terminates this Agreement before completion of all approved or active Protocol(s), then Collaborator will supply enough Test Article (and Placebo, if applicable) to complete these Protocol(s) unless termination is for safety concerns.  In the event of termination of the CRADA prior to the expiration date, or upon expiration of the CRADA, Collaborator will continue to provide cross reference letters to its DMFs and/or INDs in order to enable ICD to complete the studies approved, initiated or active.

 

ACCEPTED AND AGREED TO:

 

For the National Cancer Institute

 

 

	
[***]
    	
 
    	
4/25/2015
    
	
[***]
    	
 
    	
Date
    
	
 
    	
 
    	
 
    
	
Deputy Director for   Clinical and
    	
 
    	
 
    
	
Translational Research,   NCI
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
For Collaborator:
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
17 APR 2015
    
	
Name:
    	
[***]
    	
 
    	
Date
    
	
Title:
    	
President, Bavarian   Nordic, Inc.
    	
 
    	
 
    

 

2Exhibit 10.4

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

PUBLIC HEALTH SERVICE

 

PATENT LICENSE AGREEMENT — EXCLUSIVE

 

COVER PAGE

 

For PHS internal use only:

 

	
 
    	
License Number: L-149-2008/0
    

 

License Application Number: A-332-2007

 

Serial Number(s) of Licensed Patent(s) or Patent Application(s):

 

Group I—Exclusive Licensed Patent Rights

 

1.              U.S. Patent No. 6,946,133 issued September 20, 2005 and U.S. Patent Application No. 11/606,929 filed December 1, 2006, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No E-062-1996/0]

 

2.              U.S. Patent Application Nos. 60/334,669 and 10/497,003 filed November 30, 2001 and August 24, 2004 respectively, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-124-2001/0, 1]; and

 

3.              U.S. Patent No. 6,165,460 issued December 26, 2000 and U.S. Patent Application No. 09/693,121 filed October 20, 2000; as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No E-200-1990/4]

 

Group II—Nonexclusive Licensed Patent Rights

 

1.              U.S. Patent No. 6,969,609 issued November 29, 2005; U.S. Patent No. 7,211,432 issued May 1, 2007; U.S. Patent Application No. 11/723,666 filed March 21, 2007; as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-256-1998/0];

 

2.              U.S. Patent Application Nos. 08/686,280 filed July 25, 1996 and 08/686,281 filed July 25, 1996 as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-259-1994/3, 4];

 

3.              U.S. Patent Nos. 6,893,869, 6,548,068 and 6,045,802 issued May 17, 2005, April 15, 2003 an April 4, 2000 respectively, as well as issued and pending foreign counterparts [HHS Ref. Nos. E- 260-1994/1-US-03, US-02, US-01]; and U.S. Patent. Application No. 11/090,686 filed March 8, 2005 [HHS Ref. No E-260-1994/1-US-04];

 

4.              U.S. Patent Application Nos. 60/211,717 and 10/297,168 filed June 15, 2000 and August 16, 2003 respectively, as well as all continuations, divisionals, and foreign counterparts [HHS Ref. No. E-187-2000/0];

 

	
A-332-227
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
CONFIDENTIAL
    	
 
    	
 
    
	
PHS Patent License Agreement— Exclusive
    
	
Model 10-2005 
    	
[Final]
    	
 
    	
[BN ImmunoTherapeutics]
    	
 
    	
[August 5, 2008]
    
						

 

1

 

5.              U.S. Patent Application Nos. 60/448,591 and 10/543,944 filed February 20, 2003 and February 20, 2004 respectively, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-028-2007/0];

 

6.              U.S. Patent No. 6,699,475 issued March 2, 2004, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-134-2007/0];

 

7.              U.S. Patent No. 5,093,258 issued March 3, 1992, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-135-2007/0];

 

8.              U.S. Patent Application No. 07/205,189 filed June 10, 1988, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref No. E-136-2007];

 

9.              U.S. Patent Application No. 60/625,321 filed November 5, 2004, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-138-2007]; and

 

10.       U.S. Patent Application No. 07/340,052 filed April 18, 1989, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-147-2007].

 

Licensee:

 

BN ImmunoTherapeutics

2425 Garcia Ave

Mountain View, CA 94043

 

Cooperative Research and Development Agreement (CRADA) Number (if a subject invention):

 

N/A

 

Additional Remarks:

 

N/A

 

Public Benefit(s):

 

Licensee agrees, after its First Commercial Sale in the United States, to make reasonable quantities of Licensed Product(s) or materials produced through the use of Licensed Process(es) within the scope of the Group I Licensed Patent Rights available on a compassionate use basis to indigent patients subject to availability, either through the patient’s physician(s) and/or the medical center treating the patient; provided, however, that such requirement shall not keep the Licensee from commercializing such Licensed Product(s) or materials in manner typical for products of similar commercial market potential, product life, safety, efficacy, and competitive environment, and considering other relevant scientific, technical, financial and commercial factors; and

 

Licensee further agrees, after its First Commercial Sale in the United States and as part of its marketing and product promotion, to develop written educational materials (e.g., brochures, advertisements, etc.) directed to patients and physicians detailing the Licensed Product(s) and/or medical aspects of the prophylactic and therapeutic uses of the Licensed Product(s), as appropriate under the circumstances.

 

2

 

This Patent License Agreement, hereinafter referred to as the “Agreement”, consists of this Cover Page, an attached Agreement, a Signature Page, Appendix A (List of Patent(s) or Patent Application(s)), Appendix B (Fields of Use and Territory), Appendix C (Royalties), Appendix D (Benchmarks and Performance), Appendix E (Commercial Development Plan), Appendix F (Example Royalty Report), and Appendix G (Royalty Payment Options). The Parties to this Agreement are:

 

1)                                     The National Institutes of Health (“NIH”) or the Food and Drug Administration (“FDA”), hereinafter singly or collectively referred to as “PHS”, agencies of the United States Public Health Service within the Department of Health and Human Services (“HHS”); and

 

2)                                     The person, corporation, or institution identified above or on the Signature Page, having offices at the address indicated on the Signature Page, hereinafter referred to as “Licensee”.

 

3

 

PHS PATENT LICENSE AGREEMENT — EXCLUSIVE

 

PHS and Licensee agree as follows:

 

1.                                      BACKGROUND

 

1.1                               In the course of conducting biomedical and behavioral research, PHS investigators made inventions that may have commercial applicability

 

1.2                               By assignment of rights from PHS employees and other inventors, HHS, on behalf of the Government, owns intellectual property rights claimed in any United States or foreign patent applications or patents corresponding to the assigned inventions HHS also owns any tangible embodiments of these inventions actually reduced to practice by PHS,

 

1.3                               The Secretary of HHS has delegated to PHS the authority to enter into this Agreement for the licensing of rights to these inventions.

 

1.4                               PHS desires to transfer these Licensed Patent Rights to the private sector through commercialization licenses to facilitate the commercial development of products and processes for public use and benefit.

 

1.5                               Licensee desires to acquire commercialization rights to the Licensed Patent Rights in order to develop processes, methods, or marketable products for public use and benefit.

 

2.                                      DEFINITIONS

 

2.1                               “Affiliate” means any person, corporation, firm, limited liability company, partnership or other entity that directly controls or is controlled by or is under common control with Licensee. For purposes of this Paragraph 2.1, “control” means ownership, directly or indirectly through one or more Affiliates, of fifty percent (50%) or more of the shares of stock entitled to vote for the election of directors, in the case of a corporation, or fifty percent (50%) or more of the equity interests in the case of any other type of legal entity, status as a general partner in any partnership, or any other arrangement whereby a person or entity controls or has the right to control the Board of Directors or equivalent governing body of a corporation or other entity.

 

2.2                               “Benchmarks” mean the performance milestones that are set forth in Appendix D.

 

2.3                               “Commercial Development Plan” means the written commercialization plan attached as Appendix E.

 

2.4                               “First Commercial Sale” means the initial transfer by or on behalf of Licensee or its sublicensees (through multiple tiers) of Licensed Products or the initial practice of a Licensed Process by or on behalf of Licensee or its sublicensees (through multiple tiers) in a country after obtaining approval (including pricing and reimbursement approvals), product and establishment licenses, registrations or authorizations of any kind of the U.S. Food and Drug Administration or any foreign equivalent necessary for the marketing and sale of such Licensed Product or practice of such Licensed Process in exchange for cash or some equivalent consideration to which value can be assigned for the purpose of determining Net Sales.

 

2.5                               “Government” means the Government of the United States of America.

 

4

 

2.6                               “Licensed Fields of Use” means the fields of use identified in Appendix B.

 

2.7                               “Licensed Patent Rights” shall mean:

 

(a)                                 Patent applications (including provisional patent applications and PCT patent applications) or patents listed in Appendix A, all divisions and continuations of these applications, all patents issuing from these applications, divisions, and continuations, and any reissues, reexaminations, and extensions of these patents;

 

(b)                                 to the extent that the following contain one or more claims directed to the invention or inventions disclosed in 2.7(a):

 

(i)                                     continuations-in-part of 2.7(a);

 

(ii)                                  all divisions and continuations of these continuations-in-part;

 

(iii)                               all patents issuing from these continuations-in-part, divisions, and continuations;

 

(iv)                              priority patent application(s) of 2.7(a); and

 

(v)                                 any reissues, reexaminations, and extensions of these patents;

 

(c)                                  to the extent that the following contain one or more claims directed to the invention or inventions disclosed in 2.7(a): all counterpart foreign and U.S. patent applications and patents to 2.7(a) and 2.7(b), including those listed in Appendix A; and

 

(d)                                 Licensed Patent Rights shall not include 2.7(b) or 2.7(c) to the extent that they contain one or more claims directed to new matter which is not subject matter disclosed in 2.7(a).

 

2.8                               “Licensed Processes” means processes which, in the course of being practiced, would be within the scope of one or more claims of the Licensed Patent Rights that have not been held unpatentable, invalid or unenforceable by an unappealed or unappealable judgment of a court of competent jurisdiction

 

2.9                               “Licensed Products” means tangible materials which, in the course of manufacture, use, sale, or importation, would be within the scope of one or more claims of the Licensed Patent Rights that have not been held unpatentable, invalid or unenforceable by an unappealed or unappealable judgment of a court of competent jurisdiction.

 

2.10                        “Licensed Territory” means the geographical area identified in Appendix B.

 

5

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

2.11                        “Net Sales” means [***] or on behalf of [***], less[***]. No deductions shall be made for [***]. “Net Sales” shall not include [***].

 

(a)                                 In the event that a [***], then “Net Sales,” for purposes of determining royalty payments on [***] for the purposes of the calculation of Net Sales.

