Exhibit 10.1 

 

Amendment #1

 

Cooperative Research and Development Agreement # 02734

 

“Cooperative Research and Development Agreement for the

Development and Evaluation of the NCI Proprietary Adoptive Cell

Transfer Immunotherapy Using Tumor Infiltrating Lymphocytes in

Patients with Metastatic Melanoma, Utilizing Genesis Biopharma’s

Business Development Expertise in Adoptive Cell Transfer

Immunotherapy”

 

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. Two originals of this amendment
are provided for execution; one is to remain with the National Cancer Institute
and the other is to remain with the Collaborator.

 

1)     The Collaborator’s name is revised from Genesis Biopharma, Inc. to Lion
Biotechnologies, Inc., with accompanying address corrections; the Collaborator
Principal Investigator (PI) is revised from Anthony J. Cataldo to Elma S.
Hawkins, Ph.D., M.B.A.

 

2)     Appendix A - TIL (tumor infiltrating lymphocytes) for the following
cancer indications are added to the Appendix A Research Plan: bladder, lung,
triple-negative breast, and HPV-associated cancers. Appendix A is also amended
for the NCI Surgery Branch to send fresh melanoma, bladder, lung,
triple-negative breast, and HPV-associated cancer tumor specimens collected
under NCI protocol 03-C-0277 entitled “Cell Harvest and Preparation for Surgery
Branch Adoptive Cell Therapy Protocols” to Lion or its agents for performing
studies of improved TIL selection and/or for studies related to TIL scale-out
production and process development.

 

3)     Appendix B the Collaborator’s yearly funding is increased to
$2,000,000.00 per year, with quarterly payments of $500,000.00 (except for the
first payment which is $250,000 prorated from the amendment execution date to
2/4/15). Appendix B is also amended to add the NCI Surgery Branch’s contribution
of melanoma, bladder, lung, triple-negative breast, and HPV-associated cancer
specimens to Lion or its agents for studies under this CRADA.

 

5) Appendix C — Section 8.8 and a definition for “Multi-Party Data” is added,
along with accompanying revisions to Section 7.2 and 7.6 licensing provisions;
Section 13.9 is revised to add language relating to the use of Collaborator’s
agents, contractors or consultants.

 

SIGNATURES BEGIN ON THE NEXT PAGE

 

 

 

 

ACCEPTED AND AGREED TO:           For the National Cancer Institute          
/s/ JAMES H. DOROSHOW   1/16/2015 James H. Doroshow, M.D.   Date Deputy Director
for Clinical and Translational     Research, NCI           For Collaborator:    
      /s/ ELMA S. HAWKINS   1/22/2015 Elma S. Hawkins, Ph.D., M.B.A.   Date
Chief Executive Officer    

 

 

 

 

PUBLIC HEALTH SERVICE

 

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

FOR INTRAMURAL-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 “IC”) of the

National Institutes of Health

 

and

 

Lion Biotechnologies, Inc.

hereinafter referred to as the “Collaborator”,

having offices at 21900 Burbank Blvd., 3rd Floor, Woodland Hills, CA 91367

created and operating under the laws of Nevada.

 

PHS ICT-CRADA CRADA Ref. No. 02734 MODEL ADOPTED June 18, 2009 Page 1 of 15
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CONTACTS INFORMATION PAGE

 

CRADA Notices

 

For ICD: For Collaborator:     Technology Transfer Center, NCI Lion
Biotechnologies, Inc. 6120 Executive Blvd., Suite 450 21900 Burbank Blvd., 3rd
Floor Rockville, MD  20852 Woodland Hills, CA  91367 Tel.  301-496-0477
Tel.  818-992-3126 Fax: 301-402-2117 www.lionbio.com

 

Patenting and Licensing

 

For ICD: For Collaborator (if separate from above):     Division Director,
Division of Technology Peter D. Ho, Ph.D., M.B.A. Development and Transfer
Director, Business Development NIH Office of Technology Transfer Lion
Biotechnologies, Inc. 6011 Executive Boulevard, Suite 325 21900 Burbank Blvd.,
3rd Floor Rockville, Maryland 20852-3804 Woodland Hills, CA  91367
Tel:  301-496-7057 Tel.  818-992-3126 Fax:  301-402-0220  

 

