Document:

Exhibit 10.30

 

 

May 7,
2007

 

Dr. Charles
Link

NewLink
Genetics Corporation

Suite 3900

2901
South Loop Drive

Ames, IA
50010 USA

 

Re:                               Letter of
Intent for a Cooperative Research and Development Agreement #02166

NCI
Principal Investigators: Drs. Sherry S. Ansher, Lee Jia and Howard
Streicher Collaborator Investigators: Drs. Charles Link and Nicholas
Vahanian

Title:   Preclinical
and Clinical Development of [*]

 

Dear
Dr. Link:

 

It
is my understanding that a cooperative research and development project between
the parties referenced below is being considered. Accordingly, until the formal
Cooperative Research and Development Agreement (CRADA) is reviewed by the CRADA
Subcommittee and approved by the Director, National Cancer Institute (NCI),
this Letter is offered to permit the joint research to commence. However, in
the case of human clinical trials which are a part of the subject CRADA, the
parties agree that all such trials which may begin prior to the execution of
the formal CRADA shall be preceded by the appropriate regulatory approvals
(U.S. Food and Drug Administration IND approval or international equivalents
thereof).

 

It
is acknowledged by the parties below that cooperative research pursuant to the
Research Plan, attached as Appendix A, will be conducted informally by the NCI
Principal Investigators and Collaborator pending formal approval of the CRADA.
It is further acknowledged that patentable inventions may be made by NCI
employees and employees of the Collaborator. Pursuant to its authority under the
Federal Technology Transfer Act of 1986, as amended, NCI agrees that should
this CRADA be approved, it will have retroactive effect to the date that the
last party has executed this Letter for any inventions that may be made under
this Research Plan. NCI further agrees that should this CRADA be approved it
will have retroactive effect to the date that the last party has executed this
Letter for confidentiality obligations specified in the NIH Model CRADA. The
Model CRADA for Extramural-PHS Clinical Research (2005) provisions for the
protection of proprietary information are incorporated in this Letter by
reference and are considered controlling during the period of informal joint
research. These provisions include, but are not limited to Articles 2.0 and 8.
The Model CRADA for Extramural-PHS Clinical Research 

 

 

(2005)
is attached as Appendix B and the CTEP Exceptions or Modifications to this
CRADA (6/27/06) is attached as Appendix C.

 

You
understand, however, that this Letter is not a commitment on the part of either
party to enter into a CRADA. Further, this Letter is effective for a term not
to exceed six (6) months. The six month term may be extended, provided the
CRADA is under active negotiation and the collaborative research is continuing.
Assuming that the necessary approvals are forthcoming, we look forward to a
successful collaboration.

 

	
  Sincerely,

  	
   

  
	
   

  	
   

  
	
   

  	
   

  
	
  /s/
  Kathleen Carroll for

  	
   

  
	
  Karen
  Maurey, M.S.

  	
   

  
	
  Chief,
  Technology Transfer Center, NCI

  	
   

  

 

 

 

	
  AGREED
  AND ACCEPTED:

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  National
  Cancer Institute

  	
   

  	
  NewLink
  Genetics Corporation

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  /s/Anna
  D. Barker

  	
   

  	
  /s/

  
	
  Anna
  D. Barker, Ph.D.

  	
   

  	
   

  
	
  Deputy
  Director

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  05/14/07

  	
   

  	
  05/23/07

  
	
  Date

  	
   

  	
  Date

  

 

Attachments:                                                Appendix A -
Letter of Intent Research Plan

Appendix B - Model CRADA for Extramural-PHS Clinical Research (2005)

Appendix C - CTEP Exceptions or Modifications to this CRADA (6/27/06)

 

 

Appendix A

 

Letter of Intent Research Plan

 

 

APPENDIX A: LETTER OF INTENT RESEARCH PLAN

 

Pre-Clinical and Clinical Development of [*]

 

National Cancer Institute (NCI) Investigators:

Dr. Sherry Ansher

Dr. Lee Jia

Dr. Howard Streicher

 

NewLink Genetics Corporation Investigators:

Dr. Charles Link

Dr. Nicholas Vahanian

 

Term of Proposed CRADA:

Four (4) years from the date of CRADA execution

 

1.                          RESEARCH
GOALS OF PROPOSED CRADA

 

The
overall goal of this proposed CRADA is to collaborate with NewLink Genetics
Corporation (hereafter NewLink) on the pre-clinical and clinical development of
[*] (also known as [*],
or Investigational Agent) for the treatment of [*]
and other [*].