 

(b)                                 Net Sales of [***] shall be determined as follows:

 

(i)                                     By [***], and [***]; or

 

(ii)                                  [***], Net Sales, for the purposes of determining royalty payments [***]

 

6

 

2.12                        “Practical Application” means to manufacture in the case of a composition or product, to practice in the case of a process or method, or to operate in the case of a machine or system; and in each case, under these conditions as to establish that the invention is being utilized and that its benefits are to the extent permitted by law or Government regulations available to the public in the United States on reasonable terms not inconsistent with the terms applicable to similar products or processes and taking into account the efficacy and safety profile of the Licensed Product or the utility of the Licensed Process and other relevant commercial, scientific, technical and other factors.

 

2.13                        “Research License” means a nontransferable, nonexclusive license to make and to use Licensed Products or Licensed Processes as defined by the Group I and II Licensed Patent Rights for purposes of research only and not for purposes of commercial sale, manufacture or distribution or in lieu of purchase.

 

2.14                        “Group I” means patent applications and/or patents listed in Group I of Appendix A, including all counterpart U.S. and foreign patent applications and patents pursuant to Paragraph 2.7 of this Agreement.

 

2.15                        “Group II” means patent applications and/or patents listed in Group II of Appendix A, including all counterpart U.S. and foreign patent applications and patents pursuant to Paragraph 2.7 of this Agreement.

 

3.                                      GRANT OF RIGHTS

 

3.1                               PHS hereby grants and Licensee accepts, subject to the terms and conditions of this Agreement, an exclusive license under the Group I Licensed Patent Rights in the Licensed Territory to make and have made, to use and have used, to sell and have sold, to offer to sell, and to import any Licensed Products in the Licensed Fields of Use and to practice and have practiced any Licensed Processes in the Licensed Fields of Use

 

3.2                               PHS hereby grants and Licensee accepts, subject to the terms and conditions of this Agreement, a non-exclusive license under the Group II Licensed Patent Rights in the Licensed Territory to make and have made, to use and have used, to sell and have sold, to offer to sell, and to import any Licensed Products in the Licensed Fields of Use and to practice and have practiced any Licensed Processes in the Licensed Fields of Use

 

3.3                               This Agreement confers no license or rights by implication, estoppel, or otherwise under any patent applications or patents of PHS other than the Licensed Patent Rights regardless of whether these patents are dominant or subordinate to the Licensed Patent Rights.

 

7

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

4.                                      SUBLICENSING

 

4.1                               Upon written approval, which shall include prior review of any sublicense agreement by PHS and which shall not be unreasonably withheld or delayed, Licensee may enter into sublicensing agreements under the Licensed Patent Rights and any of Licensee’s approved sublicensees may enter into sublicense agreements under the Licensed Patent Rights sublicensed to them; provided, however, that the approval of PHS shall not be required for any sublicense to an Affiliate of Licensee or to a third party providing research, manufacturing or development services to Licensee, its Affiliates or PHS’s approved sublicensee(s). [***].

 

4.2                               Licensee agrees that any sublicenses required to be approved by PHS as provided in Paragraph 4.1 (including sublicenses granted by Licensee’s sublicensees) shall provide that the obligations to PHS of Paragraphs 5.1-5.4, 8.1, 10.1, 10.2, 12.5, and 13.8-13.10 of this Agreement shall be binding upon the sublicensee as if it were a party to this Agreement. Licensee further agrees to cause copies of these Paragraphs to be attached to all sublicense agreements.

 

4.3                               Any sublicenses subject to the approval of PHS as provided in Paragraph 4.1 shall provide for the termination of the sublicense, or the conversion to a license directly between the sublicensees and PHS, at the option of the sublicensee, upon termination of this Agreement under Article 13.13 (except Paragraph 13.1). This conversion is subject to PHS approval, which will not be unreasonably denied or delayed, and contingent upon acceptance by the sublicensee of the remaining provisions of this Agreement.

 

4.4                               Licensee agrees to forward to PHS a complete copy of each fully executed sublicense agreement subject to the approval requirements of Paragraph 4.1 postmarked within thirty (30) days of the execution of the agreement. To the extent permitted by law, PHS agrees to maintain each sublicense agreement in confidence.

 

5.                                      STATUTORY AND PHS REQUIREMENTS AND RESERVED GOVERNMENT RIGHTS

 

5.1                               (a)                                 PHS reserves on behalf of the Government an irrevocable, nonexclusive, nontransferable, royalty-free license for the practice of all inventions licensed under the Group I Licensed Patent Rights throughout the world by or on behalf of the Government and on behalf of any foreign government or international organization pursuant to any existing or future treaty or agreement to which the Government is a signatory.

 

(b)                                 Prior to the First Commercial Sale, Licensee agrees to provide PHS with adequate quantities of Licensed Products or materials made through the Licensed Processes for PHS’s reasonable internal research use including but not limited to pre-clinical and clinical studies undertaken at the NCI; and

 

8

 

(c)                                  In the event that the Licensed Patent Rights are Subject Inventions made under a Cooperative Research and Development Agreement (CRADA), Licensee grants to the Government, pursuant to 15 U.S.C. §3710a(b)(1)(A), a nonexclusive, nontransferable, irrevocable, paid-up license to practice Licensed Patent Rights or have Licensed Patent Rights practiced throughout the world by or on behalf of the Government. In the exercise of this license, the Government shall not publicly disclose trade secrets or commercial or financial information that is privileged or confidential within the meaning of 5 U.S.C. §552(b)(4) or which would be considered as such if it had been obtained from a non-Federal party. Prior to the First Commercial Sale, Licensee agrees to provide PHS reasonable quantities of Licensed Products or materials made through the Licensed Processes for PHS research use.

 

5.2                               Licensee agrees that products used or sold in the United States embodying Licensed Products or produced through use of Licensed Processes shall be manufactured substantially in the United States unless a written waiver is obtained in advance from PHS.

 

5.3                               Licensee acknowledges that PHS may enter into future CRADAs under the Federal Technology Transfer Act of 1986 that relate to the subject matter of this Agreement. Licensee agrees not to unreasonably deny requests for a Research License from future collaborators with PHS when acquiring these rights is necessary in order to make a CRADA project feasible. Licensee may request an opportunity to join as a party to the proposed CRADA.

 

5.4                               (a)                                 In addition to the reserved license of Paragraph 5.1, PHS reserves the right to grant Research Licenses directly or to require Licensee to grant Research Licenses on reasonable terms. The purpose of these Research Licenses is to encourage basic research, whether conducted at an academic or corporate facility. In order to safeguard the Licensed Patent Rights, however, PHS shall consult with Licensee before granting to commercial entities a Research License or providing to them research samples of materials made through the Licensed Processes; and

 

(b)                                 In exceptional circumstances, and in the event that Licensed Patent Rights are Subject Inventions made under a CRADA, the Government, pursuant to 15 U.S.C. §3710a(b)(1)(B), retains the right to require the Licensee to grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense to use the Licensed Patent Rights in the Licensed Field of Use on terms that are reasonable under the circumstances, or if Licensee fails to grant this license, the Government retains the right to grant the license itself. The exercise of these rights by the Government shall only be in exceptional circumstances and only if the Government determines:

 

(i)                                     the action is necessary to meet health or safety needs that are not reasonably satisfied by Licensee;

 

(ii)                                  the action is necessary to meet requirements for public use specified by Federal regulations, and these requirements are not reasonably satisfied by the Licensee; or

 

9

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

(iii)                               the Licensee has failed to comply with an agreement containing provisions described in 15 U.S.C. §3710a(c)(4)(B); and

 

(c)                                  The determination made by the Government under this Paragraph 5.4 is subject to administrative appeal and judicial review under 35 U.S.C. §203(2).

 

6.                                      ROYALTIES AND REIMBURSEMENT

 

6.1                               Licensee agrees to pay PHS a noncreditable, nonrefundable license issue royalty as set forth in Appendix C.

 

6.2                               Licensee agrees to pay PHS a nonrefundable minimum annual royalty as set forth in Appendix C.

 

6.3                               Licensee agrees to pay PHS earned royalties as set forth in Appendix C.

 

6.4                               Licensee agrees to pay PHS benchmark royalties as set forth in Appendix C.

 

6.5                               Licensee agrees to pay PHS sublicensing royalties as set forth in Appendix C.

 

6.6                               A patent or patent application within the Licensed Patent Rights licensed under this Agreement shall cease to fall within the Licensed Patent Rights for the purpose of computing earned royalty payments on Net Sales in any given country on the earliest of the dates that:

 

(a)                                 the application has been abandoned and not continued or has been pending for a period of [***] from the first date of examination;

 

(b)                                 the patent expires or irrevocably lapses, or

 

(c)                                  the claim has been held to be invalid or unenforceable by an unappealed or unappealable decision of a court of competent jurisdiction or administrative agency.

 

6.7                               No multiple royalties shall be payable because any Licensed Products or Licensed Processes are covered by more than one of the Licensed Patent Rights.

 

6.8                               On sales of Licensed Products by Licensee to sublicensees or to such sublicensees’ sublicensees or on sales made in other than an arms-length transaction, the value of the Net Sales attributed under this Article 6 to this transaction shall be that which would have been received in an arms-length transaction, based on sales of like quantity and quality products on or about the time of this transaction.

 

6.9                               With regard to unreimbursed expenses associated with the preparation, filing, prosecution, and maintenance of all patent applications and patents included within the Licensed Patent Rights and incurred by PHS prior to the effective date of this Agreement, Licensee shall pay PHS, as an additional royalty, within sixty (60) days of PHS’ submission of a statement and request for payment to Licensee, an amount equivalent to these unreimbursed expenses previously incurred by PHS as follows:

 

(a)                                 Licensed Patent Rights. Group I. Licensee will pay the amount set forth in Appendix C; and

 

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(b)                                 Licensed Patent Rights. Group II. Licensee will pay the amount set forth in Appendix C.

 

6.10                        With regard to unreimbursed expenses associated with the preparation, filing, prosecution, and maintenance of all patent applications and patents included within the Group I Licensed Patent Rights and incurred by PHS on or after the effective date of this Agreement, for the preparation, filing, prosecution and maintenance of such Licensed Patent Rights, as provided in Paragraph 7.3, PHS, at its sole option, may require Licensee:

 

(a)                                 to pay PHS on an annual basis, within sixty (60) days of PHS’ submission of a statement and request for payment, a royalty amount equivalent to these unreimbursed expenses incurred during the previous calendar year(s);

 

(b)                                 to pay these unreimbursed expenses directly to the law firm employed by PHS to handle these functions. However, in this event, PHS and not Licensee shall be the client of the law firm; or

 

(c)                                  in limited circumstances, Licensee may be given the right to assume responsibility for the preparation, filing, prosecution, or maintenance of any patent applications and patents included with the Group I Licensed Patent Rights. In that event, Licensee shall directly pay the attorneys or agents engaged to prepare, file, prosecute, or maintain these patent applications or patents and shall provide PHS with copies of each invoice associated with these services as well as documentation that these invoices have been paid.

 

6.11                        PHS agrees, upon written request, to provide Licensee with summaries of patent prosecution invoices for which PHS has requested payment from the Licensee under Paragraphs 6.9 and 6.10. Licensee agrees that all information provided by PHS related to patent prosecution costs shall be treated as confidential commercial information and shall not be released to a third party (other than its Affiliates) except as required by law or a court of competent jurisdiction.