Delivery of Materials Identified In Appendix B (if any)

 

For ICD: For Collaborator:     Steven A. Rosenberg, M.D., Ph.D. Elma S. Hawkins,
Ph.D., M.B.A. Surgery Branch, NCI Clinical Development 10 Center Drive, MSC 1201
Lion Biotechnologies, Inc. Bldg. 10, CRC Room 3-3940 21900 Burbank Blvd., 3rd
Floor Bethesda, MD  20892-1201 Woodland Hills, CA  91367 Tel. 301-496-4164
Tel.  646-775-4817 Fax: 301-402-1738  

 

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SUMMARY PAGE

 

EITHER PARTY MAY, WITHOUT FURTHER CONSULTATION OR PERMISSION,

RELEASE THIS SUMMARY PAGE TO THE PUBLIC.

 

TITLE OF CRADA:            Cooperative Research and Development Agreement for
the Development and Evaluation of the NCI Proprietary Adoptive Cell Transfer
Immunotherapy Using Tumor Infiltrating Lymphocytes in Patients with Metastatic
Melanoma, Bladder, Lung, Triple-negative Breast, and HPV-associated Cancers,
Utilizing Lion Biotechnologies’ Business Development Expertise in Adoptive Cell
Transfer Immunotherapy

 

PHS [IC] Component: National Cancer Institute     IC CRADA Principal
Investigator: Steven A. Rosenberg, M.D., Ph.D.     Collaborator: Lion
Biotechnologies, Inc.     Collaborator CRADA Principal Investigator: Elma S.
Hawkins, Ph.D., M.B.A.     Term of CRADA: Five (5) years from the Effective Date

 

ABSTRACT OF THE RESEARCH PLAN:

 

The principal goal of this CRADA is to develop and evaluate effective adoptive
cell transfer-based immunotherapies (ACT) using Tumor Infiltrating Lymphocytes
(TIL), where the ACT/TIL therapy approach is proprietary to the NCI, for the
treatment of patients with metastatic melanoma, bladder, lung, triple-negative
breast, and HPV-associated cancers, utilizing the business development expertise
and resources of Lion Biotechnologies, Inc., Specifically this CRADA will (1)
support the in vitro development of improved methods for the large scale
generation and selection of TIL with anti-tumor reactivity from patients with
metastatic melanoma, bladder, lung, triple-negative breast, and HPV-associated
cancers, based on ACT therapies developed by and proprietary to the NCI Surgery
Branch, to be used for large scale production of TIL for the ACT treatment of
patients with these cancers; (2) develop these approaches for large scale TIL
generation that are in accord with Good Manufacturing Practice (GMP) procedures
suitable for use in treating patients with metastatic melanoma, bladder, lung,
triple-negative breast, and HPV-associated cancers; and (3) develop clinical
trials using these improved methods of large scale TIL generation as well as
improved patient preparative regimens with the goal of commercializing the
ACT/TIL therapy approach for treating patients with metastatic melanoma,
bladder, lung, triple-negative breast, and HPV-associated cancers.

 

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PUBLIC HEALTH SERVICE

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

 

FOR INTRAMURAL-PHS CLINICAL RESEARCH

 

APPENDIX A

 

RESEARCH PLAN

 

Title of CRADA

Cooperative Research and Development Agreement for the Development and
Evaluation of the NCI Proprietary Adoptive Cell Transfer Immunotherapy Using
Tumor Infiltrating Lymphocytes in Patients with Metastatic Melanoma, Bladder,
Lung, Triple-negative Breast, and HPV-associated Cancers, Utilizing Lion
Biotechnologies, Inc.’s Business Development Expertise in Adoptive Cell Transfer
Immunotherapy

 

 

NCI Principal Investigator

Steven A. Rosenberg, M.D., Ph.D.

Chief, Surgery Branch

Center for Cancer Research (CCR)

National Cancer Institute (NCI)

 

Collaborator Principal Investigator

Elma S. Hawkins, Ph.D., M.B.A.

Chief Operating Officer, Clinical Development

Lion Biotechnologies, Inc.

 

Term of CRADA

Five (5) years from the date of the final CRADA signature.