 

The
Division of Cancer Treatment and Diagnosis (DCTD), NCI and NewLink will both
provide resources and expertise for the pre-clinical development of [*] and will work together towards the successful clinical
development of [*] as a safe and effective novel
pharmaceutical compound. The DCTD will provide expertise in designing,
implementing and monitoring [*] clinical
trials through its intramural and extramural clinical trials network.
Additionally, the DCTD will work jointly with NewLink to obtain all the
necessary regulatory approval by the U.S. Food and Drug Administration (FDA)
for [*] as [*].
NewLink will provide expertise in the development, formulation and production
of [*]. The Parties will work together in
the design, implementation and monitoring of the clinical trials planned under
this CRADA as well as all regulatory aspects and New Drug Application (NDA)
filings as necessary for marketing approval for [*]
as [*].

 

2.                          SCIENTIFIC
BACKGROUND

 

[*]

 

[*]

 

[*]

 

3.                          PRE-CLINICAL
DEVELOPMENT OF [*]

 

[*]

 

The
following sections summarize the pre-clinical studies conducted by the NCI
prior to this CRADA Letter of Intent.

 

1

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

4.                          BACKGROUND
OF THE COLLABORATOR

 

NewLink
is a biopharmaceutical company applying innovative techniques in cancer biology
to produce new diagnostic and therapeutic agents for cancer patients. NewLink
is privately held and was incorporated in June 1999. The core of NewLink
is a Cancer Vaccine Development Division that exists to accelerate the
deployment of oncology pharmaceuticals, including HyperAcuteTM Vaccines, into clinical testing and
commercialization. NewLink has recently acquired a worldwide, exclusive license
to patents covering therapeutic uses of [*] as [*] for [*], and [*] undertakes the development [*].[*] is envisioned as [*] and as [*] for use in [*] for the
purpose of [*] of the [*].
NewLink expects to start [*] clinical
trials in [*] ([*]),
subject to the filing of one or more NewLink-sponsored INDs to support such
studies.

 

5.                          DETAILED
DESCRIPTION OF THE RESEARCH PLAN

 

The
Division of Cancer Treatment and Diagnosis (DCTD), NCI and NewLink are
interested in the evaluation of [*] in a
pre-clinical and clinical development program that includes [*] and other [*]. The
pre-clinical work will include IND-directed toxicology studies and formulation
studies. In addition, [*] may conduct
pre-clinical research aimed at enhancing the understanding of the mechanism of
action of [*] and its targets and optimizing its
clinical development program. NCI’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 DCTD-sponsored clinical
studies. DCTD will sponsor [*] clinical
trials that will help determine the [*] of [*]. DCTD and NewLink are also interested in evaluating [*] in [*] or [*] such as [*] in clinical
trials.

 

6.                          RESPECTIVE
CONTRIBUTIONS OF THE PARTIES

 

A.                        Joint
Responsibilities

 

1.                           Steering
Committee and Communication Plan

 

2

 

A
Steering Committee will be employed by the Parties to exchange information and
data and to discuss and to plan the proposed and ongoing clinical research. The
Steering Committee shall be composed of the CRADA Principal Investigators from
NCI and NewLink. In addition, other NCI and NewLink staff with expertise in
toxicology, pharmacology, pharmaceutical development, project management and
other disciplines as pertinent to the current development stage of the
Investigational Agent at the time of a meeting may participate in the meetings
of the Steering Committee. Both Parties shall report regularly to the Steering
Committee on the progress of the clinical research and development efforts
covered by this CRADA, will review the current progress, and will make any
required decisions. The routes of communication, format of written minutes, etc.
will be determined at the Steering Committee meetings and will be driven by the
needs of the project. The Parties have been meeting regularly prior to the
execution of this CRADA Letter of Intent, and will continue to do so.

