EXHIBIT 10.21

 
 
AMENDMENT

Current CRADA Terms

CRADA#: 01303
Effective Date: 12/14/01
Executed Date: 12/14/01
Orig. Term (mo): 60
Total Term (mo): 120
Expirations: 12/14/2006
 
Term extension(s) (mo):
60
NIH PI: Steven A. Rosenberg
IC DIV LAB: NCI CCR SB
 
Collaborating PI: Richard L. Taney
Collaborator: Delcath Systems, Inc.
Title: Amendment No. 3 to Extend the Cooperative Research and Development
Agreement for the
Development of the "Delcath System" for the Delivery of Chemotherapeutics in the
Treatment of Cancer
 

New CRADA Terms
The purpose of this amendment is to change certain terms of the above referenced
Cooperative Research and Development
Agreement. These changes are reflected below and except for these changes and
those of any previous amendments, all
other provisions remain in full force and effect. Two originals of this
amendment are provided for execution--one is to remain
with NCI and the other with the collaborator.
 
PHS and the Delcath Systems, Inc. (the "Parties") hereby agree to amend CRADA
no. 01303, identified above, as follows:
 
Amendment #3
 
1) The term of the CRADA is extended to an additional five (5) years (December
14, 2006 - December 14, 2011).
2) All previous CRADA amendments are incorporated into this revised CRADA.
3) Research will continue as set forth in the Research Plan, attached as
Appendix A of the revised CRADA.
4) The financial and staffing contributions of the Parties are set forth in
Appendix B of the revised CRADA.
5) Exceptions or modifications to this CRADA are set forth in Appendix C of the
revised CRADA.
 
ACCEPTED AND AGREED TO:
 
Surgery Branch
 
Delcath Systems, Inc.
 
/s/Anna D. Barker
 
/s/Richard Taney
 
Anna D. Barker, Ph.D.
 
Richard L. Taney, J.D.
 
Deputy Director for Advanced Technologies and Strategic Partnerships
 
Chief Executive Officer
 
2/23/07
 
3/29/07
 
Date
 
Date
                 

 
 

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PUBLIC HEALTH SERVICE

COOPERATIVE  RESEARCH AND DEVELOPMENT AGREEMENT

This Cooperative Research and Development Agreement, hereinafter referred to as
the “CRADA,” consists of this Cover Page, an attached Agreement, and various
Appendices referenced in the Agreement.  This Cover Page serves to identify the
Parties to this CRADA:

(1)  the following Bureau(s), Institute(s), Center(s) or Division(s) of the
National Institutes of Health (“NIH”), the Food and Drug Administration (“FDA”),
and the Centers for Disease Control and Prevention (“CDC”): National Cancer
Institute, hereinafter singly or collectively referred to as the Public Health
Service (“PHS”); and

 
(2)               Delcath Systems, Inc.,
which has offices at

1100 Summer Street, 3rd Floor
Stamford, Connecticut 06905
hereinafter referred to as the “Collaborator.”

 
 

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COOPERATIVE  RESEARCH AND DEVELOPMENT AGREEMENT
 

 
Article 1.    Introduction

This Cooperative Research and Development Agreement (CRADA) between PHS and the
Collaborator will be effective when signed by all Parties.  The research and
development activities which will be undertaken by each of the Parties in the
course of this CRADA are detailed in the Research Plan (RP) which is attached as
Appendix A.  The funding and staffing commitments of the Parties are set forth
in Appendix B.  Any exceptions or changes to the CRADA are set forth in Appendix
C.  This CRADA is made under the authority of the Federal Technology Transfer
Act, 15 U.S.C. § 3710a, and is governed by its terms.
 

 
Article 2.  Definitions

As used in this CRADA, the following terms shall have the indicated meanings:

2.1
“Affiliate” means any corporation or other business entity controlled by,
controlling, or under common control with Collaborator.  For this purpose,
“control” means direct or indirect beneficial ownership of at least fifty (50)
percent of the voting stock or at least fifty (50) percent interest in the
income of such corporation or other business.

2.2
“Cooperative Research and Development Agreement” or “CRADA” means this
Agreement, entered into by PHS pursuant to the Federal Technology Transfer Act
of 1986, as amended, 15 U.S.C. § 3710a et seq. and Executive Order 12591 of
October 10, 1987.

2.3
“Government” means the Government of the United States as represented through
the PHS agency that is a Party to this agreement.

2.4
“IP” means intellectual property.

2.5
“Invention” means any invention or discovery which is or may be patentable or
otherwise protected under Title 35, United States Code, or any novel variety or
plant which is or may be protectable under the Plant Variety Protection Act (7
U.S.C. § 2321 et seq.).

2.6
“Principal Investigator(s)” or “PIs” means the persons designated respectively
by the Parties to this CRADA who will be responsible for the scientific and
technical conduct of the RP.

2.7
“Proprietary/Confidential Information” means confidential scientific, business,
or financial information provided that such information does not include:

 
2.7.1
information that is publicly known or available from other sources who are not
under a confidentiality obligation to the source of the information;

 
2.7.2
information which has been made available by its owners to others without a
confidentiality obligation;

 
2.7.3
information which is already known by or available to the receiving Party
without a confidentiality obligation; or

 
2.7.4
information which relates to potential hazards or cautionary warnings associated
with the production, handling or use of the subject matter of the Research Plan
of this CRADA.

2.8
“Research Materials” means all tangible materials other than Subject Data first
produced in the performance of this CRADA.

2.9
“Research Plan” or “RP” means the statement in Appendix A of the respective
research and development commitments of the Parties to this CRADA.

2.10
“Subject Invention” means any Invention of the Parties, conceived or first
actually reduced to practice in the performance of the Research Plan of this
CRADA.

2.11
“Subject Data” means all recorded information first produced in the performance
of this CRADA by the Parties.

 
Article 3.  Cooperative Research

3.1
Principal Investigators.  PHS research work under this CRADA will be performed
by the PHS laboratory identified in the RP, and the PHS Principal Investigator
(PI) designated in the RP will be responsible for the scientific and technical
conduct of this project on behalf of PHS.  Also designated in the RP is the
Collaborator PI who will be responsible for the scientific and technical conduct
of this project on behalf of the Collaborator.

 
 
 
 

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3.2
Research Plan Change.  The RP may be modified by mutual written consent of the
Principal Investigators.  Substantial changes in the scope of the RP will be
treated as amendments under Article 13.6.

Article 4.  Reports

4.1
Interim Reports.  The Parties shall exchange formal written interim progress
reports on a schedule agreed to by the PIs, but at least within twelve (12)
months after this CRADA becomes effective and at least within every twelve (12)
months thereafter.  Such reports shall set forth the technical progress made,
identifying such problems as may have been encountered and establishing goals
and objectives requiring further effort, any modifications to the Research Plan
pursuant to Article 3.2, and identify Subject Inventions pursuant to Article
6.1.

4.2
Final Reports.  The Parties shall exchange final reports of their results within
four (4) months after completing the projects described in the RP or after the
expiration or termination of this CRADA.

Article 5.  Financial and Staffing Obligations

5.1
PHS and Collaborator Contributions. The contributions of the Parties, including
payment schedules, if applicable, are set forth in Appendix B.  PHS shall not be
obligated to perform any of the research specified herein or to take any other
action required by this CRADA if the funding is not provided as set forth in
Appendix B.  PHS shall return excess funds to the Collaborator when it sends its
final fiscal report pursuant to Article 5.2, except for staffing support
pursuant to Article 10.3.  Collaborator acknowledges that the U.S. Government
will have the authority to retain and expend any excess funds for up to one (1)
year subsequent to the expiration or termination of the CRADA to cover any costs
incurred during the term of the CRADA in undertaking the work set forth in the
RP.

5.2
Accounting Records.  PHS shall maintain separate and distinct current accounts,
records, and other evidence supporting all its obligations under this CRADA, and
shall provide the Collaborator a final fiscal report pursuant to Article 4.2.

5.3
Capital Equipment.  Equipment purchased by PHS with funds provided by the
Collaborator shall be the property of PHS.  All capital equipment provided under
this CRADA by one party for the use of another Party remains the property of the
providing Party unless other disposition is mutually agreed upon by in writing
by the Parties.  If title to this equipment remains with the providing Party,
that Party is responsible for maintenance of the equipment and the costs of its
transportation to and from the site where it will be used.

Article 6.  Patent Applications

6.1
Reporting.  The Parties shall promptly report to each other in writing each
Subject Invention and any patent applications filed thereon resulting from the
research conducted under this CRADA that is reported to them by their respective
employees.  Each Party shall report all Subject Inventions to the other Party in
sufficient detail to determine inventorship.  Such reports shall be treated as
Proprietary/Confidential Information in accordance with Article 8.4.

6.2
Filing of Patent Applications. Each party shall be responsible for filing patent
or other IP applications in a timely manner and at its own expense and after
consultation with the other Party.  The Parties will consult and mutually
determine a filing strategy for jointly owned subject inventions.

6.3
Patent Expenses.  The expenses attendant to the filing of patent or other IP
applications generally shall be paid by the Party filing such application.  If
an exclusive license to any Subject Invention is granted to the Collaborator,
the Collaborator shall be responsible for all past and future out-of-pocket
expenses in connection with the preparation, filing, prosecution and maintenance
of any applications claiming such exclusively licensed inventions and any
patents or other IP grants that may issue on such applications.  The
Collaborator may waive its exclusive license rights on any application, patent
or other IP grant at any time, and incur no subsequent compensation obligation
for that application, patent or IP grant.

6.4
Prosecution of Intellectual Property Applications.  Within one month of receipt
or filing, each Party shall provide the other Party with copies of the
applications and all documents received from or filed with the relevant patent
or other IP office in connection with the prosecution of such
applications.  Each Party shall also provide the other Party with the power to
inspect and make copies of all documents retained in the patent or other IP
application files by the applicable patent or other IP office.  Where licensing
is contemplated by Collaborator, the Parties agree to consult with each other
with respect to the prosecution of applications for PHS Subject Inventions and
joint Subject Inventions.  If the Parties agree that Collaborator shall file and
prosecute IP applications on joint Subject Inventions, then Collaborator agrees
to grant PHS an associate power of attorney (or its equivalent) on such IP
applications.