 

6.12                        Licensee may elect to surrender its rights in any country of the Licensed Territory under any of the Licensed Patent Rights upon ninety (90) days written notice to PHS and owe no payment obligation under Paragraph 6.10 for patent-related expenses incurred in that country after ninety (90) days of the effective date of the written notice.

 

7.                                      PATENT FILING, PROSECUTION, AND MAINTENANCE

 

7.1                               Except as otherwise provided in this Article 7, PHS agrees to take responsibility for, but to consult with, the Licensee in the preparation, filing, prosecution, and maintenance of any and all patent applications or patents included in the Licensed Patent Rights, shall timely pay all required maintenance and other fees and costs, and shall furnish copies of relevant patent-related documents to Licensee.

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

7.2                               Upon PHS’ written request, Licensee shall assume the responsibility for the preparation, filing, prosecution, and maintenance of any and all patent applications or patents included in the Group I Licensed Patent Rights and shall, on an ongoing basis, promptly furnish copies of all patent-related documents to PHS. In this event, Licensee shall, subject to the prior approval of PHS, select registered patent attorneys or patent agents to provide these services on behalf of Licensee and PHS. PHS shall provide appropriate powers of attorney and other documents necessary to undertake this action to the patent attorneys or patent agents providing these services. Licensee and its attorneys or agents shall consult with PHS in all aspects of the preparation, filing, prosecution and maintenance of patent applications and patents included within the Group I Licensed Patent Rights and shall provide PHS sufficient opportunity to comment on any document that Licensee intends to file or to cause to be filed with the relevant intellectual property or patent office.

 

7.3                               At any time, PHS may provide Licensee with written notice that PHS wishes to assume control of the preparation, filing, prosecution, and maintenance of any and all patent applications or patents included in the Licensed Patent Rights. If PHS elects to reassume these responsibilities, Licensee agrees to cooperate fully with PHS, its attorneys, and agents in the preparation, filing, prosecution, and maintenance of any and all patent applications or patents included in the Licensed Patent Rights and to provide PHS with complete copies of any and all documents or other materials in Licensee’s possession or control that PHS deems necessary to undertake such responsibilities. Licensee shall be responsible for all costs associated with transferring patent prosecution responsibilities to an attorney or agent of PHS’ choice.

 

7.4                               Each party shall promptly inform the other as to all material matters that come to its attention that may affect the preparation, filing, prosecution, or maintenance of the Licensed Patent Rights and permit each other to provide comments and suggestions with respect to the preparation, filing, prosecution, and maintenance of Licensed Patent Rights, which comments and suggestions shall be considered by the other party.

 

8.                                      RECORD KEEPING

 

8.1                               Licensee agrees to keep accurate and correct records of Licensed Products made, used, sold, or imported and Licensed Processes practiced under this Agreement appropriate to determine the amount of royalties due PHS. These records shall be retained for at least five (5) years following a given reporting period and shall be available during normal business hours for inspection, at the expense of PHS, by an accountant or other designated auditor selected by PHS for the sole purpose of verifying reports and royalty payments hereunder. Licensee may require such auditor or accountant to enter into a confidentiality agreement with Licensee containing reasonable terms and conditions for the protection of Licensee’s non-public and proprietary information. The accountant or auditor shall only disclose to PHS information relating to the accuracy of reports and royalty payments made under this Agreement. If an inspection shows an underreporting or underpayment in excess of [***] percent ([***]%) for any twelve (12) month period, then Licensee shall reimburse PHS for the cost of the inspection at the time Licensee pays the unreported royalties, including any additional royalties as required by Paragraph 9.8. All royalty payments required under this Paragraph shall be due within thirty (30) days of the date PHS provides Licensee notice of the payment due.

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

8.2                               Licensee agrees to have an audit of sales and royalties conducted by an independent auditor at least every two (2) years if annual sales of the Licensed Products or Licensed Processes exceed [***] dollars. The audit shall address, at a minimum, the amount of gross sales by or on behalf of Licensee during the audit period, terms of the license as to percentage or fixed royalty to be remitted to the Government, the amount of royalties owed to the Government under this Agreement, and whether the royalties owed have been paid to the Government and is reflected in the records of the Licensee. The audit shall also indicate the PHS license number, product, and the time period being audited. A report certified by the auditor shall be submitted promptly by the auditor directly to PHS on completion. Licensee shall pay for the entire cost of the audit.

 

9.                                      REPORTS ON PROGRESS, BENCHMARKS, SALES, AND PAYMENTS

 

9.1                               Prior to signing this Agreement, Licensee has provided PHS with the Commercial Development Plan in Appendix E, under which Licensee intends to bring Licensed Product(s) or Licensed Process(es) within the subject matter of the Licensed Patent Rights to the point of Practical Application. This Commercial Development Plan is hereby incorporated by reference into this Agreement. Based on this plan, performance Benchmarks are determined as specified in Appendix D.

 

9.2                               Licensee shall provide written annual reports on its product development progress or efforts to commercialize under the Commercial Development Plan for each of the Licensed Fields of Use within sixty (60) days after December 31 of each calendar year. These progress reports shall include, but not be limited to: progress on research and development, status of applications for regulatory approvals, manufacturing, sublicensing, marketing, importing, and sales during the preceding calendar year, as well as, plans for the present calendar year. PHS 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 from that projected in the Commercial Development Plan and Benchmarks, Licensee shall explain the reasons for these differences. In the annual report, Licensee may propose amendments to the Commercial Development Plan, acceptance of which by PHS may not be denied unreasonably. Licensee agrees to provide any additional information reasonably required by PHS to evaluate Licensee’s performance under this Agreement. Licensee may amend the Benchmarks at any time upon written approval by PHS. PHS shall not unreasonably withhold approval of any request of Licensee to extend the time periods of this schedule if the 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 Practical Application as defined in 37 CFR §404.3(d). Licensee shall amend the Commercial Development Plan and Benchmarks at the request of PHS to address any Licensed Fields of Use not specifically addressed in the plan originally submitted.

 

9.3                               Licensee shall report to PHS the dates for achieving Benchmarks specified in Appendix D and the First Commercial Sale in each country in the Licensed Territory within thirty (30) days of such occurrences.

 

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9.4                               Following the First Commercial Sale, Licensee shall submit to PHS, within sixty (60) days after each calendar half-year ending June 30 and December 31, a royalty report, as described in the example in Appendix F, setting forth for the preceding half-year period the amount of the Licensed Products sold or Licensed Processes practiced by or on behalf of Licensee in each country within the Licensed Territory, the Net Sales, and the amount of royalty accordingly due. With each royalty report, Licensee shall submit payment of earned royalties due. If no earned royalties are due to PHS for any reporting period, the written report shall so state. The royalty report shall be certified as correct by an authorized officer of Licensee and shall include a detailed listing of all deductions made under Paragraph 2.11 to determine Net Sales made under Article 6 to determine royalties due.

 

9.5                               Licensee agrees to forward semi-annually to PHS a copy of these reports received by Licensee from its sublicensees during the preceding half-year period as shall be pertinent to a royalty accounting to PHS by Licensee for activities under the sublicense.

 

9.6                               Royalties due under Article 6 shall be paid in U.S. dollars and payment options are listed in Appendix G. For conversion of foreign currency to U.S. dollars, the conversion rate shall be the New York foreign exchange rate quoted in The Wall Street Journal on the day preceding the day that the payment is due. Any loss of exchange, value, taxes, or other expenses incurred in the transfer or conversion to U.S. dollars shall be paid entirely by Licensee. The royalty report required by Paragraph 9.4 shall be mailed to PHS at its address for Agreement Notices indicated on the Signature Page.

 

9.7                               Licensee shall be solely responsible for determining if any tax on royalty income is owed outside the United States and shall pay the tax and be responsible for all filings with appropriate agencies of foreign governments. As reasonably requested by Licensee, PHS shall cooperate with Licensee in applying for any valid exemption or obtaining any valid refund of such taxes paid by Licensee.

 

9.8                               Additional royalties may be assessed by PHS on any payment that is more than ninety (90) days overdue at the rate of one percent (1%) per month. This one percent (1%) per month rate may be applied retroactively from the original due date until the date of receipt by PHS of the overdue payment and additional royalties. The payment of any additional royalties shall not prevent PHS from exercising any other rights it may have as a consequence of the lateness of any payment.

 

9.9                               All plans and reports required by this Article 9 and marked “confidential” by Licensee shall, to the extent permitted by law, be treated by PHS as commercial and financial information obtained from a person and as privileged and confidential, and any proposed disclosure of these records by the PHS under the Freedom of Information Act (FOIA), 5 U.S.C. §552 shall be subject to the predisclosure notification requirements of 45 CFR §5.65(d).

 

10.                               PERFORMANCE

 

10.1                        Licensee shall use its reasonable commercial efforts to bring the Licensed Products and Licensed Processes to Practical Application. “Reasonable commercial efforts” for the purposes of this provision shall include reasonable adherence to the Commercial Development Plan in Appendix E and performance of the Benchmarks in Appendix D, in each case as either may be amended from time to time. The efforts of a sublicensee (through multiple tiers) or an Affiliate of Licensee shall be considered the efforts of Licensee.

 

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10.2                        Upon the First Commercial Sale, until the expiration or termination of this Agreement, Licensee shall use its reasonable commercial efforts to make Licensed Products and Licensed Processes reasonably accessible to the United States public.

 

10.3                        Licensee agrees, after its First Commercial Sale in the United States, to make reasonable quantities of Licensed Products or materials produced through the use of Licensed Processes within the scope of the Group I Licensed Patent Right available on a compassionate use basis to indigent patients, either through the patient’s physician(s) or the medical center treating the patient; provided, however, that such requirement shall not keep the Licensee from commercializing such Licensed Product(s) or materials in a manner typical for products of similar commercial market potential, product life, safety, efficacy, and competitive environment, and considering other relevant scientific, technical, financial and commercial factors.

 

10.4                        Licensee agrees, after its First Commercial Sale in the United States and as part of its marketing and product promotion, to develop educational materials (e.g., brochures, website, etc.) directed to patients and physicians detailing the Licensed Products or medical aspects of the prophylactic and therapeutic uses of the Licensed Products as appropriate under the circumstances.

 

10.5                        Licensee agrees to supply, to the Mailing Address for Agreement Notices indicated on the Signature Page, the Office of Technology Transfer, NIH with inert samples of the Licensed Products or Licensed Processes or their packaging for educational and display purposes only.

 

11.                               INFRINGEMENT AND PATENT ENFORCEMENT

 

11.1                        PHS and Licensee agree to notify each other promptly of each infringement or possible infringement of the Licensed Patent Rights, as well as, any facts which may affect the validity, scope, or enforceability of the Licensed Patent Rights of which either party becomes aware.