 

The
Steering Committee will function under the oversight of Co-Chairs, one from NCI
and one from the Collaborator. NCI’s Steering Committee Co-Chair will be
appointed by the DCTD Division Director and report to the DCTD Division
Director or his or her designee. Steering Committee meeting minutes summarizing
all key decisions and issues under discussion will be provided to all the
Steering Committee members and to the DCTD Division Director within [*] of each meeting. Steering Committee decisions will be
made [*].

 

2.                           DCTD’s
preclinical and ancillary studies shall be conducted [*],
as per [*].

 

3.                           The DCTD and
NewLink will explore the clinical utility of [*]
for [*]. As [*]
are identified, it will be important to develop [*]
and [*] and to [*]
and [*] with [*]
for these [*].[*]
studies may be important in diseases where [*] and where
there is a [*] following [*].

 

4.                           Both Parties
shall collaborate in the collection and analysis of data generated under the
Research Plan.

 

5.                           Both Parties
will work closely together to ensure that the pre-clinical and clinical studies
move forward expeditiously.

 

6.                           Subject to the
obligations of the Parties to maintain the data under this CRADA as
confidential and proprietary, the Parties may publicly disclose the results of
their research under the circumstances set forth in the model CRADA.

 

7.                           When
pre-clinical studies and/or a CRADA clinical protocol involves either [*] or involves [*], the NCI,
NewLink [*] will jointly determine a reasonable
and appropriate mechanism for intellectual property and data access and sharing
prior to initiation of the pre-clinical studies and/or the clinical trial.

 

8.                           For activities
conducted pursuant to this CRADA in the United States of America, both Parties
agree to comply with all appropriate DHHS regulations relating to Human
Subjects Use, all U.S. Department of Agriculture regulations, and all Public
Health Service policies relating to the use and care of laboratory animals. For

 

3

 

activities conducted pursuant to this CRADA outside of the United
States of America, both Parties shall conduct such in accordance with GLPs and
all applicable rules, regulations and statutes, both local and national,
governing such activity in that country.

 

9.                           The Parties
acknowledge that [*] means any [*]
that is either readily usable as a [*] or is [*] that will be useful to [*]
in developing [*] (rather than useful [*] or [*]). A [*] may simultaneously be a [*]
and be the essence of a [*], or [*] (or an integral component of such [*]).
For the purposes of this CRADA, [*] shall
include, but not be limited to, a [*]. If NewLink
elects to request [*] that is a [*], such [*] will
ensure, as appropriate for the circumstances, that (a) the [*] will undertake to make the [*]
on a [*] to [*]
for [*] under [*],
such [*], or (b) [*] the
right to make the [*] on a [*] to [*] for [*] purposes under [*].

 

B.                        NewLink
Responsibilities

 

1.                           Following
execution of the CRADA, [*] will
provide [*] funding for pre-clinical studies
including the IND-directed toxicity studies and formulation studies which will
be conducted by [*]. The exact amount of funding
and the payment schedule will be agreed upon and addressed in an Appendix B to
the executed CRADA.

 

2.                           Following CRADA
execution, [*] will be responsible for the [*] cost of GMP-grade [*] in current [*] inventories manufactured to support pre-clinical
studies, NCI-sponsored [*] clinical
trials, and NewLink-sponsored [*] clinical
trials. The exact amount of funding and the payment schedule will be agreed
upon and addressed in an Appendix B to the executed CRADA.

 

If
additional formulated [*] is required
for clinical studies under this CRADA Research Plan, [*]
will be responsible for the provision and costs of such extra supply of
formulated and acceptably labeled [*].[*] may elect to produce bulk [*]
and formulated [*] through contractors other than
established [*] contractors in order to obtain
the most competitive pricing. [*] will then
be responsible for subsequent payment of such contractors, and [*] will have no obligations with respect to such
contractors. If [*] elects to perform any portion
of this CRADA Research Plan through a contractor or consultant, [*] shall incorporate into such contracts all provisions
necessary to ensure that the work of the contractor or consultant 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 [*]; such inventions shall be deemed [*]
of [*]. In addition, [*]
will ensure that any contractor or consultant is obligated to maintain [*] Confidential Information regarding [*]
manufacturing and formulation in confidence at least to the extent provided for
by the terms of the CRADA.