_____________________________________________________________________________

 

Goals of this CRADA

 

The principal goal of this CRADA is to develop and evaluate effective adoptive
cell transfer-based immunotherapies (ACT) using Tumor Infiltrating Lymphocytes
(TIL), where the ACT/TIL therapy approach is proprietary to the NCI, for the
treatment of patients with metastatic melanoma, bladder, lung, triple-negative
breast, and HPV (Human Papilloma Virus)-associated cancers, utilizing the
business development expertise and resources of Lion Biotechnologies, Inc.,
Specifically this CRADA will (1) support the in vitro development of improved
methods for the large scale generation and selection of TIL with anti-tumor
reactivity from patients with metastatic melanoma, bladder, lung,
triple-negative breast, and HPV-associated cancers, based on ACT therapies
developed by and proprietary to the NCI Surgery Branch, to be used for large
scale production of TIL for the ACT treatment of patients with these cancers;
(2) develop these approaches for large scale TIL generation that are in accord
with Good Manufacturing Practice (GMP) procedures suitable for use in treating
patients with metastatic melanoma, bladder, lung, triple-negative breast, and
HPV-associated cancers; and (3) develop clinical trials using these improved
methods of large scale TIL generation as well as improved patient preparative
regimens with the goal of commercializing the ACT/TIL therapy approach for
treating patients with metastatic melanoma, bladder, lung, triple-negative
breast, and HPV-associated cancers. The scope of this CRADA, including any in
vitro and in vivo testing conducted by Dr. Steven A. Rosenberg and members of
the NCI Surgery Branch within the CCR is strictly limited to the development of
TIL as a single agent therapy in conjunction with commercially available
reagents routinely used for ACT therapy (aldesleukin (IL-2), other
chemotherapeutic agents) in treating patients with metastatic melanoma, bladder,
lung, triple-negative breast, and HPV-associated cancers, utilizing Lion’s
expertise in the large scale production of adoptive cell transfer
immunotherapies. Additional research or clinical activities involving current or
prospective NCI Surgery Branch adoptive immunotherapy protocols are outside the
scope of this CRADA unless and until the Parties mutually agree to these studies
which shall be added by written amendment to this CRADA.

 

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Expertise of the Parties

 

Dr. Steven A. Rosenberg has extensive experience in the development and
application of his proprietary adoptive cell-based therapies (ACT) for patients
with cancer. His laboratory has developed in vitro techniques for generating
anti-tumor T cells obtained from patient tumors (TIL) under conditions suitable
for subsequent infusion. Dr. Rosenberg and his colleagues in the NCI Surgery
Branch have extensive experience in the development of cell-based reagents and
the conduct of clinical trials utilizing these cells in immunotherapeutic
protocols.

 

Lion Biotechnologies, Inc. has assembled a team of senior level scientists and
clinicians who have experience in the application of cell-based immunotherapies
to help guide the commercial development of ACT therapy for the treatment of
metastatic melanoma, bladder, lung, triple-negative breast, and HPV-associated
cancers, as specified in “Goals of this CRADA” (“Goals”) based on the NCI
Surgery Branch proprietary technologies for TIL preparation and administration
of ACT to patients. Lion is developing GMP facilities to perform this work
emphasizing the development and evaluation of improved techniques for TIL
generation that meet GMP standards as well as to conduct clinical trials of
ACT/TIL therapy designed to meet the standards of the FDA to achieve approval
for the commercialization of this treatment approach. Thus the combination of
the scientific and clinical expertise of the NCI Surgery Branch with the
scientific and clinical expertise of Lion, and availability of Lion’s GMP
production facilities, represents an ideal opportunity that can lead to the
commercialization of the ACT/TIL treatment approach for patients with those
cancers as specified in “Goals”, making these treatments more widely available
to patients in need.

 

The NCI Surgery Branch and Lion thus have complementary expertise and facilities
that can develop technologies and clinical treatment approaches that have the
potential to improve cell transfer therapy and make it more widely available to
patients through commercialization by Lion.

 

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Experimental Plan

 

The experimental details that follow are approximate and may be changed upon
mutual agreement of the NCI and Collaborator. Any change in the scope of this
CRADA will be by mutual consent and written Amendment to the CRADA.

 

I.           Develop improved methods for the generation and selection of TIL
with anti-tumor reactivity from patients with metastatic melanoma, bladder,
lung, triple-negative breast, and HPV-associated cancers, as specified in
“Goals”, based on adoptive cell transfer therapies proprietary to and developed
by the NCI Surgery Branch, for use in the large scale production of TIL for this
ACT treatment of these cancers.