 

11.2                        Pursuant to this Agreement and the provisions of Chapter 29 of Title 35, United States Code, Licensee may:

 

(a)                                 bring suit in its own name, at its own expense, and on its own behalf for infringement of presumably valid claims in the Licensed Patent Rights;

 

(b)                                 in any suit, enjoin infringement and collect for its use, damages, profits, and awards of whatever nature recoverable for the infringement; or

 

(c)                                  settle any claim or suit for infringement of the Licensed Patent Rights provided, however, that PHS and appropriate Government authorities shall have the first right to take such actions; and

 

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(d)                                 If Licensee desires to initiate a suit for patent infringement, Licensee shall notify PHS in writing. If PHS does not notify Licensee of its intent to pursue legal action within ninety (90) days, Licensee shall be free to initiate suit. PHS shall have a continuing right to intervene in the suit. Licensee shall take no action to compel the Government either to initiate or to join in any suit for patent infringement. Licensee may request the Government to initiate or join in any suit if necessary to avoid dismissal of the suit. Should the Government be made a party to any suit, Licensee shall reimburse the Government for any costs, expenses, or fees which the Government incurs as a result of the motion or other action, including all costs incurred by the Government in opposing the motion or other action. In all cases, Licensee agrees to keep PHS reasonably apprised of the status and progress of any litigation. Before Licensee commences an infringement action, Licensee shall notify PHS and give careful consideration to the views of PHS and to any potential effects of the litigation on the public health in deciding whether to bring suit.

 

11.3                        In the event that a declaratory judgment action alleging invalidity or non-infringement of any of the Licensed Patent Rights shall be brought against Licensee or raised by way of counterclaim or affirmative defense in an infringement suit brought by Licensee under Paragraph 11.2, pursuant to this Agreement and the provisions of Chapter 29 of Title 35, United States Code or other statutes, Licensee may:

 

(a)                                 defend the suit in its own name, at its own expense, and on its own behalf for presumably valid claims in the Licensed Patent Rights;

 

(b)                                 in any suit, ultimately to enjoin infringement and to collect for its use, damages, profits, and awards of whatever nature recoverable for the infringement; and

 

(c)                                  settle any claim or suit for declaratory judgment involving the Licensed Patent Rights-provided, however, that PHS and appropriate Government authorities shall have the first right to take these actions and shall have a continuing right to intervene in the suit; and

 

(d)                                 If PHS does not notify Licensee of its intent to respond to the legal action within a reasonable time, Licensee shall be free to do so. Licensee shall take no action to compel the Government either to initiate or to join in any declaratory judgment action. Licensee may request the Government to initiate or to join any suit if necessary to avoid dismissal of the suit Should the Government be made a party to any suit by motion or any other action of Licensee, Licensee shall reimburse the Government for any costs, expenses, or fees, which the Government incurs as a result of the motion or other action. If Licensee elects not to defend against the declaratory judgment action, PHS, at its option, may do so at its own expense. In all cases, Licensee agrees to keep PHS reasonably apprised of the status and progress of any litigation. Before Licensee commences an infringement action, Licensee shall notify PHS and give careful consideration to the views of PHS and to any potential effects of the litigation on the public health in deciding whether to bring suit.

 

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11.4                        In any action under Paragraphs 11.2 or 11.3 the expenses including costs, fees, attorney fees, and disbursements, shall be paid by Licensee. The value of any recovery made by Licensee through court judgment or settlement actually collected shall first be applied by Licensee to reimburses it for all of its costs and expenses (including attorneys’ fees, expert witness fees, and any reimbursement payments made to PHS or the Government) and the balance shall be treated as Net Sales and subject to earned royalties as provided in Appendix C when and as collected.

 

11.5                        PHS shall cooperate fully with Licensee in connection with any action under Paragraphs 11.2 or 11.3. PHS agrees promptly to provide access to all necessary documents and to render reasonable assistance in response to a request by Licensee.

 

12.                               NEGATION OF WARRANTIES AND INDEMNIFICATION

 

12.1                        PHS offers no warranties other than those specified in Article 1.

 

12.2                        PHS represents that (i) it owns the Licensed Patent Rights in the Licensed Fields of Use, (ii) it is duly authorized to enter into this Agreement, and (iii) it has no actual knowledge of any claim by or on behalf of a third party of rights in or to the Licensed Patent Rights in the Licensed Field of Use. PHS does not warrant the validity of the Licensed Patent Rights and makes no representations whatsoever with regard to the scope of the Licensed Patent Rights, or that the Licensed Patent Rights may be exploited without infringing other patents or other intellectual property rights of third parties.

 

12.3                        PHS MAKES NO WARRANTIES, EXPRESS OR IMPLIED, OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OF ANY SUBJECT MATTER DEFINED BY THE CLAIMS OF THE LICENSED PATENT RIGHTS

 

12.4                        PHS does not represent that it shall commence legal actions against third parties infringing the Licensed Patent Rights.

 

12.5                        Licensee shall indemnify and hold PHS, its employees, students, fellows, agents, and consultants harmless from and against all liability , demands, damages, expenses, and losses, including but not limited to death, personal injury, illness, or property damage in connection with or arising out of:

 

(a)                                 the use by or on behalf of Licensee, its sublicensees, directors, employees, or third parties of any Licensed Patent Rights; or

 

(b)                                 the design, manufacture, distribution, or use of any Licensed Products, Licensed Processes or materials by Licensee, or other products or processes developed in connection with or arising out of the Licensed Patent Rights.

 

12.6                        Licensee agrees to maintain a liability insurance program consistent with sound business practice.

 

13.                               TERM, TERMINATION, AND MODIFICATION OF RIGHTS

 

13.1                        This Agreement is effective when signed by all parties, unless the provisions of Paragraph 14.17 are not fulfilled, and shall extend to the expiration of the last to expire of the Licensed Patent Rights unless sooner terminated as provided in this Article 13.

 

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13.2                        In the event that Licensee is in default in the performance of any material obligations under this Agreement, including but not limited to the obligations listed in Paragraph 13.5, and if the default has not been remedied within ninety (90) days after the date of notice in writing of the default or if not reasonably capable of remedy within such period, Licensee has not taken substantial steps to remedy the alleged default within such ninety (90) day period, PHS may terminate this Agreement by written notice and pursue outstanding royalties owed through procedures provided by the Federal Debt Collection Act.

 

13.3                        In the event that Licensee (i) becomes insolvent, or (ii) files a petition in bankruptcy or has such a petition filed against it and, in either case, such petition is not dismissed within sixty (60) days, Licensee shall immediately notify PHS in writing. Furthermore, PHS shall have the right to terminate this Agreement immediately upon Licensee’s receipt of written notice.

 

13.4                        Licensee shall have a unilateral right to terminate this Agreement or any licenses in any country or territory by giving PHS sixty (60) days written notice to that effect.

 

13.5                        PHS shall specifically have the right to terminate or modify, at its option, this Agreement, if PHS determines that the Licensee:

 

(a)                                 is not executing the Commercial Development Plan submitted with its request for a license and the Licensee cannot otherwise demonstrate to PHS’ satisfaction that the Licensee has taken, or can be expected to take within a reasonable time, effective steps to achieve Practical Application of the Licensed Products or Licensed Processes;

 

(b)                                 has not achieved and is not reasonably likely to achieve the Benchmarks as may be modified under Paragraph 9.2;

 

(c)                                  has willfully made a material false statement of, or willfully omitted a material fact in the license application or in any report required by the license Agreement;

 

(d)                                 has committed a material breach of a covenant or agreement contained in this Agreement;

 

(e)                                  is not keeping Licensed Products or Licensed Processes within the scope of the Group I Licensed Patent Rights reasonably accessible to the public after commercial use commences in the United States;

 

(f)                                   cannot reasonably satisfy unmet health and safety needs; or

 

(g)                                  cannot reasonably justify a failure to comply with the domestic production requirement of Paragraph 5.2 unless waived.

 

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13.6                        In making the determination referenced in Paragraph 13.5, PHS shall take into account the normal course of such commercial development programs conducted with sound and reasonable business practices and judgment and the annual reports submitted by Licensee under Paragraph 9.2. Prior to invoking termination or modification of this Agreement under Paragraph 13.5, PHS shall give written notice to Licensee providing Licensee specific notice of, and a ninety (90) day opportunity to respond to, PHS’ concerns as to the items referenced in 13.5(a)-13.5(g). If Licensee fails to alleviate PHS’ reasonable concerns as to the items referenced in 13.5(a)-13.5(g) or fails to initiate corrective action to PHS’ reasonable satisfaction, PHS may terminate this Agreement.

 

13.7                        When the public health and safety so require, and after written notice to Licensee providing Licensee a sixty (60) day opportunity to respond, PHS shall have the right to require Licensee to grant sublicenses to responsible applicants, on commercially reasonable terms, in any Licensed Fields of Use under the Group I Licensed Patent Rights, unless Licensee can reasonably demonstrate that the granting of the sublicense would not materially increase the availability to the public of the subject matter of the Group I Licensed Patent Rights. PHS shall not require the granting of a sublicense unless the responsible applicant has first negotiated in good faith with Licensee for a sublicense on commercially reasonable terms and conditions.

 

13.8                        PHS reserves the right according to 35 U.S.C. §209(d)(3) to terminate or modify this Agreement if it is determined that this action is necessary to meet the requirements for public use specified by federal regulations issued after the date of the license and these requirements are not reasonably satisfied by Licensee.

 

13.9                        Within thirty (30) days of receipt of written notice of PHS’ unilateral decision to modify or terminate this Agreement, Licensee may, consistent with the provisions of 37 CFR §404.11, appeal the decision by written submission to the designated PHS official. The decision of the designated PHS official shall be the final agency decision. Licensee may thereafter exercise any and all administrative or judicial remedies that may be available,

 

13.10                 Within ninety (90) days of expiration or termination of this Agreement under this Article 13, a final report shall be submitted by Licensee. Any royalty payments, including those incurred but not yet paid (such as the full minimum annual royalty), and those related to patent expense, due to PHS shall become immediately due and payable upon termination or expiration. If terminated under this Article 13, sublicensees may elect to convert their sublicenses to direct licenses with PHS pursuant to Paragraph 4.3. Unless otherwise specifically provided for under this Agreement, upon termination or expiration of this Agreement, Licensee shall return all Licensed Products or other materials included within the Licensed Patent Rights to PHS or provide PHS with certification of the destruction thereof.

 

14.                               GENERAL PROVISIONS

 

14.1                        Neither party may waive or release any of its rights or interests in this Agreement except in writing. The failure of either party to assert a right hereunder or to insist upon compliance with any term or condition of this Agreement shall not constitute a waiver of that right by that party or excuse a similar subsequent failure to perform any of these terms or conditions by the other party.

 

14.2                        This Agreement constitutes the entire agreement between the parties relating to the subject matter of the Licensed Patent Rights, Licensed Products and Licensed Processes, and all prior negotiations, representations, agreements, and understandings are merged into, extinguished by, and completely expressed by this Agreement.