 
 
 

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Article 7.  Licensing

7.1
Option for Commercialization License.  With respect to Government IP rights to
any Subject Invention not made solely by the Collaborator's employees for which
a patent or other IP application is filed, PHS hereby grants to the Collaborator
an exclusive option to elect an exclusive or nonexclusive commercialization
license, which is substantially in the form of the appropriate model PHS license
agreement.  This option does not apply to Subject Inventions conceived prior to
the effective date of this CRADA that are reduced to practice under this CRADA,
if prior to that reduction to practice, PHS has filed a patent application on
the invention and has licensed it or offered to license it to a third
party.  The terms of the license will fairly reflect the nature of the
invention, the relative contributions of the Parties to the invention and the
CRADA, the risks incurred by the Collaborator and the costs of subsequent
research and development needed to bring the invention to the marketplace.  The
field of use of the license will be commensurate with the scope of the RP.
 

7.2
Exercise of License Option.  The option of Article 7.1 must be exercised by
written notice mailed within three (3) months after either (i) Collaborator
receives written notice from PHS that the patent or other IP application has
been filed; or (ii) the date Collaborator files such IP application.  Exercise
of this option by the Collaborator initiates a negotiation period that expires
nine (9) months after the exercise of the option.  If the last proposal by the
Collaborator has not been responded to in writing by PHS within this nine (9)
month period, the negotiation period shall be extended to expire one (1) month
after PHS so responds, during which month the Collaborator may accept in writing
the final license proposal of PHS.  In the absence of such acceptance, or an
extension of the time limits by PHS, PHS will be free to license such IP rights
to others.  In the event that the Collaborator elects the option for an
exclusive license, but no such license is executed during the negotiation
period, PHS agrees not to make an offer for an exclusive license on more
favorable terms to a third party for a period of six (6) months without first
offering Collaborator those more favorable terms. These times may be extended at
the sole discretion of PHS upon good cause shown in writing by the Collaborator.

7.3
License for PHS Employee Inventions and Joint Inventions.  Pursuant to 15 U.S.C.
§ 3710a(b)(1)(A), for Subject Inventions made under this CRADA by a PHS
employee(s) or jointly by such employee(s) and employees of the Collaborator and
licensed pursuant to the option of Article 7.1, the Collaborator grants to the
Government a nonexclusive, nontransferable, irrevocable, paid-up license to
practice the invention or have the invention practiced throughout the world by
or on behalf of the Government.  In the exercise of such license, the Government
shall not publicly disclose trade secrets or commercial or financial information
that is privileged or confidential within the meaning of 5 U.S.C. § 552(b)(4) or
which would be considered as such if it had been obtained from a non-Federal
party.

7.4
License in Collaborator Inventions.  Pursuant to 15 U.S.C. § 3710a(b)(2), for
inventions made solely by Collaborator employees under this CRADA, the
Collaborator grants to the Government a nonexclusive, nontransferable,
irrevocable, paid-up license to practice the invention or have the invention
practiced throughout the world by or on behalf of the Government for research or
other Government purposes.

7.5
Third Party License.  Pursuant to 15 U.S.C. § 3710a(b)(1)(B), if PHS grants an
exclusive license to a Subject Invention made wholly by PHS employees or jointly
with a Collaborator under this CRADA, the Government shall retain the right to
require the Collaborator to grant to a responsible applicant a nonexclusive,
partially exclusive, or exclusive sublicense to use the invention in
Collaborator’s licensed field of use on terms that are reasonable under the
circumstances; or if the Collaborator fails to grant such a license, to grant
the license itself.  The exercise of such rights by the Government shall only be
in exceptional circumstances and only if the Government determines (i) the
action is necessary to meet health or safety needs that are not reasonably
satisfied by Collaborator, (ii) the action is necessary to meet requirements for
public use specified by Federal regulations, and such requirements are not
reasonably satisfied by the Collaborator; or (iii) the 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 Article is
subject to administrative appeal and judicial review under 35 U.S.C. § 203(2).

7.6
Joint Inventions Not Exclusively Licensed.  In the event that the Collaborator
does not acquire an exclusive commercialization license to IP rights in all
fields in joint Subject Inventions then each Party shall have the right to use
the joint Subject Invention and to license its use to others in all fields not
exclusively licensed to Collaborator.  The Parties may agree to a joint
licensing approach for such IP rights.

Article 8.  Proprietary Rights and Publication

8.1
Right of Access.  PHS and the Collaborator agree to exchange all Subject Data
produced in the course of research under this CRADA.  Research Materials will be
shared equally by the Parties to the CRADA unless other disposition is agreed to
by the Parties.  All Parties to this CRADA will be free to utilize

 Subject Data and Research Materials for their own purposes, consistent with
their obligations under this CRADA.

8.2
Ownership of Subject Data and Research Materials.  Subject to the sharing
requirements of Paragraph 8.1 and the regulatory filing requirements of
Paragraph 8.3, the producing Party will retain ownership of and title to all
Subject Inventions, all Subject Data and all Research Materials produced solely
by their investigators.  Jointly developed Subject Inventions, Subject Data and
Research Materials will be jointly owned.

8.3
Dissemination of Subject Data and Research Materials.  To the extent permitted
by law, the Collaborator and PHS agree to use reasonable efforts to keep Subject
Data and Research Materials confidential until published or until corresponding
patent applications are filed.  Any information that would identify human
subjects of research or patients will always be maintained confidentially.  To
the extent permitted by law, the Collaborator shall have the exclusive right to
use any and all CRADA Subject Data in and for any regulatory filing by or on
behalf of Collaborator, except that PHS shall have the exclusive right to use
Subject Data for that purpose, and authorize others to do so, if the CRADA is
terminated or if Collaborator abandons its commercialization
efforts.  Collaborator acknowledges the basic research mission of the PHS, and
agrees that after publication, PHS may make unpatented research materials
arising out of this CRADA available to third parties for further research.

8.4
Proprietary/Confidential Information.  Each Party agrees to limit its disclosure
of Proprietary/Confidential Information to the amount necessary to carry out the
Research Plan of this CRADA, and shall place a confidentiality notice on all
such information.  Confidential oral communications shall be reduced to writing
within 30 days by the disclosing Party.  Each Party receiving
Proprietary/Confidential Information agrees that any information so designated
shall be used by it only for the purposes described in the attached Research
Plan.  Any Party may object to the designation of information as
Proprietary/Confidential Information by another Party.  Subject Data and
Research Materials developed solely by the Collaborator may be designated as
Proprietary/Confidential Information when they are wholly separable from the
Subject Data and Research Materials developed jointly with PHS investigators,
and advance designation of such data and material categories is set forth in the
RP.  The exchange of other confidential information, e.g., patient-identifying
data, should be similarly limited and treated.  Jointly developed Subject Data
and Research Material derived from the Research Plan may be disclosed by
Collaborator to a third party under a confidentiality agreement for the purpose
of possible sublicensing pursuant to the Licensing Agreement and subject to
Article 8.7.

8.5
Protection of Proprietary/Confidential Information.  Proprietary/Confidential
Information shall not be disclosed, copied, reproduced or otherwise made
available to any other person or entity without the consent of the owning Party
except as required under court order or the Freedom of Information Act (5 U.S.C.
§ 552).  Each Party agrees to use its best efforts to maintain the
confidentiality of Proprietary/Confidential Information.  Each Party agrees that
the other Party is not liable for the disclosure of Proprietary/Confidential
Information which, after notice to and consultation with the concerned Party,
the other Party in possession of the Proprietary/Confidential Information
determines may not be lawfully withheld, provided the concerned Party has been
given an opportunity to seek a court order to enjoin disclosure.

8.6
Duration of Confidentiality Obligation.  The obligation to maintain the
confidentiality of Proprietary/Confidential Information shall expire at the
earlier of the date when the information is no longer Proprietary Information as
defined in Article 2.7 or three (3) years after the expiration or termination
date of this CRADA.  The Collaborator may request an extension to this term when
necessary to protect Proprietary/Confidential Information relating to products
not yet commercialized.

8.7
Publication.  The Parties are encouraged to make publicly available the results
of their research.  Before either Party submits a paper or abstract for
publication or otherwise intends to publicly disclose information about a
Subject Invention, Subject Data or Research Materials, the other Party shall be
provided thirty (30) days to review the proposed publication or disclosure to
assure that Proprietary/Confidential Information is protected.  The publication
or other disclosure shall be delayed for up to thirty (30) additional days upon
written request by any Party as necessary to preserve U.S. or foreign patent or
other IP rights.

Article 9.  Representations and Warranties

9.1
Representations and Warranties of PHS.  PHS hereby represents and warrants to
the Collaborator that the official signing this CRADA has authority to do so.

9.2
Representations and Warranties of the Collaborator.

(a)  The Collaborator hereby represents and warrants to PHS that the
Collaborator has the requisite power and authority to enter into this CRADA and
to perform according to its terms, and that the Collaborator's official signing
this CRADA has authority to do so.  The Collaborator further represents that it
is financially able to satisfy any funding commitments made in Appendix B.

(b)  The Collaborator certifies that the statements herein are true, complete,
and accurate to the best of its knowledge.  The Collaborator is aware that any
false, fictitious, or fraudulent statements or claims may subject it to
criminal, civil, or administrative penalties.

 
 

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Article 10.  Termination

10.1
Termination By Mutual Consent.  PHS and the Collaborator may terminate this
CRADA, or portions thereof, at any time by mutual written consent.  In such
event the Parties shall specify the disposition of all property, inventions,
patent or other IP applications and other results of work accomplished or in
progress, arising from or performed under this CRADA, all in accordance with the
rights granted to the Parties under the terms of this Agreement.

10.2
Unilateral Termination.  Either PHS or the Collaborator may unilaterally
terminate this entire CRADA at any time by giving written notice at least thirty
(30) days prior to the desired termination date, and any rights accrued in
property, patents or other IP rights shall be disposed of as provided in
paragraph 10.1, except that PHS may, at its option, retain funds transferred to
PHS prior to unilateral termination by Collaborator for use in completing the
Research Plan solely or with another partner.

10.3
Staffing.  If this CRADA is mutually or unilaterally terminated prior to its
expiration, funds will nevertheless remain available to PHS for continuing any
staffing commitment made by the Collaborator pursuant to Article 5.1 above and
Appendix B, if applicable, for a period of six (6) months after such
termination.  If there are insufficient funds to cover this expense, the
Collaborator agrees to pay the difference.