 

Simplified and better methods for TIL selection and growth are needed to
supplement current NCI Surgery Branch efforts in order to expand ACT/TIL therapy
to greater numbers of patients with those cancers as specified in “Goals”,
Studies of improved methods for TIL selection will be investigated by the NCI
Surgery Branch and Lion. This will include use of in vitro assays of specificity
that are based on specific blocking of Class I MHC (Major Histocompatibility
Complex) molecules that can provide evidence for the specific recognition of
autologous tumor and use of sensitive assays of the upregulation of molecules
such as 4-1-BB or others on the lymphocyte cell surface. Such studies in the NCI
Surgery Branch may also include the separation of phenotypically different
lymphocyte subsets present in TIL such as central memory, effector memory and
terminally differentiated effector cells. NCI Surgery Branch studies in mice
have shown that lymphocyte subsets such as central memory cells can be more
effective in the adoptive immunotherapy of experimental tumors and this needs to
be studied in humans with those cancers as specified in “Goals.” In addition,
NCI Surgery Branch may send fresh melanoma, bladder, lung, triple-negative
breast, and HPV-associated cancer specimens from NCI protocol 03-C-0277 entitled
“Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy
Protocols” to Lion or its agents to develop techniques for growing TIL and for
performing assays involving criteria which are designed to improve TIL
selection. Assays will be performed on the growing TIL to evaluate their
recognition of autologous tumor cells assessed by gamma interferon release in
overnight co-culture with tumor and to evaluate the phenotypic expression of
cell surface markers on TIL such as CD62L, CD45RO, CD45RA and CD127. Such
studies would form the basis for TIL selection and generation for use in the
large scale production of TIL for the treatment of patients with those cancers
as specified in “Goals.”

 

II.          Develop approaches to large scale TIL generation that are in accord
with Good Manufacturing Practice (GMP) procedures suitable for their use in
treating patients with metastatic melanoma, bladder, lung, triple-negative
breast, and HPV-associated cancers, as specified in “Goals”

 

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The selection and growth of autologous TIL from patients with those cancers as
specified in “Goals” is a vital part of the successful use of this approach.
Prior NCI Surgery Branch methods for TIL growth involved extensive in vitro
testing using multiple cell lines and fresh tissue samples as well as the growth
of cells in up to 40 2-liter culture bags using large amounts of medium to treat
each patient. Under this CRADA, studies will be conducted of improved methods
for the generation of the large numbers of TIL necessary for patient treatment.
These studies will explore the use of alternate culture vessels including those
that involve the use of gas permeable membranes. The NCI Surgery Branch has
begun some of these studies but extensive additional studies are required to
optimize cell growth including the determination of the best concentrations of
feeder cells, timing of media change and concentrations of growth factors such
as IL-2 (commercially available). These studies will be conducted by the NCI
Surgery Branch with advice, input and expertise provided by Lion. In addition,
the NCI Surgery Branch may send tumor samples from those cancers as specified in
“Goals” which were collected from NCI protocol 03-C-0277 to Lion or its agents
for studies including scale-out for the methods of expansion of individualized
lymphocyte treatments, assays for product and in-process performance, and
harmonization assays for centralized process development and determination of
TIL product consistency. Additionally, biological reagents and materials may be
sent to Lion or its agents for the development of qualifying assays and process
development related to scale-out of the TIL expansion process. Techniques thus
described will need to be adapted to meet the GMP requirements of the Food and
Drug Administration for infusion into patients. This may require modification of
the procedures developed in the NCI Surgery Branch. Lion and the NCI Surgery
Branch will work together to develop Standard Operating Procedures (SOP) for
large scale TIL growth, selection and testing that meet the approval of the FDA.
Joint meetings with the FDA will be required to define the exact format and
criteria need to meet FDA approval.