 

Following
the use of [*] supplies of [*],[*] will
provide [*] to [*]
for use by [*] in [*]
studies, studies designed to [*], and other
studies relevant to the development of [*] as provided
in the Research Plan.

 

4

 

3.                           NewLink will
prepare and submit to the FDA an Investigational New Drug Application (IND) for
NewLink sponsored clinical studies of [*], which will
cross-reference the DCTD IND.

 

4.                           NewLink agrees
to permit DCTD to supply formulated [*] for all
clinical trials set forth in this CRADA. This includes:

 

·                  Provision of
appropriately packaged and labeled [*] for all
NCI-sponsored clinical studies;

 

·                  Supply of [*] for compassionate use, as described in the NCI
Investigator Handbook; and

 

·                  Supply of [*] for, and any resources necessary for the management of,
Group C distribution, as described in the NCI Investigator Handbook. Group C
distribution shall be initiated if such action is justified by clinical results
and is feasible based on adequate [*] supply,
such that NewLink’s NDA efforts are not negatively impacted.

 

NewLink
agrees to supply [*], or to provide unformulated
analytical grade [*] or metabolites, if available,
to DCTD for DCTD to provide to DCTD intramural and extramural investigators for
the development of analytical assays or ancillary correlative studies conducted
in conjunction with DCTD-approved protocols. NewLink also agrees to provide [*] for distribution for pre-clinical studies designed to [*]. These will include pre-clinical studies designed to
support clinical trials in [*]; pre-clinical
[*] studies to provide data in support
of a clinical trial; and other pertinent requests.

 

5.                           Upon CRADA
execution, NewLink will provide resources for data collection and management,
beyond that normally carried out by the DCTD as set forth in the CRADA for
CTEP-sponsored studies, if NewLink desires such data collection and management.
This would include the collection of the data required to submit an NDA to the
FDA.

 

6.                           Upon CRADA
execution, NewLink may provide funds for partial support of the DCTD-sponsored
clinical trials and IND.

 

7.                           Upon CRADA
execution, NewLink will provide funds for travel by DCTD staff to attend
meetings sponsored by NewLink concerning [*] clinical
trials, such funds not to exceed [*] per year of
the term of the CRADA.

 

8.                           NewLink intends
and will use reasonable efforts to prepare and submit an NDA to the FDA
expeditiously when justified by clinical studies, with the object of obtaining
pharmaceutical regulatory approval for the commercial marketing of [*].

 

9.                           NewLink may
sponsor its own clinical trials using [*]. Such
Collaborator-sponsored trials are outside the scope of this CRADA. For these
clinical trials, NewLink will maintain possession and control of the clinical
trial results. NewLink will permit 

 

5

 

DCTD to review and use the results for DCTD-sponsored clinical trials
which are under the CRADA.

 

10.                     NewLink will update DCTD on
the progress of its preclinical studies of [*] to help
ensure optimal experimental designs and avoid duplication.

 

C.                        NCI
Responsibilities

 

I.                             Division
of Cancer Treatment and Diagnosis, NCI

 

1.                           DCTD will
develop and implement its preclinical/pharmacodynamic program for [*]. DCTD also may conduct [*]
studies to [*]. DCTD will update Collaborator
regarding progress and findings to help ensure optimal experimental designs and
avoid duplication.

 

2.                           DCTD will
conduct [*] studies in [*],
and [*] studies using existing supplies of
[1MT]. As stated in B(l) above, upon execution of the CRADA, NewLink will
be responsible for partial costs associated with such studies.

 

3.                           DCTD will
provide GMP-grade [*] for [*] clinical studies, initial [*]
clinical studies, and [*] clinical
trials. As stated in [*], upon
execution of the CRADA, [*] will be
responsible for the costs associated with the drug production for such clinical
studies.

 

4.                           The DCTD, as
sponsor, will prepare and submit to the FDA an IND for [*]
for NCI-sponsored clinical studies. DCTD will permit NewLink to participate in
DCTD’s IND preparation process.

 

5.                           The DCTD will
collaborate solely with NewLink for [*]
development, and will assist NewLink in all aspects of the regulatory approval
process, so long as NewLink is pursuing clinical development of [*].