10.4
New Commitments.  No Party shall make new commitments related to this CRADA
after a mutual termination or notice of a unilateral termination and shall, to
the extent feasible, cancel all outstanding commitments and contracts by the
termination date.

10.5
Termination Costs.  Concurrently with the exchange of final reports pursuant to
Articles 4.2 and 5.2, PHS shall submit to the Collaborator for payment a
statement of all costs incurred prior to the date of

termination and for all reasonable termination costs including the cost of
returning Collaborator property or removal of abandoned property, for which
Collaborator shall be responsible.

Article 11.  Disputes

11.1
Settlement.  Any dispute arising under this CRADA which is not disposed of by
agreement of the Principal Investigators shall be submitted jointly to the
signatories of this CRADA.  If the signatories 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) shall propose a
resolution.  Nothing in this Article shall 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, the Parties agree that performance of all obligations shall be
pursued diligently in accordance with the direction of the PHS signatory.

Article 12.  Liability

12.1
Property.  The U.S. Government shall not be responsible for damages to any
Collaborator property provided to PHS, where Collaborator retains title to the
property, or any property acquired by Collaborator for its own use pursuant to
this CRADA.

12.2
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 PRODUCT, WHETHER TANGIBLE OR
INTANGIBLE, MADE, OR DEVELOPED UNDER THIS CRADA, OR THE OWNERSHIP,
MERCHANTABILITY, OR FITNESS FOR A PARTICULAR PURPOSE OF THE RESEARCH OR ANY
INVENTION OR PRODUCT.

12.3
Indemnification.  The Collaborator agrees to hold the U.S. Government harmless
and to indemnify the Government for all liabilities, demands, damages, expenses
and losses arising out of the use by the Collaborator for any purpose of the
Subject Data, Research Materials and/or Subject Inventions produced in whole or
part by PHS employees under this CRADA, unless due to the negligence or willful
misconduct of PHS, its employees, or agents.  The Collaborator shall be liable
for any claims or damages it incurs in connection with this CRADA.  PHS has no
authority to indemnify the Collaborator.

12.4
Force Majeure.  Neither Party shall be liable for any unforeseeable event beyond
its reasonable control not caused by the fault or negligence of such Party,
which causes such 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.  In the event of the occurrence of such a force majeure event, the
Party unable to perform shall promptly notify the other Party.  It shall further
use its best efforts to resume performance as quickly as possible and shall
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
shall be governed by Federal law, as applied by the Federal Courts in the
District of Columbia.  Federal law and regulations will preempt any conflicting
or inconsistent provisions in this CRADA.

13.2
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.

13.3
Headings.  Titles and headings of the articles and subarticles of this CRADA are
for convenient reference only, do not form a part of this CRADA, and shall in no
way affect its interpretation.  The PHS component that is the Party for all
purposes of this CRADA is the Bureau(s), Institute(s), Center(s) or Division(s)
listed on the Cover Page herein.

13.4
Waivers.  None of the provisions of this CRADA shall be considered waived by any
Party unless such 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,
shall not be deemed a waiver of any rights of any Party.

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

13.6
Amendments.  If either Party desires a modification to this CRADA, the Parties
shall, upon reasonable notice of the proposed modification or extension by the
Party desiring the change, confer in good faith to determine the desirability of
such modification or extension.  Such modifica­tion shall not be effective until
a written amendment is signed by the signatories to this CRADA or by their
representatives duly authorized to execute such amendment.

13.7
Assignment.  Neither this CRADA nor any rights or obligations of any Party
hereunder shall be assigned or otherwise transferred by either Party without the
prior written consent of the other Party.

13.8
Notices.  All notices pertaining to or required by this CRADA shall be in
writing and shall be signed by an authorized representa­tive and shall be
delivered by hand or sent by certified mail, return receipt requested, with
postage prepaid, to the addresses indicated on the signature page for each
Party.  Notices regarding the exercise of license options shall be made pursuant
to Article 7.2.  Any Party may change such 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 shall maintain sole and exclusive control over its
personnel and operations.  Collaborator employees who will be working at PHS
facilities may be asked to sign a Guest Researcher or Special Volunteer
Agreement appropriately modified in view of the terms of this CRADA.

 
13.10
Use of Name or Endorsements.  By entering into this CRADA, PHS does not directly
or indirectly endorse any product or service provided, or to be provided,
whether directly or indirectly related to either this CRADA or to any patent or
other IP license or agreement which implements this CRADA by its successors,
assignees, or licensees.  The Collaborator shall not in any way state or imply
that this CRADA is an endorsement of any such product or service by the U.S.
Government or any of its organizational units or employees.  Collaborator issued
press releases that reference or rely upon the work of PHS under this CRADA
shall be made available to PHS at least 7 days prior to publication for review
and comment.

13.11
Exceptions to this CRADA.  Any exceptions or modifications to this CRADA that
are agreed to by the Parties prior to their execution of this CRADA are set
forth in Appendix C.

13.12
Reasonable Consent.  Whenever a Party's consent or permission is required under
this CRADA, such consent or permission shall not be unreasonably withheld.

Article 14.  Duration of Agreement

14.1
Duration.  It is mutually recognized that the duration of this project cannot be
rigidly defined in advance, and that the contemplated time periods for various
phases of the RP are only good faith guidelines subject to adjustment by mutual
agreement to fit circumstances as the RP proceeds.  In no case will the term of
this CRADA extend beyond the term indicated in the RP unless it is revised in
accordance with Article 13.6.

14.2
Survivability.  The provisions of Articles 4.2, 5-8, 10.3-10.5, 11.1, 12.2-12.4,
13.1, 13.10 and 14.2 shall survive the termination of this CRADA.

SIGNATURES BEGIN ON THE FOLLOWING PAGE

 
 

--------------------------------------------------------------------------------

 

SIGNATURES

FOR PHS:
   
/s/Anna D. Barker
    2/27/07
Anna D. Barker, Ph.D.
 
Date
Deputy Director for Advanced Technologies and Strategic Partnerships, NCI
         
Mailing Address for Notices:
   
NCI Technology Transfer Branch
   
6120 Executive Blvd, EPS Suite 450
   
Rockville, MD 20852
   
(301) 496-0477
   
(301) 402-2117 (Facsimile)
         
FOR THE COLLABORATOR:
   
/s/Richard L. Taney
    3/29/07
Richard L. Taney
 
Date
Chief Executive Officer
         
Delcath Systems, Inc.
   
1100 Summer Street, 3rd Floor
   
Stamford, Connecticut 06905
   
(203) 323-8668
   
(203) 961-0120
         

 
 
 

--------------------------------------------------------------------------------

 
 
 
 
 
CONFIDENTIAL TREATMENT
[***] Indicates that text has been omitted which is the subject of a
confidential treatment request. This text has been separately filed with the
Securities and Exchange Commission.

APPENDIX A

RESEARCH  PLAN

Title of CRADA

Cooperative Research and Development Agreement for the Development of the
"Delcath System" for the Delivery of Chemotherapeutics in the Treatment of
Cancer

NCI Principal Investigator
Steven A. Rosenberg, M.D., Ph.D.
Surgery Branch
Center for Cancer Research, NCI

Collaborator Principal Investigator
Richard L. Taney
Chief Executive Officer
Delcath Systems, Inc.

Term of CRADA Extension
Five (5) years from the expiration of the original CRADA term (12/14/2001 -
12/14/2006; upon amendment to expire 12/14/2011)

Conflict of Interest Information
See attached Conflict of Interest and Fair Access Survey form.

Goals of this CRADA Amendment No. 3

The principal goal of this CRADA is to continue the development of a novel form
of regional cancer therapy by designing clinical protocols utilizing the
“Delcath System” to regionally deliver chemotherapeutics to patients with
unresectable malignancies confined to an organ or region of the body.  The
“Delcath System” is a proprietary delivery device in which one or more
therapeutic agents are infused into the artery of a target organ and then organ
venous blood is collected, filtered to remove the therapeutic agent and
eliminate unnecessary systemic exposure and toxicity (hemofiltration), and then
returned to the systemic circulation.  The clinical evaluation of this regional
therapy began with a Phase 1 trial to determine the dose limiting toxicity and
maximum safe tolerated dose of the therapeutic agent, melphalan.  This trial was
successfully completed and has led to the initiation of a Phase 2 protocol in
addition to a Phase 3 random-assignment protocol with metastatic melanoma.  This
Phase 3 trial has been granted Fast-Track status by the U.S. Food and Drug
Administration (FDA).

 
The subject of this CRADA is strictly limited to the development of anticancer
therapies using the Delcath System to administer commercially available
chemotherapeutics.   However, the use and development of other commercially
available chemotherapeutics alone or not in combination with the Delcath System
is not the subject of this CRADA.

Introduction

The NCI Surgery Branch has conducted a number of clinical research activities
related to the regional treatment of unresectable cancers confined to the liver,
limb, and peritoneal cavity. The Delcath System represents a novel additional
method of regionally treating unresectable hepatic neoplasms, as well as other
organ neoplasms, which may provide substantial benefit to patients afflicted
with these conditions.  The Surgery Branch has carried out clinical activities
related to this CRADA relating to regional treatments including isolated limb
perfusion for in-transit melanoma or unresectable extremity sarcoma, isolated
hepatic perfusion for unresectable malignancies confined to the liver, and
continuous hyperthermic peritoneal perfusion for the treatment of cancers
confined to this region.  In addition, Dr. Steven A. Rosenberg has extensive
experience in conducting clinical trials for the development of treatments
involving a number of primary and metastatic cancers including melanoma, kidney,
pancreatic and liver.

 
Delcath Systems, Inc. has actively supported clinical research trials evaluating
the proprietary Delcath System which allows regional administration of high dose
chemotherapeutics to the liver with hepatic venous hemofiltration to eliminate
or reduce the amount of systemic exposure of the agent. This device had been
clinically applied using 5-fluorouracil and doxorubicin (these studies were
conducted by the company and are outside the scope of this CRADA) and the NCI
has recently established an extensive experience utilizing this system for the
regional administration of melphalan hydrochloride.