 

III.         Develop clinical trials using these improved methods of large scale
TIL generation as well as improved patient preparative regimens to treat
patients with metastatic melanoma, bladder, lung, triple-negative breast and
HPV-associated cancers, as specified in “Goals”

 

Clinical trials will be designed and implemented to evaluate the clinical
effectiveness of ACT/TIL therapy resulting from large scale techniques in
patients with those cancers as specified in “Goals”, based on the proprietary
NCI Surgery Branch technology and approaches developed in the first two parts of
this Experimental Plan. Lion and the NCI Surgery Branch will work together to
develop multiinstitutional clinical trials evaluating the clinical effectiveness
of the administration of autologous TIL generated using Lion technology to
patients with those cancers as specified in “Goals” that can potentially be used
as licensing trials for FDA approval. The NCI Surgery Branch does not have a
suitable GMP facility that will meet FDA standards for the conduct of such a
trial. Exploratory pilot trials may be necessary prior to beginning a licensing
trial and these may be conducted in the Surgery Branch alone or in conjunction
with other multicenter sites associated with Lion. The development and conduct
of licensing trials will require the GMP expertise of Lion and the extensive
experience of the NCI Surgery Branch working together. TIL for these trials will
be produced on a large scale by Lion at a central facility for distribution to
participating multicenter sites (including the NCI Surgery Branch). An IND with
the FDA will be filed by Lion which will serve as the Coordinating Center for
such trials. The goal of such trials will be to generate data to support the
approval by the FDA of this ACT/TIL therapy approach. In vitro testing of
patient samples from such trials will evaluate the activity and persistence
level of the transferred cells in the circulation of treated patients and will
be conducted by the NCI Surgery Branch both for any pilot trials that are
performed as well as for the large multiinstitutional trials that are planned.

 

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Description of the Contributions and Responsibilities of the Parties

 

Surgery Branch, NCI

 

-Develop and test new improved and simplified in vitro methods for the selection
and growth of TIL with anti-tumor activity for large scale preparations that can
be used in clinical cell transfer studies. As described in the Experimental Plan
above, this will include evaluation of new growth techniques, culture vessels,
and tests

 

-Perform in vitro studies of the immunologic parameters surrounding the new cell
transfer clinical protocol(s) by analyzing the phenotypic and functional
properties of the transferred cells and their persistence in the patient
following adoptive transfer in all clinical trials conducted under this CRADA,
as outlined in Section III above.

 

Lion

 

-Develop, implement and evaluate GMP procedures for the large scale production
of TIL suitable for infusion into patients with metastatic melanoma, bladder,
lung, triple-negative breast, and HPV-associated cancers as specified in
“Goals.”

 

-Conduct studies including scale-out for the methods of expansion of
individualized lymphocyte treatments, assays for product and in-process
performance, and harmonization assays for centralized process development and
determination of TIL product consistency. Additional studies may be conducted
for the development of qualifying assays and process development related to
scale-out of the TIL expansion process.

 

-Consult with the FDA to determine the appropriate clinical trial design
necessary to secure approval for the commercial development of TIL therapy for
patients with those cancers as specified in “Goals” and sponsor the IND for
these new clinical protocols Serve as the coordinating center for the
multicenter licensing clinical trials.

 

-Supply TIL in sufficient quantities to the NCI Surgery Branch and other
multicenter sites to complete the planned clinical trials (including the
licensing trial) needed for FDA approval of ACT/TIL. Support the establishment
of a central facility for the processing and provision of TIL for the studies
under this CRADA.

 

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Surgery Branch, NCI and Lion

 

  - Develop SOP for large scale TIL growth, selection and testing to support the
FDA approval of the ACT/TIL therapy approach.  Attend joint meetings with the
FDA to define the exact format and criteria needed in the clinical trial(s) to
obtain FDA approval.           Develop, conduct and evaluate multiinstitutional
clinical trials (to include the NCI Surgery Branch as a clinical trial site) for
patients with metastatic melanoma, bladder, lung, triple-negative breast and
HPV-associated cancers (as specified in”Goals”) treated with TIL that can be
used as licensing trials required for FDA approval and subsequent
commercialization of ACT/TIL.         - Conduct assays to be used in the
selection of appropriate cells (based on both functional and phenotypic
criteria) to optimize the effectiveness of the adoptive transfer.         -
Exchange information and expertise to further the successful development of TIL
therapy for patients with those cancers as specified in “Goals.”  