 

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14.3                        The provisions of this Agreement are severable, and in the event that any provision of this Agreement shall be determined to be invalid or unenforceable under any controlling body of law, this determination shall not in any way affect the validity or enforceability of the remaining provisions of this Agreement.

 

14.4                        If either party desires a modification to this Agreement, the parties shall, upon reasonable notice of the proposed modification by the party desiring the change, confer in good faith to determine the desirability of the modification. No modification shall be effective until a written amendment is signed by the signatories to this Agreement or their designees.

 

14.5                        The construction, validity, performance, and effect of this Agreement shall be governed by Federal law as applied by the Federal courts in the District of Columbia..

 

14.6                        All Agreement notices required or permitted by this Agreement shall be given by prepaid, first class, registered or certified mail or by an express/overnight delivery service provided by a commercial carrier, properly addressed to the other party at the address designated on the following Signature Page, or to another address as may be designated in writing by the other party. Agreement notices shall be considered timely if the notices are received on or before the established deadline date or sent on or before the deadline date as verifiable by U.S. Postal Service postmark or dated receipt from a commercial carrier. Parties should request a legibly dated U.S. Postal Service postmark or obtain a dated receipt from a commercial carrier or the U.S. Postal Service. Private metered postmarks shall not be acceptable as proof of timely mailing.

 

14.7                        This Agreement shall not be assigned or otherwise transferred by Licensee without the prior written consent of PHS, which consent will not be unreasonably withheld. Licensee acknowledges the applicability of 41 U.S.C. s. 15, the Anti-Assignment Act, to this Agreement. The Parties agree that the identity of the Parties is material to the formation of this Agreement and that the duties under this Agreement are nondelegable.

 

14.8                        Licensee agrees in its use of any PHS-supplied biological materials that are supplied under this Agreement to comply with all applicable statutes, regulations, and guidelines, including PHS and HHS regulations and guidelines. Licensee agrees not to use such biological materials for research involving human subjects or clinical trials in the United States without complying with 21 CFR Part 50 and 45 CFR Part 46. Licensee agrees not to use such biological materials for research involving human subjects or clinical trials outside of the United States without notifying PHS, in writing, of the research or trials and complying with the applicable regulations of the appropriate national control authorities. Written notification to PHS of research involving such biological materials and human subjects or clinical trials outside of the United States shall be given no later than sixty (60) days prior to commencement of the research or trials.

 

14.9                        Licensee acknowledges that it is subject to and agrees to abide by the United States laws and regulations (including the Export Administration Act of 1979 and Arms Export Control Act) controlling the export of technical data, computer software, laboratory prototypes, biological material, and other commodities. The transfer of these items may require a license from the appropriate agency of the U.S. Government or written assurances by Licensee that it shall not export these items to certain foreign countries without prior approval of this agency. PHS neither represents that a license is or is not required or that, if required, it shall be issued.

 

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14.10                 Licensee agrees to mark the Licensed Products or their packaging sold in the United States with all applicable U.S. patent numbers and similarly to indicate “Patent Pending” status. All Licensed Products manufactured in, shipped to, or sold in other countries shall be marked in a manner to preserve PHS patent rights in those countries.

 

14.11                 By entering into this Agreement, PHS does not directly or indirectly endorse any product or service provided, or to be provided, by Licensee whether directly or indirectly related to this Agreement. Licensee shall not state or imply that this Agreement is an endorsement by the Government, PHS, any other Government organizational unit, or any Government employee. Additionally, Licensee shall not use the names of NIH, FDA, PHS, or HHS or the Government or their employees in any advertising, promotional, or sales literature without the prior written approval of PHS.

 

14.12                 The parties agree to attempt to settle amicably any controversy or claim arising under this Agreement or a breach of this Agreement, except for appeals of modifications or termination decisions provided for in Article 13. Licensee agrees first to appeal any unsettled claims or controversies to the designated PHS official, or designee, whose decision shall be considered the final agency decision. Thereafter, Licensee may exercise any administrative or judicial remedies that may be available.

 

14.13                 Nothing relating to the grant of a license, nor the grant itself, shall be construed to confer upon any person any immunity from or defenses under the antitrust laws or from a charge of patent misuse, and the acquisition and use of rights pursuant to 37 CFR Part 404 shall not be immunized from the operation of state or Federal law by reason of the source of the grant.

 

14.14                 Any formal recordation of this Agreement required by the laws of any Licensed Territory as a prerequisite to enforceability of the Agreement in the courts of any foreign jurisdiction or for other reasons will be carried out by Licensee at its expense, and appropriately verified proof of recordation will be promptly furnished to PHS.

 

14.15                 Paragraphs 4.3, 8.1, 9.5-9.7, 9.9, 12.1-12.6, 13.9, 13.10, and 14.12 of this Agreement shall survive termination of this Agreement.

 

14.16                 The terms and conditions of this Agreement shall, at PHS’ sole option, be considered by PHS to be withdrawn from Licensee’s consideration and the terms and conditions of this Agreement, and the Agreement itself to be null and void, unless this Agreement is executed by the Licensee and a fully executed original is received by PHS within sixty (60) days from the date of PHS signature found at the Signature Page.

 

SIGNATURES BEGIN ON NEXT PAGE

 

21

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

PHS PATENT LICENSE AGREEMENT —EXCLUSIVE

 

SIGNATURE PAGE

 

For PHS:

 

	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
8-8-08
    
	
[***]
    	
 
    	
Date
    

Director, Division of Technology Development and Transfer

Office of Technology Transfer

National Institutes of Health

 

Mailing Address for Agreement notices:

 

Chief, Monitoring & Enforcement Branch, DTDT

Office of Technology Transfer

National Institutes of Health

6011 Executive Boulevard, Suite 325

Rockville, Maryland 20852-3804 U.S.A.

 

22

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

For Licensee (Upon, information and belief, the undersigned expressly certifies or affirms that the contents of any statements of Licensee made or referred to in this document are truthful and accurate.):

 

by:

 

	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
August 12, 2008
    
	
Signature of Authorized   Official
    	
 
    	
Date
    
	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
 
    
	
Printed Name
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
CEO and President
    	
 
    	
 
    
	
Title
    	
 
    	
 
    

 

I.                Official and Mailing Address for Agreement notices:

 

BN ImmunoTherapeutics

 

2425 Garcia Avenue.

 

Mountain View. CA 94043

 

II.           Official and Mailing Address for Financial notices (Licensee’s contact person for royalty payments)

 

	
[***]
    	
 
    	
 
    
	
Printed Name
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
CEO and President
    	
 
    	
 
    
	
Title
    	
 
    	
 
    

 

Mailing Address:

 

BN ImmunoTherapeutics

 

2425 Garcia Avenue.

 

Mountain View, CA 94043

 

Email Address:             [***]

 

Phone                             [***]

 

Fax:                                [***]

 

Any false or misleading statements made, presented, or submitted to the Government, including any relevant omissions, under this Agreement and during the course of negotiation of this Agreement are subject to all applicable civil and criminal statutes including Federal statutes 31 U.S.C. §§3801-3812 (civil liability) and 18 U.S.C. § 1001 (criminal liability including fine(s) or imprisonment).

 

23

 

APPENDIX A - PATENT(S) OR PATENT APPLICATION(S)

 

Patent(s) or Patent Application(s):

 

Group I—Exclusive Licensed Patent Rights

 

1.     U.S. Patent No. 6,946,133 issued September 20, 2005 and U.S. Patent Application No. 11/606,929 filed December 1, 2006, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No E-062-1996/0]

 

2.     U.S. Patent Application Nos. 60/334,669 and 10/497,003 filed November 30, 2001 and August 24, 2004 respectively, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-124-2001/0, 1]; and

 

3.     U.S. Patent No. 6,165,460 issued December 26, 2000 and U.S. Patent Application No. 09/693,121 filed October 20, 2000; as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No E-200-1990/4]

 

Group II—Nonexclusive Licensed Patent Rights

 

1.     U.S. Patent No. 6,969,609 issued November 29, 2005; U.S. Patent No. 7,211,432 issued May 1, 2007; U.S. Patent Application No. 11/723,666 filed March 21, 2007; as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-256-1998/0];

 

2.     U.S. Patent Application Nos. 08/686,280 filed July 25, 1996 and 08/686,281 filed July 25, 1996 as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E¬259-1994/3, 4];

 

3.     U.S. Patent Nos. 6,893,869, 6,548,068 and 6,045,802 issued May 17, 2005, April 15, 2003 and April 4, 2000 respectively, as well as issued and pending foreign counterparts [HHS Ref. Nos. E-260-1994/1-US-03, US-02, US-01]; and U.S. Patent. Application No. 11/090,686 filed March 8, 2005 [HHS Ref. No E-260-1994/1-US-04];

 

4.     U.S. Patent Application Nos. 60/211,717 and 10/297,168 filed June 15, 2000 and August 16, 2003 respectively, as well as all continuations, divisionals, and foreign counterparts [HHS Ref. No. E-187-2000/0];

 

5.     U.S. Patent Application Nos. 60/448,591 and 10/543,944 filed February 20, 2003 and February 20, 2004 respectively, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-028-2007/0];

 

6.     U.S. Patent No. 6,699,475 issued March 2, 2004, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-134-2007/0];

 

7.     U.S. Patent No. 5,093,258 issued March 3, 1992, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-135-2007/0];

 

8.     U.S. Patent Application No. 07/205,189 filed June 10, 1988, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref No. E-136-2007];

 

24

 

9.     U.S. Patent Application No. 60/625,321 filed November 5, 2004, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-138-2007]; and

 

10.  U.S. Patent Application No. 07/340,052 filed April 18, 1989, as well as all continuations, divisionals, and issued and pending foreign counterparts [HHS Ref. No. E-147-2007].

 

25

 

APPENDIX B — LICENSED FIELDS OF USE AND TERRITORY

 

I.             Licensed Fields of Use:

 

(a)   Use of Licensed Patent Rights for development of therapies for prostatic diseases

 

II.            Licensed Territory:

 

(a)   Worldwide

 

26

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

APPENDIX C — ROYALTIES

 

Royalties:

 

I.                                        Licensee agrees to pay to PHS a [***] royalty in the amount of [***] to be paid as follows:

 

(a)                                 [***] due within [***] from the effective date of this Agreement;

 

(b)                                 [***] due one the [***] anniversary of the execution of this Agreement, and

 

(c)                                  In the case of each of (a) and (b) above, such payments shall be due so long as Licensee has not terminated this Agreement pursuant to Paragraph 13.4.