Background

Primary or metastatic unresectable cancers confined to the liver represent a
significant clinical problem.  For example, in the United States approximately
140,000 individuals per year are afflicted with colorectal cancer of whom 10% -
20% will develop unresectable metastases confined largely or solely to the
liver.  Previously, combination systemic chemotherapy has an overall response
rate of approximately 39% and a duration of response of only 7 months
(1).  Recent data utilizing Avastin in combination with traditional multidrug
regimens have resulted in response rates greater than 50% with an increased
duration of response up to 10 months for patients with metastatic colon cancer
(8).  Recurrence, however, is the rule, and second line therapies continue to
show response rates approximately 10% (9).  A number of regional therapies are
under clinical evaluation and share the common advantage of delivering intensive
therapy to the cancer bearing organ of the body while limiting unnecessary
systemic exposure and toxicity from the therapeutic agents (2).  In general,
regional therapies have considerably higher response rates than best available
systemic treatments yet none have sufficient efficacy to be considered standard
therapy for patients afflicted with this condition. The various types of
regional therapies in clinical development include hepatic artery infusion of
chemotherapy, local ablative therapy such as cryotherapy, and isolated hepatic
perfusion.  Each of these treatments have particular advantages and
disadvantages and new approaches for the treatment of unresectable hepatic
malignancies are clearly warranted.

Hepatic arterial infusion of chemotherapy in combination with hemofiltration of
the hepatic venous effluent using percutaneously positioned catheters is a novel
strategy that may allow for dose intensive treatment with chemotherapy to be
delivered to a cancer burdened liver while eliminating by hemofiltration the
agent before the blood returns to the systemic circulation.  The initial studies
using this approach have been conducted using a proprietary system developed by
Delcath with the agents 5-fluorouracil and doxorubicin (3,4).  There is
considerable interest in the development of new regional therapies for
unresectable cancers of the liver in the Surgery Branch and previous clinical
trials have focused on the development of isolated hepatic perfusion (IHP) with
melphalan hydrochloride hyperthermia and tumor necrosis factor (5, 6,
7).  However, treatment using IHP is complex and patients must undergo a major
operative procedure in order to receive therapy. Clearly any technique that
could simplify regional delivery of chemotherapeutics to the liver while
avoiding the need for a major operative procedure would have clear
advantages.  Phase 1 and early Phase 2 data support the use of this technology
in place of IHP for patients with metastatic ocular melanoma and neuroendocrine
tumors, along with selected patients with hepatic metastases from colorectal
cancers.

Progress Report for this CRADA

Clinical Trials Conducted by the Surgery Branch Under This CRADA:

1) NCI #01-C-0215 entitled “A Phase I Study of Hepatic Arterial Infusion of
Escalating Dose Melphalan with Venous Filtration for Unresectable Cancers of the
Liver.”

2) NCI # 04-C-0273 entitled "A Phase II Study of Hepatic Arterial Infusion of
Melphalan With Venous Filtration Via Peripheral Hepatic Perfusion (PHP) for
Unresectable Primary and Metastatic Cancers of the Liver."

2) NCI # 06-C-0088 entitled "A Random-Assignment Study of Hepatic Arterial
Infusion of Melphalan with Venous Filtration via Peripheral Hepatic Perfusion
(PHP) (Delcath System) Versus Best Alternative Care for Ocular and Cutaneous
Melanoma Metastatic to the Liver."

 
 

--------------------------------------------------------------------------------

 

Prior to the initiation of NCI #01-C-0215, a Phase 1 trial, Delcath and NCI
conducted preclinical testing of [ *** ] and determined [*** ] likely to be
achieved in clinical use.  [ *** ] analysis of [ *** ] performed during the
Phase 1 study revealed [ *** ].  As a result of patient referral and protocol
accrual patterns within the Surgery Branch, a significant number of patients
treated on a Phase1 trial, had melanoma metastatic to the liver.  Although
response rate and overall survival were not designed endpoints of the trial (an
overall tumor response rate of 55% was noted in patients with metastatic
melanoma and 50% response rate in patients with metastatic pancreatic
neuroendocrine tumors), the large percentage of patients with this diagnosis
allowed the Surgery Branch to establish confidence in the Delcath System with
melphalan in the treatment of this disease, and allowed the company to apply
for, and be granted, Fast Track status by the FDA.

A Phase 2 study is currently being conducted in patients with primary and
metastatic hepatic malignancies, stratified into three cohorts: primary hepatic
tumors (hepatocellular carcinoma and cholangiocarcinoma), metastatic
adenocarcinoma of gastrointestinal origin, and metastatic pancreatic
neuroendocrine tumors.  At present, the most rapidly accruing arm is that for
patients with [*** ].

Pursuant to discussions with the FDA, a Phase 3 random-assignment trial
comparing the Delcath system to the best available care for patients with
unresectable melanoma metastatic to the liver was initiated at the NCI in
2006.  The accrual goal of this trial is 92 patients and the Surgery Branch is
awaiting IRB approval to transition this into a multi-center trial under the
direction of the NCI and Delcath Corp.   To date, eight patients have been
enrolled in the intramural trial.

Surgery Branch Publications Under This CRADA:

See Reference no. 10 below.

 

REFERENCES

1.           Saltz, L.B., Cox, J.V., Blanke, C., Rosen, L.S., Fehrenbacher, L.,
Moore, M.J., Maroun, J.A., Ackland, S.P., Locker, P.K., Pirotta, N., Elfring,
G.L., and Miller, L.L. Irinotecan plus fluorouracil and leucovorin for
metastatic colorectal cancer. Irinotecan Study Group.  N.Engl.J.Med., 343:
905-914, 2000.

2.           Alexander, H.R., Jr., Allegra, C.J., and Lawrence, T.S. Metastatic
Cancer to the Liver. In: V.T. DeVita, Jr., S. Hellman and S.A. Rosenberg (eds.),
Cancer: Principles and Practice of Oncology, pp. 2690-2713, Philadelphia:
Lippincott Williams & Wilkins. 2001.

3.           Ravikumar TS and Dixon K Isolated liver perfusion for liver
metastases: pharmacokinetic advantage?  Surg.Oncol.Clin.N.Am., 5: 443-449, 1996.

4.           Ravikumar, T.S., Pizzorno, G., Bodden, W., Marsh, J., Strair, R.,
Pollack, J., Hendler, R., Hanna, J., and D'Andrea, E. Percutaneous hepatic vein
isolation and high-dose hepatic arterial infusion chemotherapy for unresectable
liver tumors.  J Clin Oncol, 12: 2723-2736, 1994.

5.           Bartlett, D.L., Libutti, S.K., Figg, W.D., Fraker, D.L., and
Alexander, H.R. Isolated hepatic perfusion for unresectable hepatic metastases
from colorectal cancer.  Surgery, 129: 176-187, 2001.

6.           Alexander, H.R., Jr., Bartlett, D.L., Libutti, S.K., Fraker, D.L.,
Moser, T., and Rosenberg, S.A. Isolated hepatic perfusion with tumor necrosis
factor and melphalan for unresectable cancers confined to the
liver.  J.Clin.Oncol., 16: 1479-1489, 1998.

7.           Alexander, H. R. Jr. and Weinreich, D. M. Treatment of Unresectable
Cancers Confined to Liver Using Vascular Isolation and Perfusion. 15(4).
2001.  Lippincott Williams & Wilkins.

8.           Hurwitz H, Fehrenbacher L, Novotny W, et al.  Bevacizumab plus
irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N
Engl J Med. 2004 Jun 3;350(23):2335-42.

 
 

--------------------------------------------------------------------------------

 
9.           Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D,
Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont
A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal
cancer: a randomized GERCOR study.  J Clin Oncol. 2004 Jan 15;22(2):229-37.

10.           Pingpank JF, Libutti SK, Chang R, Wood BJ, Neeman Z, Kam AW, Figg
WD, Zhai S, Beresnev T, Steinberg SM, Seidel GD, Alexander HR.  A Phase I study
of hepatic arterial melphalan infusion and hepatic venous hemofiltration using
percutaneously placed catheters in patients with unresectable hepatic
malignancies.  J Clin Oncol 2005;23:3465-3474.

Work Scope of the Proposed Crada Between Surgery Branch, NCI and Delcath

I.  Complete a Delcath System-based Phase 2 treatment protocol for the regional
therapy of hepatic tumors including primary hepatic tumors and metastases from
gastrointestinal adenocarcinomas and tumors of neuroendocrine lineage.

 
 
a.
The NCI SB is currently conducting a 3-arm Phase 2 trial utilizing the Delcath
System to deliver melphalan for regional therapy of organs.  This study is using
melphalan hydrochloride administered as a 30 minute infusion into the hepatic
artery with hepatic venous hemofiltration using the Delcath System to determine
efficacy of melphalan against hepatic metastases from each of these histologies
when  administered in this manner. Pharmacokinetic (pk) analyses will be
performed by NCI SB to determine hepatic and total clearance of melphalan
hydrochloride from the circuit, the extraction efficiency, and the general
pharmacokinetic advantage of using this system by comparing the pre- and post
filtration melphalan hydrochloride concentrations.  These pk analyses will be
performed in a duplicate fashion to those completed for the Phase 1 trial in
order to compare the efficacy of the filters.  In addition, ongoing monitoring
of the

 
[ *** ] will be performed by NCI.

b.  
The manufacturing and testing of current GMP Delcath System devices as well as
Device Master Files to support Delcath’s IDE application shall be the
responsibility of Delcath.  Delcath shall be responsible for submission of the
Device Master File to support IDE applications and all required regulatory
approvals for use of the device in humans.  In addition, Delcath shall be
responsible for the filing of the IND for the use of melphalan hydrochloride for
the Delcath System device.

II.  Complete a  Delcath System-based Phase 3 treatment protocol as a follow-up
to Phase 1 studies for patients with metastatic melanoma, and expand this study
to a multi-center trial.

a.  
The NCI is currently conducting a Phase 3 clinical trial utilizing the Delcath
System for the delivery of melphalan as described above.  The Phase 3 study will
involve patients with ocular and cutaneous melanoma who have unresectable
cancers confined to the liver using the maximum safe tolerated dose of melphalan
hydrochloride administered using the Delcath System.  Patients will be randomly
assigned to one of two initial treatment arms immediate treatment with melphalan
via the Delcath System or treatment with the best alternative available
care.  The patients will be treated as specified in an institutionally approved
clinical research protocol with up to six (6) series of infusions based upon
toxicity and response to treatment. Patients will be followed for response,
patterns of failure, and overall survival.  The primary endpoint will be hepatic
progression-free survival, and cross-over will be permitted once the primary
endpoint is met.  Pharmacokinetic (pk) analyses will be performed by NCI SB and
monitoring the  [*** ] will be performed as in I (a) above.   With appropriate
NCI Institutional Review Board (IRB) approval and DSMB oversight, this trial
will be expanded to a multicenter trial (NCI IRB approval is currently pending
for the multicenter trial).  The NCI will maintain the primary database and the
statistical analysis for both the intramural and extramural studies will be
conducted by NCI.

b.  
Delcath shall be responsible for the provision of current GMP devices, as well
as all support for the regulatory IDE and IND applications for both the
intramural and extramural  studies, as described in I (b) above.