 

Related NCI and Collaborator Agreements: None

 

Related Intellectual Property and Business/Scientific Expertise of the Parties

 

NCI Surgery Branch

 

1) PCT/US03/27873 entitled “Immunotherapy with In Vitro-Selected
Antigen-specific Lymphocytes After Nonmyeloablative Lymphodepleting
Chemotherapy“, filed 9/5/03. Inventors: Mark E. Dudley, Steven A. Rosenberg,
John R. Wunderlich. This is inclusive of all U.S. continuing applications and
divisionals, and foreign applications.

 

2) USSN 12/869,390 entitled “Adoptive Cell Therapy with Young T Cells”, filed
8/26/10. Inventors: Mark E. Dudley and Steven A. Rosenberg. This is inclusive of
all U.S. continuing applications and divisionals.

 

3) PCT/US12/02974 entitled “Methods of Growing Tumor Infiltrating Lymphocytes in
Gas-Permeable Containers”, filed 3/20/12. Inventors: Steven A. Rosenberg, Mark
E. Dudley, et al.. This is inclusive of all U.S. continuing applications and
divisionals, and foreign applications.

 

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4) PCT/US14/046478 entitled “Methods of Preparing Anti-human Papillomavirus
Antigen T Cells”, filed 7/14/2014. Inventors: Christian S. Hinrichs and Steven
A. Rosenberg. This is inclusive of all U.S. continuing applications and
divisionals.

 

Lion Biotechnologies, Inc.

 

Lion has applied to NIH for a license to NIH owned intellectual property under
the license applicationsA-079-2014 and A-286-2014; Lion has a license to
NIH-owned intellectual property under license L-129-2011/0. Collaborator desires
to license NIH owned intellectual property that includes the patents describing
the NCI proprietary ACT/TIL therapy approach to be developed under this CRADA.

 

Lion Biotechnologies, Inc. is a publicly traded biotechnology company developing
therapies for the treatment of cancer. Lion’s lead therapeutic candidate will be
an autologous cell therapy product using tumor infiltrating lymphocytes for the
treatment of metastatic melanoma, bladder, lung, triple-negative breast and
HPV-associated cancers as specified in”Goals”, to be developed under this CRADA.
Lion has a partnership with a major manufacturer for the provision of TIL for
clinical trials to be conducted under this CRADA as well as post-regulatory
approval. The manufacturing facility is cGMP certified and inspected by FDA.

 

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PUBLIC HEALTH SERVICE

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

FOR INTRAMURAL-PHS CLINICAL RESEARCH

 

APPENDIX B

 

STAFFING, FUNDING AND MATERIALS/EQUIPMENT CONTRIBUTIONS

OF THE PARTIES

 

Staffing Contributions:

 

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

 

IC estimates that     3-5     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    3-5    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 $2,000,000.00 per year of
the CRADA for IC to use to acquire technical, statistical, and administrative
support for the research activities, as well as to pay for supplies and travel
expenses. Collaborator will provide funds in the amount of $500,000.00 on a
quarterly basis. The first quarterly installment of of a prorated amount of
$250,000.00 from the Amendment execution date to February 4, 2015 will be due
within thirty (30) days of the Effective Date of the Amendment. Each subsequent
installment will be due within thirty (30) days of each quarterly anniversary of
the CRADA Effective Date. Collaborator agrees that IC can allocate the funding
between the various categories in support of the CRADA research as IC’s CRADA PI
sees fit.

 

CRADA PAYMENTS:

 

Collaborator will make checks payable to the National Cancer Institute and will
reference the CRADA number 02734 and title “CRADA for the Development and
Evaluation of the NCI Proprietary Adoptive Cell Transfer Immunotherapy Using
Tumor Infiltrating Lymphocytes in Patients with Metastatic Melanoma, Bladder,
Lung, Triple-negative Breast and HPV-associated Cancers Utilizing Lion
Biotechnologies, Inc.’s Business Development Expertise in Adoptive Cell Transfer
Immunotherapy” on each check, and will send them via trackable mail or courier
to:

 

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CRADA Funds Coordinator

Technology Transfer Center, NCI

6120 Executive Blvd., Suite 450

Rockville, MD 20852

 

CRADA Travel Payments:

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

 

Materials/Equipment Contributions:

 

IC will provide the following IC Materials for use under this CRADA:

 