 

6.                           To the extent
permitted by law, the DCTD will maintain the DCTD-sponsored IND, including
protocols and other supporting information relative to [*]
as [*] in DCTD’s possession and control,
as proprietary and confidential, and make it available exclusively to NewLink.
The DCTD will permit NewLink to review, cross-reference and use the IND in
conducting clinical trials and in fulfilling all of the requirements necessary
for obtaining FDA approval to market [*] as [*].

 

7.                           To the extent
permitted by law, the DCTD will maintain the clinical data, results and raw
data from all new studies developed under this proposed CRADA in its possession
and control, as proprietary and confidential, and make them available
exclusively to NewLink for use in obtaining approval for the commercial
marketing of [*] as [*],
so long as NewLink is pursuing commercial development for [*].

 

8.                           The DCTD will
solicit protocol Letters of Intent (LOI) from the investigators in the DCTD’s
clinical trials network as appropriate.

 

The Protocol Review Committee (PRC), of the DCTD, will:

 

6

 

·                                    Evaluate the
rationale of each LOI received at the DCTD;

 

·                                    Review the LOIs
for study design, including dose, schedule and comparison groups, if relevant,
in order to address any pertinent scientific questions;

 

·                                    Examine the
characteristics of the patient population to be studied;

 

·                                    Assess the
feasibility of the projected accrual, including the ability of each
investigator to accrue the appropriate patient population in a timely manner;

 

·                                    Review competing
studies of the investigator in the specified disease(s);

 

·                                    Provide
investigator(s) with consensus review(s) of the PRC’s evaluation to
be used to revise the protocol;

 

·                                    Provide a copy
of the consensus review to NewLink. All CTEP approved clinical LOIs will be
sent by NCI to NewLink. NewLink will provide NCI with its approval or
disapproval within [*] of
receiving the CTEP approved clinical LOIs. Only LOIs that have been approved by
both the PRC and NewLink will lead to the submission of full study protocols.

 

The protocols received from investigators in response to the fully
approved LOIs will be reviewed and evaluated by the PRC and by NewLink. The PRC
will:

 

·                                    Evaluate each
protocol from agent, disease, statistical and regulatory perspectives in order
to ensure that the study design that was approved by the PRC at the LOI stage
is carried out.

 

·                                    Provide each
clinical research protocol received by DCTD to NewLink for review and comment
approximately [*] before it is reviewed by the
PRC of CTEP. Comments from NewLink 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 NewLink
or the CTEP staff that are agreed upon in the PRC meeting will be formatted as
a consensus review, which is returned to the investigator for necessary and/or
suggested changes before the protocol can be given final approval and submitted
to the FDA. In addition, the PRC will review any correlative laboratory
studies, solicited from investigators, to address cellular pharmacological
and/or pharmacokinetics questions as necessary.

 

9.                           The DCTD will
evaluate each of the active studies as they progress to ensure that the
appropriate questions are being addressed and to ensure that the studies are
modified as required based on the developing data. The DCTD will utilize its
existing procedures and mechanisms to follow the clinical studies to ensure
that all studies meet the pertinent FDA regulations.

 

II.                         Experimental
Immunology Branch, Center for Cancer Research, NCI

 

7

 

[*] studies such as [*]
in [*] will be conducted in the
Experimental Immunology Branch under the direction of [*].

 

7.                          Intellectual
Property of the Parties:

 

NCI
Patents and Patent Applications: [*]

 

NewLink
has obtained a worldwide, exclusive license to the following patents covering [*] for [*] from the
University of Georgia.

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

[*]

 

In
addition, a number of patent applications corresponding to the above patent
applications and patents have been filed in countries other than the U.S.

 

8

 

Appendix B

 

 

NIH Model CRADA for Extramural-PHS Clinical Research (version 2005)

 

 

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

[Insert the full name of the ICD]

an Institute, Center, or Division (hereinafter referred to as the “ICD”)
of the

[INSERT as appropriate: NIH, CDC, or FDA]

 

and

 

[Insert Collaborator’s official name],

hereinafter referred to as the “Collaborator”,

having offices at [Insert Collaborator’s
address],

created and operating under the laws of [Insert
State of Incorporation].