III.  Development of additional protocols utilizing the Delcath System

a.  
 Additional chemotherapeutics which are commercially available such as [ *** ]
may be selected by mutual agreement of the Parties and by amendment in
accordance with section 13.6 of the CRADA for development with the Delcath
System by Surgery Branch under a Phase 1 trial.  Prior to these studies, NCI may
conduct animal and preclinical studies to examine the utility of the Delcath
System in the regional delivery of these chemotherapeutic using an
inter-arterial route to measure the effects on normal hepatocytes.  In addition,
NCI may conduct a concurrent analysis that will examine the efficacy of the
filters in filtering the chemotherapeutic from saline and serum.

 
 

--------------------------------------------------------------------------------

 
b.  
Delcath shall be responsible for the provision of current GMP devices for these
protocols, as well as all regulatory support for the IDE application as set out
in I (b) above.  The Parties will decide by mutual agreement which Party will
hold and support the IND applications for these studies.

 
Description of the Contributions and Responsibilities of the Parties

Surgery Branch, NCI

_  
Continue conducting the Phase 2 clinical study of melphalan hydrochloride in
patients with primary and metastatic hepatic malignancies using the Delcath
System.

_  
Continue conducting the Phase 3 clinical study of melphalan hydrochloride in
patients with unresectable melanoma metastatic to the liver using the Delcath
System

_  
Conduct pharmacokinetic analyses of samples obtained during treatment from
patients on the Phase 2 and Phase 3 clinical trials to characterize the
pharmacokinetic advantage of melphalan hydrochloride delivered to the liver
using this system.

_  
Coordinate the Phase 3 multicenter clinical study of melphalan hydrochloride in
patients with unresectable melanoma metastatic to the liver using the Delcath
System.  This clinical trial is pending NCI IRB approval and will be added to
this agreement by a written amendment.

_  
Provide and perform primary data management and analysis for Phase 1, 2 and 3
melphalan trials and provide Delcath with a complete copy of the NCI-formatted
database to support FDA and other regulatory submissions, subject to Article
8.9.

_­  
Conduct ongoing hematological biocompatibility testing of filters with
melphalan; generate reports and provide reports to Delcath.

_­  
Conduct filter testing in human plasma and whole blood for melphalan extraction;
generate analyses and reports; and provide reports to Delcath.

_­  
May perform preclinical animal and filter testing to provide the basis for
supporting a Phase 1 trial for additional chemotherapeutic, to be added by
mutual agreement and writen amendment to this CRADA.

_  
Conduct Phase 1 and 2 clinical research trials using additional therapeutics as
administered by the Delcath System by mutual agreement and written amendment,
evaluating the Delcath System as outlined through IRB approved protocols, and
maintain complete data of the end points.

Delcath Systems, Inc.

_  
Provide sufficient numbers of current GMP Delcath System devices for the conduct
of Phase 2 and Phase 3 intramural (and extramural studies, upon IRB approval)
clinical research and studies.

_  
Submit Device Master Files to support their Investigational Device Exemption
(IDE) applications.  Delcath shall hold the IND for the development of melphalan
hydrochloride under this research plan.  The parties will decide by mutual
agreement which party will hold subsequent INDs for selected studies.  Delcath
will provide NCI access to Delcath safety data and review of the Delcath IDE and
INDs for FDA submission.

Surgery Branch, NCI and Delcath Systems, Inc.

_  
Collaborate in the joint development and evaluation of melphalan hydrochloride
as administered by the Delcath System device under the Surgery Branch protocol
in Appendix D.

 
_  
Exchange information and expertise to evaluate the advisability of developing
additional commercial agents for use with the Delcath System for regional cancer
therapy of various  organs.

 
 

--------------------------------------------------------------------------------

 
Description of Predecessor CRADA and Other NCI-Delcath Systems, Inc. Agreements
and Intellectual Property of the Parties

CRADAs:
CRADA No. 01303 “Cooperative Research and Development Agreement for the
Development of the ‘Delcath System’ for the Delivery of Chemotherapeutics in the
Treatment of Cancer” was executed on December 14, 2001 between the Surgery
Branch, NCI and the Delcath Systems, Inc.  The original goal of the CRADA was
the same as this Amendment, namely to develop a novel form of regional cancer
therapy by designing clinical protocols utilizing the “Delcath System” to
regionally deliver chemotherapeutics to patients with unresectable malignancies
confined to an organ or region of the body.   The orignal CRADA, however, began
with a Phase 1 trial measuring the effects of escalating dosages of melphalan in
patients with unrespectable cancers of the liver.   The original Principal
Investigators were H. Richard Alexander, Jr., M.D. of the Surgery Branch, and
M.S. Koly of Delcath Systems, Inc.   The original term of the CRADA was five (5)
years (12/14/2001 - 12/14/2006).  The CRADA was not renewed prior to the
expiration date due to a change in company management and issues relating to IRB
approval of the planned extramural Phase 3 trial.

Amendments to CRADA No. 01303:

1)  
The CRADA was amended October 10, 2002 to delete the requirement for Delcath to
hire a Nurse Practitioner for clinical activities under the CRADA, and instead
to provide an additional $75,000 per year to support a Data Manager.  This
resulted in a total CRADA support level of $195,000 per year.

2)  
The CRADA was amended March 28, 2006 to add Steven A. Rosenberg, M.D., Ph.D. as
NCI Principal Investigator (PI) and to remove H. Richard Alexander, Jr., M.D. as
NCI PI (Dr. Alexander resigned his position at NCI in January 2006).  In
addition, two clinical protocols were added to the CRADA, NCI #04-C-273 and NCI
# 06-C-0088 as outlined in “Progress Report” above.

Other NCI CRADAs: None

MTAs: None

CTAs: None

PATENTS/PATENT APPLICATIONS:

Delcath Systems, Inc.

1) U.S. Issued Patent No. 5,069,662 entitled “Cancer Treatment.”  Inventor:
William L. Bodden  (Assignee: Delcath Systems, Inc.).

1) U.S. Issued Patent No. 5,411,479 entitled “Cancer Treatment and Catheter for
Use in Treatment.”  Inventor: William L. Bodden  (Assignee: Delcath Systems,
Inc.).

3) U.S. Issued Patent No. 5,817,046 entitled “Apparatus and Method for Isolated
Pelvic Perfusion.”  Inventor: Morton G. Glickman  (Assignee: Delcath Systems,
Inc.).

4) U.S. Issued Patent No. 5,893,841 entitled “Balloon Catheter with Occluded
Segment Bypass.”  Inventor: Morton Glickman  (Assignee: Delcath Systems, Inc.).
5) U.S. Issued Patent No. 5,897,533 entitled “Catheter Flow and Lateral Movement
Controller.”  Inventor:  Morton G. Glickman  (Assignee: Delcath Systems, Inc.).

6) U.S. Issued Patent No. 5,919,163 entitled “Catheter with Slidable Balloon.”
Inventor:  Morton G. Glickman  (Assignee: Delcath Systems, Inc.).

7) U.S. Issued Patent No. 6,186,146 entitled “Cancer Treatment Method.”
Inventor: Morton Glickman  (Assignee: Delcath Systems, Inc.).

 
 

--------------------------------------------------------------------------------

 
8)  U.S. Issued Patent No. 7,022,097 entitled “Method for Treating Glandular
Diseases and Malignancies.”
Inventor: Morton G. Glickman  (Assignee: Delcath Systems, Inc.).

NCI

None

Abstract of the Research Plan of the CRADA for Public Release

 
The principal goal of this CRADA is to develop a novel form of regional cancer
therapy by designing clinical protocols utilizing the “Delcath System” to
deliver chemotherapeutics to organs for patients with unresectable
malignancies.  The “Delcath System” is a delivery device in which a therapeutic
agent is infused into the artery of a target organ and then organ venous blood
is collected and the compound filtered to eliminate unnecessary systemic
exposure and toxicity.

 
 

--------------------------------------------------------------------------------

 

APPENDIX B
FINANCIAL AND STAFFING CONTRIBUTIONS OF THE PARTIES

For NCI

The Surgery Branch will commit the efforts of 1.0 full-time equivalent staff per
year, as well as office support staff.  In addition, Surgery Branch will provide
materials to the various clinical projects using CRADA funds as supplied by the
Delcath Systems, Inc. (“Delcath”), and as specified below under this CRADA.

For Delcath Systems, Inc.

Delcath will commit the efforts of 4.0 full-time equivalent personnel per year
as necessary to the various research and product development projects.  The
level of commitment to the various phases of the CRADA research plan will be
established and agreed to by Delcath and NCI.

Upon mutual consent of NCI and Delcath, additional Delcath employees may also
work at the Surgery Branch to conduct CRADA related activities under an
appropriate NCI Guest Researcher or Special Volunteer Agreement as set out in
paragraph 13.9 of the CRADA.  Personnel paid with CRADA funds will dedicate the
majority of their time to work under the Research Plan; however, both parties
acknowledge that personnel paid with CRADA funds are free to participate in
other projects and interactions typically found within the laboratory.

The key personnel who will be participating in this CRADA for Delcath as part of
the product development and administrative teams are:

Richard Taney, Chief Executive Officer
Seymour Fein, M.D., Medical Monitor

In addition to the above "in kind" provisions, Delcath will contribute
$1,000,000 per year, for a period of five (5) years for clinical support. These
funds shall be payable in quarterly amounts of $250,000 with the first payment
due within 30 days of the CRADA Amendment effective date. These funds will be
used for material support of the CRADA (including equipment, supplies, travel,
and other related CRADA support), as well as for support of existing or new
scientific or clinical staff to be hired by NCI who are to perform work under
this CRADA.  No CRADA funds will be used to support the salaries of full-time
tenured federal employees.