 

II.                                   Licensee agrees to pay to PHS a [***] royalty in the amount of [***] as follows:

 

(a)         If the Licensee has executed a Cooperative Research and Development Agreement (CRADA) within [***] of the effective date of this Agreement with the National Cancer Institute (NCI) to develop any of the Licensed Patent Rights the first [***] royalty will be due within [***] of termination of the CRADA;

 

(b)         If the Licensee has not executed a Cooperative Research and Development Agreement (CRADA) with the NCI to develop any of the Licensed Patent Rights the first [***] royalty is due within [***] of the effective date of this Agreement and may be prorated according to the [***] remaining between the effective date of this Agreement and the next [***]; and

 

(c)   Subsequent [***] royalty payments are due and payable on [***] and may be credited against any earned royalties due for sales made in that year.

 

III.                              Licensee agrees to pay PHS earned royalties of [***] percent ([***]%) on Net Sales by or on behalf of Licensee and its sublicensees.

 

a)    Licensee shall be entitled to reduce the earned royalty rate by [***] percent ([***]%) for each percent royalty in excess of [***] percent ([***]%) the Licensee or its sublicensees must pay to one or more third party(ies), separately or cumulatively, in respect of the manufacture, sale or importation of the Licensed Product or use of Licensed Processes in the Licensed Territory. Reduction shall however not reduce the earned royalty rate due to PHS under this Agreement below [***] percent ([***]%).

 

IV.                               Licensee agrees to pay PHS Benchmark royalties within [***] of achieving each Benchmark:

 

(a)         [***] upon successful completion of the [***]. For purposes of this Agreement [***].

 

27

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

(b)         [***] upon [***] of first [***] for the [***] in any one of the following [***].

 

(c)          [***] upon First Commercial Sale anywhere in the world of the first Licensed Product or Licensed Process.

 

V.                                    Licensee agrees to pay PHS additional sublicensing royalties for each sublicense required to be approved by PHS pursuant to Paragraph 4.1 of [***] percent ([***]%) on the fair market value of any consideration received for granting such sublicense within [***] of the execution of such sublicense grant; provided that, notwithstanding anything to the contrary, any such consideration will not include the following:

 

(c)          [***], and limited to support [***] specifically excluding any support [***] to the effective date of this Agreement;

 

(d)         [***] the effective date of this Agreement, to the extent that [***];

 

(e)          [***] the effective date of this Agreement [***] to the extent that [***] does not exceed by more than [***] percent ([***]%) the [***] for the [***], or if such [***], then the [***] of [***] as reasonably agreed to by the parties or as [***];

 

(f)           As [*** ]; and

 

(g)          Any [***] which is specifically in the form of [***], if such [*** ].

 

VI.          Pursuant to Paragraph 6.9(a), Licensee will pay [***] percent ([***]%)(of unreimbursed patent expenses for Group I Licensed Patent Rights incurred after February 16, 2007.  Pursuant to Paragraph 6.9(b), Licensee will pay [***] percent ([***]%) of the unreimbursed patent expenses for Group II Licensed Patent Rights incurred after February 16, 2007.

 

28

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

APPENDIX D — BENCHMARKS AND PERFORMANCE

 

Licensee agrees to the following Benchmarks for its performance under this Agreement and, within [***] of achieving a Benchmark, shall notify PHS that the Benchmark has been achieved.

 

I.             Signature of the Agreement

 

[***]

 

29

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

I.             APPENDIX E — COMMERCIAL DEVELOPMENT PLAN

 

Licensee intends to continue the clinical development of PROSTVAC and, if feasible, to commercialize that product in the United States.  Clinical development undertaken by BNIT will include co-development with the NCI under a CRADA.  This agreement (CRADA 2377) is currently in final stages of discussion and is intended to be finalized at the time of signature of this license agreement.

 

The CRADA includes a research plan that contemplates strategy and studies for the development of PROSTVAC.  Key anticipated activities and timelines for US development are summarized as follows.  In addition, the design and timelines of the pivotal studies are subject to FDA acceptance of the design and endpoints as well as to the uncertainties associated with timely enrolment of patients into clinical studies.

 

[***]

 

30

 

APPENDIX F - EXAMPLE ROYALTY REPORT

 

Required royalty report information includes:

 

·                                          OTT license reference number (L-XXX-200X/0)

·                                          Reporting period

·                                          Catalog number and units sold of each Licensed Product (domestic and foreign)

·                                          Gross Sales per catalog number per country

·                                          Total Gross Sales

·                                          Itemized deductions from Gross Sales

·                                          Total Net Sales

·                                          Earned Royalty Rate and associated calculations

·                                          Gross Earned Royalty

·                                          Adjustments for Minimum Annual Royalty (MAR) and other creditable payments made

·                                          Net Earned Royalty due

 

Example

 

	
Catalog Number
    	
 
    	
Product Name
    	
 
    	
Country
    	
 
    	
Units Sold
    	
 
    	
Gross Sales
   (US$)
    	
 
    
	
1
    	
 
    	
A
    	
 
    	
US
    	
 
    	
250
    	
 
    	
62,500
    	
 
    
	
1
    	
 
    	
A
    	
 
    	
UK
    	
 
    	
32
    	
 
    	
16,500
    	
 
    
	
1
    	
 
    	
A
    	
 
    	
France
    	
 
    	
25
    	
 
    	
15,625
    	
 
    
	
2
    	
 
    	
B
    	
 
    	
US
    	
 
    	
0
    	
 
    	
0
    	
 
    
	
3
    	
 
    	
C
    	
 
    	
US
    	
 
    	
57
    	
 
    	
57,125
    	
 
    
	
4
    	
 
    	
D
    	
 
    	
US
    	
 
    	
12
    	
 
    	
1,500
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
Total Gross   Sales
    	
 
    	
153,250
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
Less Deductions:
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
Freight
    	
 
    	
3,000
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
Returns
    	
 
    	
7,000
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
Total Net Sales
    	
 
    	
143,250
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
Royalty Rate
    	
 
    	
8
    	
%
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
Royalty Due
    	
 
    	
11,460
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
Less Creditable Payments
    	
 
    	
10,000
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    	
Net   Royalty Due
    	
 
    	
1,460
    	
 
    
											

 

31

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

APPENDIX G — ROYALTY PAYMENT OPTIONS

 

NIH/PHS License Agreements

 

*In order to process payment via Electronic Funds Transfer sender MUST supply the following information:

 

Procedure for Transfer of Electronic Funds to NIH for Royalty Payments

 

[***]

 

NOTE: Only U.S. banks can wire directly to the Federal Reserve Bank.  Foreign banks cannot wire directly to the Federal Reserve Bank, but must go through an intermediary U.S. bank Foreign banks may send the wire transfer to the U.S. bank of their choice, who, in turn forwards the wire transfer to the Federal Reserve Bank.

 

Checks drawn on a U.S. bank account should be sent directly to the following address:

 

National Institutes of Health (NIH)

P.O. Box 979071

St. Louis, MO 63197-9000

 

Overnight or courier deliveries should be sent to the following address:

 

US Bank

Government Lockbox SL-MO-C2GL

1005 Convention Plaza

St. Louis, MO 63101

Phone: 314-418-4087

 

Checks drawn on a foreign bank account should be sent directly to the following address:

 

National Institutes of Health (NIH)

Office of Technology Transfer

Royalties Administration Unit

6011 Executive Boulevard

Suite 325, MSC 7660

Rockville, Maryland 20852

Phone: 301-496-7057

 

All checks should be made payable to “NIH Patent Licensing”.

 

The OTT Reference Number MUST appear on checks, reports and correspondence

 

32

 

PUBLIC HEALTH SERVICE

 

FIRST AMENDMENT TO L-149-2008/0

 

This is the first amendment (“First Amendment”) of the agreement by and between the National Institutes of Health (“NIH”) or the Food and Drug Administration (“FDA”), hereinafter singly or collectively referred to as agencies of the United States Public Health Service (“PHS”) within the Department of Health and Human Services (“HHS”), and BN ImmunoTherapeutics, having an effective date of August 12, 2008 and having NIH Reference Number L-149-2008/0 (“Agreement”).  This First Amendment, having NIH Reference Number L-149-2008/1, is made between the PHS through the Office of Technology Transfer, NIH, having an address at 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804, U.S.A., and BN ImmunoTherapeutics, having an office at 2425 Garcia Ave., Mountain View, California 94043 (“Licensee”).  This First Amendment includes, in addition to the amendments made below, 1) a Signature Page, Attachment 1 (Modified Appendix E Timelines) and 3) Attachment 2 (Royalty Payment Information).

 

WHEREAS, PHS and Licensee desire that the Agreement be amended a first time as set forth below in order to 1) Modify Paragraphs 11.2 and 11.3 and 2) Modify Appendix E timelines.

 

NOW, THEREFORE, in consideration of the mutual covenants and promises contained herein, PHS and Licensee, intending to be bound, hereby mutually agree to the following:

 

1) Paragraph 11.2 (a)-(d) shall be deleted and replaced with the following:

 

Pursuant to this Agreement and the provisions of Chapter 29 of Title 35, United States Code, Licensee may:

 

(a)                                 bring suit in its own name, at its own expense, and on its own behalf for infringement of presumably valid claims in the Licensed Patent Rights;

 

(b)                                 in any suit, enjoin infringement and collect for its use, damages, profits, and awards of whatever nature recoverable for the infringement; or

 

(c)                                  Upon written approval of PHS, settle any claim or suit for infringement of the Licensed Patent Rights; and

 

	
A-058-2011
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
CONFIDENTIAL
    	
 
    	
 
    	
 
    	
 
    
	
First Amendment of L-149-2008/0
    	
 
    	
Final BN ImmunoTherapeutics,
    	
 
    	
February 15, 2011
    
	
Model 09-2006 (updated 8-2010)
    	
 
    	
 
    	
 
    	
1.-149-2008/1
    

 

1

 

(d)                                 If Licensee desires to initiate a suit for patent infringement, Licensee shall notify PHS in writing.  If PHS does not notify Licensee of its intent to pursue legal action within ninety (90) days, Licensee shall be free to initiate suit.  PHS shall have a continuing right to intervene in the suit.  Licensee shall take no action to compel the Government either to initiate or to join in any suit for patent infringement.  Licensee may request the Government to initiate or join in any suit if necessary to avoid dismissal of the suit.  Should the Government be made a party to any suit, Licensee shall reimburse the Government for any costs, expenses, or fees which the Government incurs as a result of the motion or other action, including all costs incurred by the Government in opposing the motion or other action.  In all cases, Licensee agrees to keep PHS reasonably apprised of the status and progress of any litigation.  Before Licensee commences an infringement action, Licensee shall notify PHS and give careful consideration to the views of PHS and to any potential effects of the litigation on the public health in deciding whether to bring suit.