 

	
  PHS
  ECT-CRADA

  	
   

  	
  Case Ref. No.          

  	
   

  	
  MODEL ADOPTED 2005

  

 

1

 

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).

 

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

 

2

 

“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.

 

“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.

 

3

 

“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.

 

“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.

 

4

 

“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.

 

“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.

 

5

 

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.

 

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 

 

6

 

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.

 

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.

 

7

 

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.

 

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

 

8

 

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 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 

 

9

 

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. 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 

 

10

 

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
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 

 

11

 

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 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 

 

12

 

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
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. 

 

13

 

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 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.

 

14

 

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.

 

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.

 

15

 

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 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.

 

16

 

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.

 

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 

 

17

 

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 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

 

18

 

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.

 

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.

 

19

 

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

 

20

 

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:

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  Signature

  	
   

  	
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  Title:

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  FOR
  COLLABORATOR:

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  Signature

  	
   

  	
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21

 

CONTACTS INFORMATION PAGE

 

CRADA Notices

 

	
  For
  ICD:

  	
   

  	
  For
  Collaborator:

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  

 

Patenting and Licensing

 

	
  For
  ICD:

  	
   

  	
  For
  Collaborator (if separate from above):

  
	
   

  	
   

  	
   

  
	
  Division
  Director, Division of Technology

  	
   

  	
   

  
	
  Development and Transfer

  	
   

  	
   

  
	
  NIH
  Office of Technology Transfer

  	
   

  	
   

  
	
  6011
  Executive Boulevard, Suite 325

  	
   

  	
   

  
	
  Rockville,
  Maryland 20852-3804

  	
   

  	
   

  
	
  Tel:
  301-496-7057

  	
   

  	
   

  
	
  Fax:
  301-402-0220

  	
   

  	
   

  

 

Delivery of Materials Identified In Appendix B (if any)

 

	
  For
  ICD:

  	
   

  	
  For
  Collaborator:

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  

 

ICD Project Officer for Extramural Investigators

 

Name:

Branch:

Address:

Telephone:

 

22

 

SUMMARY PAGE

 

EITHER PARTY MAY, WITHOUT FURTHER CONSULTATION OR PERMISSION, 

RELEASE THIS SUMMARY PAGE TO THE PUBLIC.

 

TITLE
OF CRADA:

 

 

PHS [ICD] Component:

ICD CRADA Principal Investigator:

 

Collaborator:

Collaborator CRADA Principal Investigator:

 

Term of CRADA:                                                                                 (    )
years from the Effective Date

 

 

ABSTRACT OF THE RESEARCH PLAN:

 

 

 

 

23

 

Appendix C

 

CTEP Exceptions or Modifications to this CRADA (6/26/06)

 

 

Appendix C

 

Exceptions or Modifications to this CRADA

 

Additions
and deletions within Articles of the extramural clinical trial CRADA appear as
underline and strikeout, respectively.

 

“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. For this 
Agreement, Investigational Agent means xxxxxxxxxxxx.

 

Add
the following new sections to the Article 2.
Definitions:

 

“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 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.

 

“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 preclinical 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.

 

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 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 background data and information necessary to
support the IND. Collaborator further agrees to provide a letter of
cross-reference to all pertinent regulatory filings including an IND and/or
DMF 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. 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 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.

 

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.

 

 

3.8           Test-Article-Investigational
Agent  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 Investigational Agent (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  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.

 

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.

 

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
pre-clinical studies conducted in conjunction with DCTD-sponsored protocols.

 

Collaborator
agrees to allow Investigational Agent to be distributed to NCI investigators
for mutually agreeable preclinical studies designed to enhance the basic
understanding and development of Investigational Agent. These will include
preclinical studies designed to support clinical trials in pediatric patients;
preclinical 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
Investigational Agent to Collaborator and include intellectual property and
publication provisions consistent with those in this Agreement and for clinical
trials.

 

For
many investigational agents for which NCI collaborates in development, NCI will
undertake non-clinical studies to enhance the understanding of the mechanism of
action of the investigational agent and its targets such as, but not limited
to, the development of assays to detect target modulation, biomarker studies,
and pharmacodynamics in conjunction with the conduct of clinical studies
sponsored by DCTD. Collaborator agrees to provide Investigational Agent to DCTD
for these non-clinical studies. A general plan for the non-clinical studies of
the Investigational Agent will be established by the Steering Committee.
Manuscripts and presentations related to non-clinical studies will be handled
in accordance with Article 8.7 of this CRADA.