Checks should be made payable to the “National Cancer Institute” and sent to:

CRADA Funds Coordinator
Technology Development and Commercialization Branch, NCI
6120 Executive Blvd, Suite 450
Rockville, MD 20852

The check must clearly reference the NCI CRADA Number and Title: CRADA No. 1303,
“Cooperative Research and Development Agreement for the Development of the
"Delcath System" for the Deliver of Chemotherapeutics in the Treatment of
Cancer.”  Subsequent payments shall be due at the beginning of each quarter,
allowing for a thirty (30) day grace period for payment.

Delcath will also consider NCI requests for additional support, including travel
in excess of one (1) round trip visit to Delcath per year, the latter to be
funded from the $1,000,000 CRADA yearly funding, as well as additional expenses,
on a case-by-case basis.  Prior to the start of intramural and extramural
clinical trials added by amendment to develop the “Delcath System”, Delcath will
negotiate in good faith NCI’s request for additional funding to support
activities required for these clinical trials, including IND filings, the
services of additional clinical support staff (including a perfusionist and/or
data manager),  pharmacokinetic/pharmacodynamic studies, and the training of
extramural principal investigators in surgical procedures relating to the use of
the Delcath System.   However, any additional funds to this CRADA will only be
provided following an amendment to the CRADA.

 
 

--------------------------------------------------------------------------------

 
NCI will provide no funding to Delcath for collaborative research and
development pursuant to this CRADA, inasmuch as financial contributions by the
U.S. government to non-Federal parties under a CRADA is prohibited under the
Federal Technology Transfer Act of 1986 (15 U.S.C.§ 3710a(d)(1)).

Materials

Delcath will provide the “Delcath System” for use in intramural clinical trials
(and extramural trials, upon IRB approval and amendment to this CRADA)  by the
Surgery Branch, NCI (see Appendix A, “Description of the Contributions and
Responsibilities of the Parties, Delcath Systems, Inc.” for a detailed
description).

 
Surgery Branch, NCI will provide the study drug melphalan hydrochloride, in
addition to material support for conducting clinical trials (see Appendix A,
“Description of Contributions and Responsibilities of the Parties, Surgery
Branch, NCI” for a detailed description).

 
 

--------------------------------------------------------------------------------

 

Confidential
APPENDIX C

EXCEPTIONS OR MODIFICATIONS TO THE STANDARD CRADA
AND
STANDARD MODIFICATIONS FOR INTRAMURAL CLINICAL TRIAL CRADAS
(orignal modifications are indicated by single underline and single strike-out;
amendment  modifications are indicated by double underline and double
strike-out)

Amend Article 1 to read as follows:

Article 1.    Introduction

This Cooperative Research and Development Agreement (CRADA) between PHS and the
Collaborator will be effective when signed by all Parties.  The research and
development activities which will be undertaken by each of the Parties in the
course of this CRADA are detailed in the Research Plan (RP) which is attached as
Appendix A.  The funding and staffing commitments of the Parties are set forth
in Appendix B.  Any exceptions or changes to the CRADA are set forth in Appendix
C. The clinical protocol referenced in Article 2.18 is attached as Appendix
D. This CRADA is made under the authority of the Federal Technology Transfer
Act, 15 U.S.C. § 3710a and is governed by its terms.

Amend Article 2.11 to read as follows:

2.11
“Subject Data” means all recorded information first produced in the performance
of this CRADA by the Parties.  “Subject Data” shall specifically exclude
“Identifiable Private Information.”

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

2.12
“Adverse Drug Experience” means an adverse clinical experience as defined under
21 C.F.R.  § 310.305 or § 312.32 as applicable.

2.13
“Annual Report” means the brief report of the progress of an IND associated
investigation which the IND sponsor is required to submit to the FDA within 60
days of the anniversary date that the IND went into effect (pursuant to 21
C.F.R. § 312.33).  “Annual Report” also means the report of the progress of an
IDE associated investigation which the IDE sponsor is required to submit to the
FDA at least yearly (pursuant to 21 C.F.R. § 812.150).

2.14
“FDA” means the U.S. Food and Drug Administration.

2.15
“IDE” means an Investigational Device Exemption application submitted to the FDA
in order to receive approval for an investigational device to be used in an
experimental clinical trial.

2.16
“Identifiable Private Information” means patient-identifying data from medical
records or attached to patient specimens, to be obtained prospectively or from
stored medical records or specimens, that can be linked to individual human
subjects, either directly or indirectly through codes.

 
2.1517  “IND” means an Investigational New Drug Application submitted to the FDA
to     receive approval to conduct experimental clinical trials.

 
2.1618  “Protocol” means the Protocols, including the Standard Operating
Procedure(SOP) numbered:

01-C-0215A, entitled “A Phase I Study of Hepatic Arterial Infusion of Escalating
Dose Melphalan with Venous Filtration for Unresectable Cancers of the Liver”;
04-C-0273 entitled "A Phase II Study of Hepatic Arterial Infusion of Melphalan
With Venous Filtration Via Peripheral Hepatic Perfusion (PHP) for Unresectable
Primary and Metastatic Cancers of the Liver”; and
06-C-0088 entitled "A Random-Assignment Study of Hepatic Arterial Infusion of
Melphalan with Venous Filtration via Peripheral Hepatic Perfusion (PHP) (Delcath
System) Versus Best Alternative Care for Ocular and Cutaneous Melanoma
Metastatic to the Liver"

 
 

--------------------------------------------------------------------------------

 
 which is attached hereto as Appendix D and is made a part of this Agreement.

2.17
“Steering Committee” means the joint PHS/Collaborator research and
development team whose composition and responsibilities with regard to the
clinical experiments performed under this CRADA are detailed in the Protocol
attached hereto as Appendix D.

2.1819  “Study” means the work performed by the Principal Investigators in
connection with the Protocol.

2.20
“Study Device” means the Delcath System, a double balloon catheter device
designed to isolate organs, including the liver, from the general circulatory
system during liver cancer treatments with chemotherapy and which returns blood
exiting the liver to the general circulatory system only after the
chemotherapeutic has been substantially removed by filtration.

 
2.1921  “Study Drug” means melphalan hydrochloride in a finished dosage form,
for example, tablet, capsule, namely, a solution, etc., that contains melphalan
hydrochloride as the active agent generally, but not necessarily, in association
with inactive ingredients.  The term also includes a finished dosage form that
does not contain an agent but is intended to be used as a placebo, as stated in
the definition of “Drug product” at 21 C.F.R. 210.3(a)(4). Additional Study
Drugs may be added by mutual agreement of the parties and by amendment in
accordance with section 13.6 of this CRADA.

 
Add a new Article 3.3 as follows:

3.3
Protocol Modification.  The Study shall be done in strict accordance with the
Protocol and no changes in the finalized Protocol will be made unless mutually
agreed upon in writing by both Parties.  In the event that the appropriate
Institutional Review Board (IRB) requires changes in the Protocol or the
Informed Consent Form, both Parties agree to modify the Protocol and/or Informed
Consent Form as appropriate.  Clinical protocols for each study within the scope
of the CRADA Research Plan will be developed by the PHS CRADA PI.  Each clinical
protocol will describe in detail the research to be conducted intramurally or
extramurally.  Each clinical protocol developed by PHS CRADA PI will be
forwarded to Collabo­rator for review and comment approximately four (4) weeks
before it is reviewed by the IRB.  Com­ments from Collaborator received by the
NCI PI before the IRB meeting will be discussed by the IRB, will be given due
consideration, and will be incor­porat­ed into the protocol, absent good
cause.  Comments from either Collaborator or the NCI PI  that are agreed upon in
the IRB meeting will be formatted as a con­sensus review before the proto­col
will be given final approval and submitted to the FDA.  A copy of the final
ap­proved protocol will be forwarded to Collaborator at the same time as it is
submitted to the FDA.

Add a new Article 3.4 as follows:

3.4
Investigational New Drug Application and Investigational Device Exemption.  The
Parties expect that either PHS or Collaborator will submit an IND which may
cross-reference an IND, Drug Master File, or New Drug Application held by the
other.  The Parties will decide by mutual agreement which Party shall hold the
IND for a selected Study.  In the event PHS elects to file its own IND, the
Collaborator agrees to provide PHS background data and information and agrees to
execute such documents as may be reasonably required to effect such
cross-reference.  The Collaborator’s employees will be reasonably available to
respond to inquiries from the FDA regarding information or data contained in the
Collaborator’s IND, Drug Master File, New Drug Application, or other information
and data provided to PHS by the Collaborator pursuant to this Article
3.4.  Nothing herein shall require the Collaborator to undertake additional
studies of any kind or to prepare and submit any additional data to the FDA
which are not already included in the Collaborator’s IND, Drug Master File, or
New Drug Applications.  In the event that Collaborator supplies CONFIDENTIAL
information directly to PHS in support of a PHS IND, such information will be
protected in accordance with the corresponding Confidentiality provisions of
Article 8 of this Agreement.   The Collaborator may sponsor its own clinical
trials and hold its own IND for studies performed outside the scope of this
CRADA from which all data is proprietary to the Collaborator for purposes of
this CRADA.

 
 

--------------------------------------------------------------------------------

 
Collaborator shall submit the IDE for all studies under this agreement.  The
Collaborator’s employees will be reasonably available to respond to inquiries
from the FDA regarding information or data contained in the Collaborator’s IDE,
Device Master File, Pre-Market Approval, or other information and data provided
to PHS by the Collaborator pursuant to this Article 3.4.  Nothing herein shall
require the Collaborator to undertake additional studies of any kind or to
prepare and submit any additional data to the FDA which are not already included
in the Collaborator’s IDE, Device Master File, or Pre-Market Approval
application. The Collaborator may sponsor its own clinical trials and hold its
own IDE for studies performed outside the scope of this CRADA from which all
data is proprietary to the Collaborator for purposes of this CRADA.

Add a new Article 3.5 as follows:

3.5
Device and Drug Information and Supply.  Collaborator agrees to provide PHS
without charge clinical-grade current GMP Study Drug Device in sufficient
quantity to complete the preclinical studies and clinical trial Protocol(s)
sponsored by PHS.  Furthermore, Collaborator agrees to provide without charge
Study Drug, placebo or unformulated analytical grade Study Drug or metabolites,
if available, to PHS for the development of mutually agreed upon analytical
assays or ancillary correlative studies conducted in conjunction with
PHS-sponsored protocols.  Collaborator will provide Cer­tifi­cates of Analysis
Study Device specifications to PHS for each lot of finished product Study Device
provided.