 

2)            Paragraph 11.3 shall be deleted and replaced with the following:

 

In the event that a declaratory judgment action alleging invalidity or non-infringement of any of the Licensed Patent Rights shall be brought against Licensee or raised by way of counterclaim or affirmative defense in an infringement suit brought by Licensee under Paragraph 11.2, pursuant to this Agreement and the provisions of Chapter 29 of Title 35, United States Code or other statutes, Licensee may:

 

(a)                                 defend the suit in its own name, at its own expense, and on its own behalf for presumably valid claims in the Licensed Patent Rights;

 

(b)                                 in any suit, ultimately to enjoin infringement and to collect for its use, damages, profits, and awards of whatever nature recoverable for the infringement; and

 

(c)                                  Upon written approval of PHS, settle any claim or suit for declaratory judgment involving the Licensed Patent Rights and PHS shall have a continuing right to intervene in the suit; and

 

(d)                                 If PHS does not notify Licensee of its intent to respond to the legal action within a reasonable time, Licensee shall be free to do so.  Licensee shall take no action to compel the Government either to initiate or to join in any declaratory judgment action.  Licensee may request the Government to initiate or to join any suit if necessary to avoid dismissal of the suit.  Should the Government be made a party to any suit by motion or any other action of Licensee, Licensee shall reimburse the Government for any costs, expenses, or fees, which the Government incurs as a result of the motion or other action.  If Licensee elects not to defend against the declaratory judgment action, PHS, at its option, may do so at its own expense.  In all cases, Licensee agrees to keep PHS reasonably apprised of the status and progress of any litigation.  Before Licensee commences an infringement action, Licensee shall notify PHS and give careful consideration to the views of PHS and to any potential effects of the litigation on the public health in deciding whether to bring suit.

 

2

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

3)             Appendix E timelines shall be deleted and replaced with the timelines as specified in Attachment 1

 

4)             Within [***] of the execution of this First Amendment, Licensee shall pay PHS an amendment issue royalty in the sum of [***], and payment options may be found in Attachment 2.

 

5)             In the event any provision(s) of the Agreement is/are inconsistent with Attachment 1 and/or 2, such provision(s) is/are hereby amended to the extent required to avoid such inconsistency and to give effect to the shipping and payment information in such Attachment 1 and/or 2.

 

6)             All terms and conditions of the Agreement not herein amended remain binding and in effect.

 

7)             The terms and conditions of this First Amendment shall, at PHS’ sole option, be considered by PHS to be withdrawn from Licensee’s consideration and the terms and conditions of this First Amendment, and the First Amendment itself, to be null and void, unless this First Amendment is executed by Licensee and a fully executed original is received by PHS within sixty (60) days from the date of PHS signature found at the Signature Page.

 

8)             This First Amendment is effective upon execution by all parties.

 

SIGNATURES BEGIN ON NEXT PAGE

 

3

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

FIRST AMENDMENT TO L-149-2008/0

 

SIGNATURE PAGE

 

In Witness Whereof, the parties have executed this First Amendment on the dates set forth below.  Any communication or notice to be given shall be forwarded to the respective addresses listed below.

 

	
For PHS:
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
2-16-11
    
	
[***]
    	
 
    	
Date
    
	
Director, Division of   Technology Development and Transfer
    	
 
    	
 
    
	
Office of Technology   Transfer
    	
 
    	
 
    
	
National Institutes of   Health
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
Mailing Address for Agreement notices:
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
Chief,   Monitoring & Enforcement Branch, DTDT
    	
 
    	
 
    
	
Office of Technology   Transfer
    	
 
    	
 
    
	
National Institutes of   Health
    	
 
    	
 
    
	
6011 Executive   Boulevard, Suite 325
    	
 
    	
 
    
	
Rockville, Maryland   20832-3804 U.S.A.
    	
 
    	
 
    

 

For Licensee (Upon information and belief, the undersigned expressly certifies or affirms that the contents of any statements of Licensee made or referred to in this document arc truthful and accurate.):

 

 

	
[***]
    	
 
    	
2-25-2011
    
	
Signature of Authorized   Official
    	
 
    	
Date
    
	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
 
    
	
Name
    	
 
    	
 
    
	
 
    	
 
    	
 
    
	
CEO and President
    	
 
    	
 
    
	
Title
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
I.
    	
Official and Mailing   Address for Agreement notices:
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
[***]
    	
 
    	
 
    
	
 
    	
Name
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
CEO and President
    	
 
    	
 
    
	
 
    	
Title
    	
 
    	
 
    

 

4

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

	
 
    	
Mailing Address:
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
BN ImmunoTherapeutics
    	
 
    
	
 
    	
2425Garcia Avenue,
    	
 
    
	
 
    	
Mountain View, CA 94043
    	
 
    
	
 
    	
Email Address: [***]
    	
 
    
	
 
    	
Phone: [***]
    	
 
    
	
 
    	
Fax: [***]
    	
 
    
	
 
    	
 
    
	
II.
    	
Official and Mailing   Address for Financial notices (Licensee’s   contact person for royalty payments):
    
	
 
    	
 
    	
 
    
	
 
    	
Reiner Laus, M.D.
    	
 
    
	
 
    	
Name
    	
 
    
	
 
    	
CEO and President
    	
 
    
	
 
    	
Title
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
Mailing Address:
    	
 
    
	
 
    	
 
    	
 
    
	
 
    	
BN ImmunoTherapeutics
    	
 
    
	
 
    	
2425Garcia Avenue,
    	
 
    
	
 
    	
Mountain View, CA 94043
    	
 
    
	
 
    	
Email Address: [***]
    	
 
    
	
 
    	
Phone: [***]
    	
 
    
	
 
    	
Fax: [***]
    	
 
    

 

Any false or misleading statements made, presented, or submitted to the Government, including any relevant omissions, under this Agreement and during the course of negotiation of this Agreement are subject to all applicable civil and criminal statutes including Federal statutes 31 U.S.C. §§3801-3812 (civil liability) and 18 U.S.C. §1001 (criminal liability including fine(s) or imprisonment).

 

5

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

ATTACHMENT 1 — MODIFIED APPENDIX E TIMELINES

 

[***]

 

6

 

***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

NATIONAL INSTITUTES OF HEALTH

 

SECOND AMENDMENT TO L-149-2008/0

 

This is the second amendment (“Second Amendment”) of the agreement by and between the National Institutes of Health (“NIH”) within the Department of Health and Human Services (“HHS”), and Bavarian Nordic Inc. (formerly known as BN ImmunoTherapeutics, Inc.) having an effective date of August 12, 2008, NIH Reference Number L-149-2008/0, and a first amendment NIH Reference Number L-149-2008/1 effective February 25, 2011 (collectively the “Agreement”).  This Second Amendment, having NIH Reference Number L-149-2008/2, is made between the NIH through the Office of Technology Transfer, NIH, having an address at 6011 Executive Boulevard, Suite 325, Rockville, MD 20852-3804, U.S.A., and Bavarian Nordic Inc., having an office at 2425 Garcia Ave, Mountain View CA 94043, U.S.A. (the “Licensee”).  This Second Amendment includes, in addition to the amendments made below, 1) a Signature Page and 2) Appendix E — Commercial Development Plan.

 

WHEREAS, Licensee’s sublicensee, Bavarian Nordic A/S, seeks to close a transaction with Bristol-Myers Squibb Company, a Delaware corporation headquartered at 345 Park Avenue, New York, NY 10154 (“BMS”) to better advance development and commercialization of the technology licensed in the following NIH Licenses - NIH Reference Number L-149-2008/0 effective August 12, 2008, and NIH Reference Number L-149-2008/1 effective February 25, 2011;

 

WHEREAS, On [***], Licensee provided the NIH with a draft copy of the sublicense entitled “Option and License Agreement” Draft dated [***] (the “Sublicense”);

 

WHEREAS, Licensee has requested extension of the agreed upon benchmark dates listed in Appendix E —Commercial Development Plan of the Agreement in the 2012 and 2013 annual progress reports submitted to the NIH;

 

WHEREAS, Licensee and BMS has requested certain amendments to the Agreement in relation to the proposed Sublicense;

 

NOW, THEREFORE, in consideration of the mutual covenants and promises contained herein, the NIH and the Licensee, intending to be bound, hereby mutually agree to the following:

 

1)             The following modifications shall be made to the Agreement:

 

a.              Appendix E —Commercial Development Plan of the Agreement shall be deleted and replaced with Appendix E — Commercial Development Plan attached to this Second Amendment.

 

b.              Paragraph 2.1 of the Agreement shall be deleted and replaced with the following:

 

2.1                               “Affiliate” means any person, corporation, firm, limited liability company, partnership or other entity that directly controls or is controlled by or is under common control with Licensee or a sublicensee respectively.  For the purposes of this Paragraph 2.1, “control” means ownership, directly or indirectly through one or more Affiliates, of fifty percent (50%) or more of the shares of stock entitled to vote for the election of directors, in the case of a corporation, or fifty percent (50%) or more of the equity interests in the case of any other type of legal entity, status as a general partner in any partnership, or any other arrangement whereby a person or entity controls or has the right to control the Board of Directors or equivalent governing body of a corporation or other entity.

 

	
A-144-2015
    	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
 
    	
 
    	
 
    
	
CONFIDENTIAL
    	
 
    	
 
    	
 
    	
 
    
	
Second Amendment of L-149-2008/0
    	
 
    	
Final BN   ImmunoTherapeutics, Inc.
    	
 
    	
March 2, 2015
    
	
Model 09-2006 (updated 8-2012)
    	
 
    	
 
    	
 
    	
 
    

 

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with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

c.               The following is added at the end of Paragraph 2.11:

 

“For clarity,

 

(A)                               Net Sales shall not [***], provided that such consideration is [***];

 

(B)                               Sales to a [***], or [***];

 

(C)                               Net Sales by [***] as Net Sales by [***]; and

 

(D)                               If a [***], then Net Sales shall be [***].

 

d.              Paragraph 4.1 of the Agreement shall be deleted and replaced with the following:

 

4.1 Upon written approval, which shall include prior review of any sublicense agreement by PHS and which shall not be unreasonably withheld or delayed, Licensee may enter into sublicensing agreements under the Licensed Patent Rights and any of Licensee’s approved sublicensees may enter into sublicense agreements under the Licensed Patent Rights sublicensed to them; [***].

 

e.               Paragraph 6.8 of the Agreement shall be deleted and replaced with the following:

 

6.8                               [***].  The value of Net Sales attributed under this Article 6 on sales to third parties made in other than an arm’s-length transaction, shall be that which would have been received in an arm’s-length transaction, based on sales of like quantity and quality products on or about the time of the relevant sale.

 

f.                The following shall be added to the Agreement as Paragraph 7.5:

 

7.5                               PHS agree that, with prior written notice to PHS, Licensee or its designated sublicensee shall be entitled to seek patent term extensions in an applicable country for U.S. Patent No. 7,247,615 and all foreign counterparts with respect to any Licensed Product.  PHS shall provide to the patent attorneys or patent agents providing this service appropriate powers of attorney and other documents necessary to undertake this action.  No party shall seek a patent term extension for any other Licensed Patent without the prior written consent of the other party.

 

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with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

g.               The second sentence of Paragraph 8.1 of the Agreement shall be deleted and replaced with the following:

 

These records shall be retained for at least [***] years

following a given reporting period and shall be available during normal business hours or inspection, at the expense of PHS, by an accountant or other designated auditor selected by PHS for the sole purpose of verifying reports and royalty payments hereunder.