 

Collaborator
agrees to provide to the PMB the Investigator’s Brochure (IB) for
Investigational Agent and all subsequent revisions/editions. In addition to
being filed to the CTEP 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 at IBCoordinator@mail.nih.gov.

 

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. ICD  NCI 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 the Test Article Investigational
Agent (and all Confidential Information supplied by Collaborator relating
to the Test Article Investigational 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 will be performed
without Collaborator’s prior written consent. At the completion of the Research
Plan, any unused quantity of Test Article Investigational Agent
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. The contact
person. for NCI will be Mr. Charles Hall, Chief, Pharmaceutical Management
Branch (Telephone Number 301-496-5725) and the Collaborator contact will be
XXXXXX (Telephone Number XXXXX).

 

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-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
DCTD 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 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 research of the Investigational Agent 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.

 

Investigational
Agent’s development under the CRADA Research Plan shall be a collaborative
undertaking by Collaborator and NCI. 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 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
preclinical and clinical data in NCI’s possession and control shall remain on
file with NCI.

 

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.

 

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. Abstracts and publications provided
to CTEP by investigators and further provided by CTEP to Collaborator will
fulfill this final report obligation.

 

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,
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.

 

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.

 

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
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.

 

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

 

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 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 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
investigators will be sent to NCI’s Regulatory Affairs Branch
[anshers@mail.nih.gov] for forwarding to Collaborator for review as soon as
they are received and in compliance with the timelines outlined above.
Abstracts to be presented by NCI investigators will be sent to NCI’s Regulatory
Affairs Branch [anshers@mail.nih.gov] for forwarding to Collaborator as soon as
they are received, preferably no less than three days prior to submission, but
prior to presentation or publication, to allow for preservation of U.S. or
foreign patent rights.

 

8.8           Clinical Investigators’
Research and Development Activities.  In pursuing the development
of Investigational Agent 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 pre-clinical, non-clinical
and clinical studies, through Funding Agreements. 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 the 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 preclinical and non-clinical
studies that are in 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
Investigational Agent 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.

 

8.8.2        With regard to Collaborator’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 Article Investigational
Agent.

 

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  Regulatory
Affairs Branch (RAB), CTEP, NCI [Telephone 301-496-7912; anshers@mail.nih.gov].
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 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.

 

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 or arrange for an independent
contractor to manufacture and provide Investigational Agent to NCI for two
years or until the completion of ongoing mutually agreed to studies.

 

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.

 

 

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.

 

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.

 

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.Exhibit
10.31

 

AMENDMENT #1

 

To Letter of Intent for Proposed CRADA #2166

 

“Pre-Clinical and Clinical Development of [*]”

 

The
purpose of this amendment is to change certain terms of the Letter of Intent
(LOI) for the proposed Cooperative Research and Development Agreement (CRADA)
entitled “Pre-Clinical and Clinical Development of [*].”
These changes are reflected below, and except for these changes, all other
provisions of the original CRADA LOI remain in full force and effect. Two
originals of this amendment are provided for execution; one is to remain with
the National Cancer Institute (NCI) and the other copy is to remain with the
Collaborator.

 

1.     Upon final signature, the
term of this CRADA Letter of Intent is extended for six months from
November 23, 2007 to May 23, 2008.

 

2.     Dr. Lee
Jia is removed as an NCI Principal Investigator. The NCI Principal
Investigators are Dr. Sherry Ansher and Dr. Howard Streicher.

 

 

	
   

  	
  ACCEPTED
  AND AGREED TO:

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  For
  the National Cancer Institute:

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  /s/Anna
  D. Barker

  	
   

  	
  01/08/08

  
	
  Anna
  D. Barker, Ph.D.

  	
   

  	
  Date

  
	
  Deputy
  Director, NCI

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  For
  NewLink Genetics Corporation:

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  /s/Charles
  Link

  	
   

  	
  1/17/08

  
	
   

  	
   

  	
  Date

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