The Parties will decide by mutual agreement which Party shall provide the Study
Drug for a selected study.  If Study Drug is supplied by Collaborator, the
following terms will apply: Collaborator agrees to provide PHS without charge
clinical-grade Study Drug in sufficient quantity to complete the preclinical
studies and clinical trial Protocol(s) sponsored by PHS.  Furthermore,
Collaborator agrees to provide without charge Study Drug, placebo or
unformulated analytical grade Study Drug or metabolites, if available, to PHS
for the development of mutually agreed upon analytical assays or ancillary
correlative studies conducted in conjunction with PHS-sponsored
protocols.  Collaborator will provide Cer­tifi­cates of Analysis to PHS for each
lot of finished Study Drug product provided.
For inquiries related to Study Drug and Study Device, the contact person for PHS
will be H. Richard Alexander, M.D. Steven A. Rosenberg, M.D., Ph.D. as the NCI
PI (Tele­phone Number 301-496-2195) and the Collaborator contact will be James
Bartley, Director of Operations Richard L. Taney, Chief Executive Officer
(Telephone Number 203-323-8668).

Add a new Article 3.6 as follows:

3.6
Device and Drug Delivery and Usage.  Collaborator shall ship Study Drug Device
to PHS in appropriately marked containers in accordance with 21 C.F.R. §
812.5.   If Collaborator supplies Study Drug, Collaborator shall ship Study Drug
to PHS in appropriately marked containers in accordance with 21 C.F.R. § 312.6.
The PIs shall take reasonable steps to ensure that appropriate record keeping
and appropriate usage of Study Drug and Study Device is are maintained in
accordance with the Protocol and any applicable laws and regulations relating
thereto.  Any unused quantity of Study Drug Device (and Study Drug, if supplied
by Collaborator) shall be returned to Collaborator by PHS at the conclusion of
the Study, or earlier termination subject to Article 10.6 of this Appendix C.

Add a new Article 3.7 as follows:

3.7
Protection of Human Subjects and Appropriate Care of Laboratory Animals. All
human clinical trials performed under this CRADA shall conform to the
appropriate federal laws, including, but not limited to all applicable FDA
regulations and DHHS regulations relating to the protection of human subjects
(see  45 C.F.R. Part 46).  PHS and Collaborator also agree to comply with all
applicable federal statutes and Public Health Service policies relating to the
use and care of laboratory animals (see 7 U.S.C. 2131 et. seq.)  Additional
information is available from the NIH Office for Protection from Research Risks
Office for Human Research Protections (OHRP), Telephone: 301-496-7163.

Add a new Article 3.8 as follows:

3.8
Monitoring.  H. Richard Alexander, M.D., Richard L. Taney as Collaborator PI
shall be responsible for clinical site monitoring and the quality assurance of
all data.  Monitoring shall be done in compliance with FDA Good Clinical
Practices Guidelines.

 
 

--------------------------------------------------------------------------------

 
Add the following to the end of Article 4.1 Interim Reports as follows:

Steering Committee reports or c Copies of Annual Reports updating the progress
of the CRADA research shall satisfy the reporting requirements under this
Article 4.1.  In addition, copies of the Annual Reports and other pertinent IND
data (including, but not limited to, clinical brochure data, and formula­tion
and preclinical data, including toxicology findings) and IDE data (including a
report of prior investigations containing clinical, animal and laboratory
testing of the device) shall be exchanged by the Parties­ as they become
available.

Add a new Article 4.3 as follows:

4.3
Adverse Drug Experience and Unanticipated Adverse Device Effect Reporting.    In
accordance with FDA requirements, the Party(ies) which hold(s) the IDE and/or
IND shall establish and maintain records and make reports to the FDA as required
by 21 C.F.R. 310.305 and 21 C.F.R. § 312.32 for the IND and 21 C.F.R. § 812.140
and § 812.150 for the IDE, as applicable.  In the conduct of research under this
CRADA, the Parties also agree to adhere to specific NIH and NCI guidelines and
policies for reporting Adverse Drug Reporting adverse events as specified in “A
Phase I Study of Hepatic Arterial Infusion of Escalating Dose Melphalan with
Venous Filtration for Unresectable Cancers of the Liver.” the Protocols. The
Party which holds the IND and/or IDE agrees to provide the other Party copies of
all Adverse Drug Experience and Unanticipated Adverse Device Effect reports
concurrently with their submission to the FDA, including copies of any warning
letters or other information affecting the safety and/or well-being of human
subjects in research conducted under this CRADA.

Add a new Article 4.4 as follows:

4.4
Annual Reports.   The IND and the IDE holder(s) shall provide the other Party a
copy of the Annual Report thirty (30) days prior to submission of the Annual
Report to the FDA.  The reviewing Party will then have fourteen (14) days to
review the Annual Report and to provide comments to the IND and the IDE
holder(s).

Amend Article 6.1 to read as follows:

6.1
Reporting.  The Parties shall promptly report to each other in writing each
Subject Invention and any patent applications filed thereon resulting from the
research conducted under this CRADA that is reported to them by their respective
employees.  Each Party shall report all Subject Inventions to the other Party in
sufficient detail to determine  inventorship.  Such reports on Subject
Inventions shall be treated as Proprietary/Confidential Information in
accordance with Article 8.4.

 
Amend Article 6.2 to read as follows:

6.2
Filing of Patent Applications. Each party shall be responsible for filing patent
or other IP applications on Subject Inventions in a timely manner and at its own
expense and after consultation with the other Party.  The Parties will consult
and mutually determine a filing strategy for jointly-owned subject inventions.  
For joint inventions, each Subject Invention made jointly by PHS and
Collaborator employees shall be jointly owned by PHS and the Collaborator.  The
Collaborator may elect to file the joint patent or other IP application(s)
thereon and shall notify PHS promptly upon making this election.  If the
Collaborator decides to file such applications, it shall do so in a timely
manner, at its own expense, and in the name of both Parties.  If the
Collaborator does not elect to file such application(s), PHS on behalf of the
U.S. Government shall have the right to file the joint application(s) in a
timely manner, at its own expense, and in the name of both Parties.  If either
Party decides not to retain its IP rights to a jointly owned Subject Invention,
it shall offer to assign such rights to the other Party.  If the other Party
declines such assignment, the offering Party may release its IP rights as it may
determine.

 
Amend Article 6.3 to read as follows:

 
 

--------------------------------------------------------------------------------

 

6.3
Patent Expenses.  The expenses attendant to the filing of patent or other IP
applications on Subject Inventions generally shall be paid by the Party filing
such application.  If an exclusive license to any Subject Invention is granted
to the Collaborator, the Collaborator shall be responsible for all past and
future out-of-pocket expenses in connection with the preparation,
filing,  prosecution and maintenance of any applications claiming such
exclusively-licensed inventions and any patents or other IP grants that may
issue on such applications.  The Collaborator may waive its exclusive license
rights on any Subject Invention  application, patent or other IP grant at any
time, and incur no subsequent compensation obligation for that Subject Invention
application, patent or IP grant.

 
Amend Article 6.4 to read as follows:

6.4
Prosecution of Intellectual Property Applications.  Within one month of receipt
or filing of a patent application on a Subject Invention(s), each Party shall
provide the other Party with copies of the applications and all documents
received from or filed with the relevant patent or other IP office in connection
with the prosecution of such applications.  Each Party shall also provide the
other Party with the power to inspect and make copies of all documents retained
in the patent or other IP application files for Subject Invention(s) by the
applicable patent or other IP office.  Where licensing is contemplated by
Collaborator, the Parties agree to consult with each other with respect to the
prosecution of applications for PHS Subject Inventions and joint Subject
Inventions.  If the Parties agree that Collaborator shall file and prosecute IP
applications on joint Subject Inventions, then Collaborator agrees to grant PHS
an associate power of attorney (or its equivalent) on such IP applications.  If
the Parties agree that Collaborator shall file and prosecute IP applications on
PHS and joint Subject Inventions, then Collaborator agrees to all Customer
Number Practice and/or granting of  power(s) of attorney (or its equivalent)
necessary to assure PHS access to its United States, International, and Foreign
intellectual property rights on said applications.

 
Amend Article 7.2 to read as follows:

7.2
Exercise of License Option.  The option of Article 7.1 must be exercised by
written notice mailed within three (3) six (6) months after either (I)
Collaborator receives written notice from PHS that the patent or other IP
application has been filed; or (ii) the date Collaborator files such IP
application.  Exercise of this option by the Collaborator initiates a
negotiation period that expires nine (9) three (3) months after the exercise of
the option.  If the last proposal by the Collaborator has not been responded to
in writing by PHS within this nine (9) three (3) month period, the negotiation
period shall be extended to expire one (1) month after PHS so responds, during
which month the Collaborator may accept in writing the final license proposal of
PHS.  In the absence of such acceptance, or an extension of the time limits by
PHS, PHS will be free to license such IP rights to others.  In the event that
the Collaborator elects the option for an exclusive license, but no such license
is executed during the negotiation period, PHS agrees not to make an offer for
an exclusive license on more favorable terms to a third party for a period of
six (6) months without first offering Collaborator those more favorable terms.
These times may be extended at the sole discretion of PHS upon good cause shown
in writing by the Collaborator.

 
Amend Article 7.4 to read as follows:

7.4
License in Collaborator Inventions.  Pursuant to 15 U.S.C. § 3710a(b)(2), for
inventions made solely by Collaborator employees under this CRADA, the
Collaborator grants to the Government a nonexclusive, nontransferable,
irrevocable, paid-up license to practice the invention or have the invention
practiced throughout the world by or on behalf of the Government for research or
other Government purposes.  In accordance with Article 8.5, in the exercise of
such license, the Government shall not publicly disclose trade secrets or
commercial or financial information that is privileged or confidential within
the meaning of 5 U.S.C 552(b)(4).

 
 

--------------------------------------------------------------------------------

 

 
Amend Article 8.3 to read as follows:

8.3
Dissemination of Subject Data and Research Materials.  To the extent permitted
by law, the Collaborator and PHS agree to use reasonable efforts to keep Subject
Data and Research Materials confidential until published or until corresponding
patent applications are filed.  Any information that would identify human
subjects of research or patients will always be maintained confidentially.  To
the extent permitted by law, the Collaborator shall have the exclusive right to
use any and all CRADA Subject Data in and for any regulatory filing by or on
behalf of Collaborator, except that PHS shall have the exclusive right to use
Subject Data for that purpose, and authorize others to do so, if the CRADA is
terminated or and if Collaborator abandons its commercialization
efforts.  Collaborator acknowledges the basic research mission of the PHS, and
agrees that after publication, PHS may make unpatented research materials
arising out of this CRADA available to third parties for further research.