 

h.              The second sentence of Paragraph 9.6 of the Agreement shall be deleted and replaced with the following:

 

For conversion of foreign currency into U.S. dollars, the conversion rate shall be the New York foreign exchange rate quoted in The Wall Street Journal on the day preceding the day that the payment is due, except with respect to Net Sales by a sublicensee or its Affiliates in foreign currency, which conversion into U.S. dollars may instead be performed in a manner consistent with the sublicensee’s normal practices used to prepare its audited financial statements for internal and external reporting purposes.

 

i.                  Paragraph 10.3 of the Agreement shall be deleted and replaced with the following:

 

10.3                        Licensee agrees, after its First Commercial Sale in the United States, to make reasonable quantities of Licensed Products or materials produced through use of Licensed Processes within the scope of the Group I Licensed Patent Rights available on a compassionate use basis to indigent patients in the United States, either through the patient’s physician(s) or the medical center treating the patient; provided, however, that such requirement shall not keep the Licensee from commercializing Licensed Product(s) or materials in a manner typical for products of similar commercial market potential, product life, safety, efficacy, and competitive environment, and considering other relevant scientific, technical, financial and commercial factors.

 

j.                 The lead-in to Paragraph 11.2 of the Agreement shall be deleted and replaced with the following:

 

11.2                        Pursuant to this Agreement and the provisions of Chapter 29 of Title 35, United States Code, Licensee or its designated sublicensee may:

 

k.              Paragraph 11.2(d) of the Agreement shall be deleted and replaced with the following:

 

(d)                                 [***].  Before Licensee or its designated sublicensee commences an infringement action, Licensee or its designated sublicensee shall notify PHS and give careful consideration to the views of PHS and to any potential effects of the litigation on the public health in deciding whether to bring suit.  PHS shall have a continuing right to intervene in the suit.  Neither Licensee nor its designated sublicensee shall take any action to compel the Government either to initiate or to join in any suit for patent infringement.  Licensee or its designated sublicensee may request the Government to initiate or join in any suit if necessary to avoid dismissal of the suit.  Should the Government be made party to any suit, Licensee or its designated sublicensee shall reimburse the Government for any costs, expenses, or fees which the Government incurs as a result of the motion or other action, including all costs incurred by the Government in opposing the motion or other action.  In all cases, Licensee or its designated sublicensee agrees to keep PHS reasonably apprised of the status and progress of any litigation.  [***].

 

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with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

l.                  Paragraph 13.2 of the Agreement shall be amended to add the following sentence to the end thereof:

 

PHS shall provide a copy of any notice of default to any sublicensee previously approved by it at the same time as PHS provides such notice to Licensee.  However, the failure of the NIH to send any notice of default to sublicensee shall not diminish the effect of such notice to Licensee.  Licensee is obligated to send a copy of such notice from the NIH to a sublicensee as well.

 

m.          Paragraph I(a) of Appendix B — Licensed Fields of Use and Territory of the Agreement shall be deleted and replaced with the following:

 

I.                                        Licensed Fields of Use:

 

(a)                                 Practice of inventions claimed in Licensed Patent Rights for development, manufacture and commercialization of therapies for prostatic diseases (including but not limited to prostate cancer)

 

2)             Upon review of the draft of the sublicense agreement entitled Option and License Agreement dated [***] (the “Sublicense”) the NIH hereby approves BMS as a sublicensee under the Agreement.

 

3)             NIH hereby clarifies that the United States Manufacturing Waiver dated April 10, 2008 applies to PROSTVAC that is manufactured by Licensee, its Affiliates or third party contractors of Licensee or its Affiliates as noted in the waiver and the Sublicense, and supplied to Related Parties for commercial sale, and in such circumstance does not require any Related Party to obtain a separate written manufacturing waiver or otherwise comply with Paragraph 5.2 with respect to Licensed Products containing PROSTVAC that is so manufactured and supplied;

 

4)             In consideration for this Second Amendment, within [***] of the execution of this Second Amendment, the Licensee shall pay the NIH an amendment issue royalty in the sum of [***], and payment options may be found in Attachment 1.

 

5)             In consideration for sublicense royalty due the NIH under Paragraph 6.5 and Appendix C, Section V of the Agreement, Licensee shall pay the NIH [***] percent ([***]%) of the Upfront Option Grant Payment and Option Exercise and License Payment received by License under Paragraph 8.1(a) and Paragraph 8.1 (b) of the Sublicense.

 

6)             In the event any provision(s) of the Agreement is/are inconsistent with Attachment 1, such provision(s) is/are hereby amended to the extent required to avoid such inconsistency and to give effect to the payment information in such Attachment 1.

 

7)             All terms and conditions of the Agreement not herein amended remain binding and in effect.

 

8)             The terms and conditions of this Second Amendment shall, at the NIH’s sole option, be considered by the NIH to be withdrawn from the Licensee’s consideration and the terms and conditions of this Second Amendment, and the Second Amendment itself, to be null and void, unless this Second Amendment is executed by the Licensee and a fully executed original is received by the NIH within [***] from the date of the NIH’s signature found at the Signature Page.

 

9)             This Second Amendment is effective on the date executed by all parties.

 

SIGNATURES BEGIN ON NEXT PAGE

 

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with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

SECOND AMENDMENT TO L-149-2008/0

 

SIGNATURE PAGE

 

In Witness Whereof, the parties have executed this Second Amendment on the dates set forth below.  Any communication or notice to be given shall be forwarded to the respective addresses listed below.

 

For the NIH:

 

	
[***]
    	
 
    	
[***]
    
	
 
    	
 
    
	
[***]
    	
Date
    
	
 
    	
 
    
	
Deputy Director,   Licensing and Entrepreneurship
    	
 
    
	
Office of Technology   Transfer
    	
 
    
	
National Institutes of   Health
    	
 
    

 

	
Mailing   Address or E-mail Address for Agreement   notices and reports:
    
	
 
    	
 
    
	
Chief,   Monitoring & Enforcement Branch, DTDT
    	
 
    
	
Office of Technology Transfer
    	
 
    
	
National Institutes of   Health
    	
 
    
	
6011 Executive   Boulevard, Suite 325
    	
 
    
	
Rockville, Maryland   20852-3804 U.S.A.
    	
 
    
	
 
    	
 
    
	
E-mail:   LicenseNotices_Reports@mail.nih.gov
    	
 
    

 

For the Licensee (Upon information and belief, the undersigned expressly certifies or affirms that the contents of any statements of the Licensee made or referred to in this document are truthful and accurate.):

 

	
 
    	
 
    	
 
    
	
[***]
    	
 
    	
03MAR2015
    
	
 
    	
 
    
	
Signature of Authorized   Official
    	
Date
    
	
 
    	
 
    
	
Name: [***]
    	
 
    
	
Title: President
    	
 
    
	
 
    
	
 
    	
I.
    	
 
    	
Official   and Mailing Address for Agreement   notices:
    	
 
    
	
 
    	
 
    	
[***]
    	
 
    
	
 
    	
 
    	
Name
    	
 
    
	
 
    	
 
    	
President
    	
 
    
	
 
    	
 
    	
Title
    	
 
    
	
 
    	
 
    	
 
    	
 
    
	
 
    	
 
    	
Mailing   Address:
    	
 
    
						

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

	
Bavarian   Nordic, Inc.
    	
 
    
	
 
    	
 
    
	
2425 Garcia Avenue
    	
 
    
	
 
    	
 
    
	
Mountain View, CA 94043
    	
 
    
	
 
    	
 
    
	
 
    	
 
    
	
 
    	
 
    
	
Email Address:
    	
[***]
    	
 
    
	
 
    	
 
    	
 
    
	
Phone:
    	
[***]
    	
 
    
	
 
    	
 
    	
 
    
	
Fax:
    	
[***]
    	
 
    
	
 
    	
 
    	
 
    

 

II.    Official and Mailing Address for Financial notices (the Licensee’s contact person for royalty payments):

 

	
[***]
    	
 
    
	
Name
    	
 
    
	
Vice President, Finance
    	
 
    
	
Title
    	
 
    
	
 
    	
 
    
	
Mailing Address:
    	
 
    
	
Bavarian   Nordic, Inc.
    	
 
    
	
 
    	
 
    
	
2425 Garcia Avenue
    	
 
    
	
 
    	
 
    
	
Mountain View, CA 94043
    	
 
    
	
 
    	
 
    
	
 
    	
 
    
	
 
    	
 
    
	
Email Address
    	
[***]
    	
 
    
	
 
    	
 
    	
 
    
	
Phone:
    	
[***]
    	
 
    
	
 
    	
 
    	
 
    
	
Fax:
    	
[***]
    	
 
    

 

Any false or misleading statements made, presented, or submitted to the Government, including any relevant omissions, under this Agreement and during the course of negotiation of this Agreement are subject to all applicable civil and criminal statutes including Federal statutes 31 U.S.C. §§3801-3812 (civil liability) and 18 U.S.C. §1001 (criminal liability including fine(s) or imprisonment).

 

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with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

ATTACHMENT 1 —ROYALTY PAYMENT OPTIONS

 

The OTT License Number MUST appear on payments, reports and correspondence.

 

Automated Clearing House (ACH) for payments through U.S. banks only

 

The NIH encourages its licensees to submit electronic funds transfer payments through the Automated Clearing House (ACH).  Submit your ACH payment through the U.S. Treasury web site located at: https://www.pay.gov.  Locate the “NIH Agency Form” through the Pay.gov “Agency List”.

 

Electronic Funds Wire Transfers

 

The following account information is provided for wire payments.  In order to process payment via Electronic Funds Wire Transfer sender MUST supply the following information within the transmission:

 

Drawn on a U.S. bank account via FEDWIRE should be sent directly to the following account:

 

[***]

 

Drawn on a foreign bank account should be sent directly to the following account.  Payment must be sent in U.S. Dollars (USD) using the following instructions:

 

[***]

 

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Checks

 

All checks should be made payable to “NIH Patent Licensing”

 

Checks drawn on a U.S. bank account and sent by US Postal Service should be sent directly to the following address:

 

National Institutes of Health (NIH)

P.O.  Box 979071

St. Louis, MO 63197-9000

 

Checks drawn on a U.S. bank account and sent by overnight or courier should be sent to the following address:

 

US Bank

Government Lockbox SL-MO-C2GL

1005 Convention Plaza

St. Louis, MO 63101

Phone: 314-418-4087

 

Checks drawn on a foreign bank account should be sent directly to the following address:

 

National Institutes of Health (NIH)

Office of Technology Transfer

Royalties Administration

Unit 6011 Executive Boulevard

Suite 325, MSC 7660

Rockville, Maryland 20852

 

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***Text Omitted and Filed Separately

with the Securities and Exchange Commission.

Confidential Treatment Requested

Under 17 C.F.R. Sections 200.80(b)(2), (4), (5) and (6) and 230.406

 

Appendix E — Commercial Development Plan

 

[***]

 

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