  Test Article: None         IC Materials: Fresh melanoma, bladder cancer, lung
cancer, triple- negative breast cancer, and HPV-associated cancer tumor
specimens collected under NCI protocol  03-C-0277 entitled “Cell Harvest and
Preparation for Surgery Branch Adoptive Cell Therapy Protocols”         Capital
Equipment: None

 

Collaborator will provide the following Collaborator Materials and/or capital
equipment for use under this CRADA:

 

  Test Article: Autologous Tumor Infiltrating Lymphocytes (TIL) grown     and
processed under GMP conditions, suitable for use in clinical trials under this
CRADA.         Collaborator Materials: None         Capital Equipment: None

 

If either Party decides to provide additional Materials for use under this
CRADA, those materials will be transferred under a cover letter that identifies
them and states that they are being provided under the terms of the CRADA.

 

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PUBLIC HEALTH SERVICE

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

FOR INTRAMURAL-PHS CLINICAL RESEARCH

 

APPENDIX C

 

MODIFICATIONS TO THE MODEL CRADA

 

Add the Definition of “Multi-Party Data” in Article 2 to read as follows:

 

“Multi-Party Data” means data from studies sponsored by IC pursuant to Clinical
Trial Agreements (CTA) or CRADAs, where such data are collected under Protocols
involving combinations of investigational agents supplied from more than one CTA
or CRADA collaborator. “Multi-Party Data” also means data from studies where
such data are collected pursuant to research involving combinations of
proprietary materials from more than one collaborator as documented in more than
one agreement.

 

Amend Section 7.2 to read as follows:

 

7.2      Collaborator’s License Option to CRADA Subject Inventions. With respect
to Government rights to any CRADA Subject Invention made solely by an IC
employee(s) or made jointly by an IC 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 or co-exclusive, if
applicable, commercialization license. The option to elect a co-exclusive
license shall apply when a CRADA Subject Invention is also an Invention made
under another agreement resulting from mutually agreed upon studies, as
described in Section 8.8 (regarding Multi-Party Data Rights)], and the field of
use of this co-exclusive license shall be limited to the use of the combination
of the Test Article 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.

 

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Amend Section 7.6 to read as follows:

 

7.6      Third Party License. Pursuant to 15 U.S.C. § 3710a(b)(1)(B), if PHS
grants Collaborator an exclusive license or co-exclusive license to a CRADA
Subject Invention made solely by an IC 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(b).

 

Section 7.8 “Joint CRADA Subject Inventions Not Exclusively Licensed by
Collaborator” is deleted in its entirety.

 

Add Section 8.8 as follows:

 

8.8      Multi-Party Data Rights. For mutually agreed upon clinical Protocol(s)
where Test Article is used in combination with another investigational agent
supplied to IC pursuant to a CTA or CRADA between IC and an entity not a Party
to this CRADA (hereinafter referred to as “Third Party”), or for non-clinical
study(ies) where research involving combinations of proprietary materials from
more than one collaborator as documented in more than one agreement, the access
and use of Multi-Party Data by the Collaborator and Third Party shall be
co-exclusive as follows:

 

8.8.1IC will provide both Collaborator and Third Party with notice regarding the
existence and nature of the agreements governing the use of the Test Article and
Third Party’s investigational agent, the design of the proposed combination
Protocol(s) or non-clinical study(ies), and the existence of any obligations
that might restrict IC’s participation in the proposed combination Protocols or
non-clinical study(ies).

 

8.8.2Collaborator 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.

 

8.8.3Collaborator and Third Party must agree in writing prior to the
commencement of the combination Protocol(s) or non-clinical study(ies) that each
will use the Multi-Party Data solely for the development, regulatory approval,
and commercialization of its own investigational agent(s).

 

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8.84The sharing of Multi-Party Data does not alter the ownership of the
Multi-Party Data or obligations of IC, Collaborator and Third Party to keep
Confidential Information owned by any other Party or Parties confidential.

 

Amend the Definition of “Independent Contractors” in Article 13.9 to read as
follows:

 

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 shall maintain sole and exclusive control over
its personnel and operations. If Collaborator elects to perform any portion of
the Research Plan through an agent, contractor or consultant, Collaborator
agrees to incorporate into such contracts all provisions necessary to ensure
that the work of such agents, contractors or consultants is governed by the
terms of the CRADA, including, but not limited to a provision for the assignment
of inventions of the agent, contractor or consultant to the Collaborator.

 

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