 
 
Amend Article 8.4 to read as follows:

8.4
Proprietary/Confidential Information.  Each Party agrees to limit its disclosure
of Proprietary/Confidential Information to the amount necessary to carry out the
Research Plan of this CRADA, and shall place a confidentiality notice on all
such information.  Confidential oral communications shall be reduced to writing
within 30 days by the disclosing Party.  Each Party receiving
Proprietary/Confidential Information agrees that any information so designated
shall be used by it only for the purposes described in the attached Research
Plan.  Any Party may object to the designation of information as
Proprietary/Confidential Information by another Party.  Although certain
research materials provided under this Agreement are CONFIDENTIAL and will be so
stamped, Collaborator recognizes that the NIH PI may need to disclose certain
information concerning CONFIDENTIAL materials to patients (or to physicians or
scientists where such disclosure is made in order to directly facilitate the
ongoing treatment of a patient, or the development of a treatment for a
patient).  Collaborator hereby authorizes such limited disclosures and the NIH
PI agrees to promptly acknowledge to Collaborator the making of any such
disclosure.  Subject Data and Research Materials developed solely by the
Collaborator may be designated as Proprietary/Confidential Information when they
are wholly separable from the Subject Data and Research Materials developed
jointly with PHS investigators, and advance designation of such data and
material categories is set forth in the RP.  The exchange of other confidential
information, e.g.,  patient-identifying data, Identifiable Private Information,
should be similarly limited and treated shall be subject to the terms of Article
8.9.  Jointly developed Subject Data and Research Material derived from the
Research Plan may be disclosed by Collaborator to a third party under a
confidentiality agreement for the purpose of possible sublicensing pursuant to
the Licensing Agreement and subject to Article 8.7.

 
 
Amend Article 8.5 to read as follows:

8.5
Protection of Proprietary/Confidential Information.  Subject to the provisions
in 8.4, Proprietary/Confidential Information shall not be disclosed, copied,
reproduced or otherwise made available to any other person or entity without the
consent of the owning Party except as required under court order or the Freedom
of Information Act (5 U.S.C. § 552).  Each Party agrees to use its best efforts
to maintain the confidentiality of Proprietary/Confidential Information.  Each
Party agrees that the other Party is not liable for the disclosure of
Proprietary/Confidential Information which, after notice to and consultation
with the concerned Party, the other Party in possession of the
Proprietary/Confidential Information determines may not be lawfully withheld,
provided the concerned Party has been given an opportunity to seek a court order
to enjoin disclosure.

 
 
Amend Article 8.6 to read as follows:

8.6
Duration of Confidentiality Obligation.  The obligation to maintain the
confidentiality of Proprietary/Confidential Information as described in Section
8.4 and 8.5 shall expire at the earlier of the date when the information is no
longer Proprietary Information as defined in Article 2.7 or three (3) years
after the expiration or termination date of this CRADA.  The Collaborator may
request an two (2) year extension to this term in writing when necessary to
protect Proprietary/Confidential Information relating to products not yet
commercialized.

 
 

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Add a new Article 8.8 as follows:

8.8
Multi-Party Data and Intellectual Property Rights.  For clinical protocol(s)
where Agent Study Device is used in combination with another investigational
compound(s)  which is (are) proprietary to an entity(ies) not a Party to this
CRADA [hereinafter referred to as Second Party], the access and use of data
derived from such combination studies, [hereinafter referred to as Multi-Party
Data], by the Collaborator and  Second Party shall be co-exclusive as follows:

 
a.
In situations where Agent Study Device is to be used in combination with another
proprietary investigational compound, PHS will provide all Parties with notice
regarding the existence and nature of any agreements governing their use of
Agent Study Device including, the design of the proposed combination protocol(s)
and the existence of any obligations that might restrict PHS’s participation in
the proposed combination protocols.

 
b.
Collaborator agrees to permit use of the Multi-Party Data from these trials by
the Second Party to the extent necessary to allow said Second Party to develop,
obtain regulatory approval or commercialize its own proprietary investigational
compound.  However, this provision will not apply unless said Second Party also
agrees to Collaborator’s reciprocal use of Multi-Party Data.

 
c.
Collaborator and Second Party must agree in writing prior to the commencement of
the combination trials that each will use the Multi-Party Data solely for
development, regulatory approval, and commercialization of its own proprietary
investigational compound(s) or Study Device.

 
Add a new Article 8.9 as follows:

8.9.
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 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 8.9.

 
 

 
Amend Article 10.2 to read as follows:

10.2
Unilateral Termination.  Either PHS or the Collaborator may unilaterally
terminate this entire CRADA at any time by giving written notice at least thirty
(30) days prior to the desired termination date, and any rights accrued in
property, patents or other IP rights shall be disposed of as provided in
paragraph 10.1, except that PHS may, at its option, retain funds transferred to
PHS prior to unilateral termination by  Collaborator for use in completing the
Research Plan solely or with another partner. Any Research Materials within
Collaborator’s possession which are a product of the Study must be transferred
immediately to PHS before the desired termination date of the CRADA.

 
Amend Article 10.3 to read as follows:

10.3
Staffing.  If this CRADA is mutually or unilaterally terminated prior to its
expiration, funds already received will nevertheless remain available to PHS for
continuing any staffing commitment made by the Collaborator pursuant to Article
5.1 above and Appendix B, if applicable, for a period of six months after such
termination.  If there are insufficient funds to cover this expense, the
Collaborator agrees to pay the difference sufficient funds to cover this initial
six month period following termination.

 
Add a new Article 10.6 as follows:

10.6
Research License and Alternative Sources of Supply In the Event Collaborator
Terminates Development of Agent Study Device (and Study Drug, if Supplied by
Collaborator)

a.  In the event Collaborator elects to terminate its development of Study Drug
Device (and Study Drug, if supplied by Collaborator) without the transfer of its
development efforts and obligations under this agreement to another party within
ninety (90) days of discontinuation, and PHS wants to continue its development
of Study Drug Device by completing the clinical studies which are then approved
and/or ongoing, then Collaborator will for a period of no more than two (2)
years:
 
 
 
 

--------------------------------------------------------------------------------

 
(i)  
provide PHS with Study Drug Device (and Study Drug, if supplied by Collaborator)
and/or matching placebo from Collaborator inventory sufficient to complete the
Study in the manner described in the Protocol.  Or,

 
(ii)
arrange, at Collaborator’s expense, for an independent contractor to manufacture
and/or provide PHS Study Drug Device (and Study Drug, if supplied by
Collaborator) and/or matching placebo sufficient to complete the Study in the
manner described in the Protocol.

 
b.
In the event that Collaborator is unable to meet the obligations imposed by (i)
or (ii) above, at the discretion of PHS, Collaborator shall provide PHS all
information necessary to allow PHS to contract and manufacture said Study Drug
Device and/ or matching placebo independent of Collaborator for use in
preclinical studies and clinical trials.  Such obligation shall last until
either a date on which an alternate source of equivalent materials, acceptable
to PHS, can be obtained by PHS, or two years after the date of notification by
Collaborator to PHS that Collaborator elects to terminate its development of
Study Drug Device, whichever comes first.

 
c.
Collaborator hereby grants to PHS a nonexclusive, nontransferable,irrevocable,
paid-up license to practice or have practiced for or on behalf of the United
States any invention which Collaborator may have or obtain on Study Drug Device,
its manufacture, or on the process for use of Study Drug Device, throughout the
world, for medical research purposes, but this license shall become effective
only if and when Collaborator  terminates its development of Study Drug Device
without the transfer of its development efforts to another party within ninety
(90) days of termination, and PHS elects to continue the development of Study
Drug Device.

 
 
Replace the text under Article 12.3 Indemnification with the following:

No indemnification for any loss, claim, damage, or liability is intended or
provided by any party under this agreement.  Each party shall be liable for any
loss, claim, damage, or liability that said party incurs as a result of said
party’s activities under this agreement, except that PHS, as an agency of the
United States, assumes liability only to the extent as provided under the
Federal Tort Claims Act (28 U.S.C. Ch. 171).

 
Amend Article 13.1 to read as follows:

13.1
Governing Law.  The construction, validity, performance and effect of this CRADA
shall be governed by Federal law, as applied by the Federal Courts in the
District of Columbia.  Federal law and regulations will preempt any conflicting
or inconsistent provisions in this CRADA.  NCI and Collaborator, if Collaborator
is sponsoring trials at the NIH under this CRADA, shall comply with all
Department of Health and Human Services regulations relating to Human Subject
use, and all Public Health Service policies relating to the use and care of
laboratory animals.

 
Amend Article 13.2 to read as follows:

13.2
Entire Agreement.  This CRADA together with the Appendices constitutes the
entire agreement between the Parties concerning the subject matter of this CRADA
and supersedes any prior understanding or written or oral agreement.

 
 
Amend Article 13.10 to read as follows:

13.10
Use of Name or Endorsements.  By entering into this CRADA, PHS does not directly
or indirectly endorse any product or service provided, or to be provided,
whether directly or indirectly related to either this CRADA or to any patent or
other IP license or agreement which implements this CRADA by its successors,
assignees, or licensees.  The Collaborator shall not in any way state or imply
that this CRADA is an endorsement of any such product or service by the U.S.
Government or any of its organizational units or employees.  Collaborator issued
p Press releases issued by either Party that reference or rely upon the work of
PHS under this CRADA shall be made available to PHS the other Party at least 7
days prior to publication for review and comment.

 
 

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Add a new Article 13.13 as follows:

13.13
FDA Meetings.  All meetings with FDA concerning clinical studies for the
development of Agent Study Drug and Study Device within the scope of the CRADA
Research Plan will be discussed by Collabo­rator and NIH in advance and will be
held on mutually agreed upon dates.  Collabo­rator reserves the right to set
jointly with NIH the agenda for any such meeting.
 
 

 
Add a new Article 13.14 as follows:

13.14
Conflicts.  In the event of a conflict between the Protocol as attached as
Appendix D and the Model CRADA as modified by this Appendix C, the terms of the
Model CRADA and this Appendix C shall prevail.

 
Add a new Article 13.15 as follows:

13.15
Statutory Compliance.  PHS and Collaborator agree to conduct the Study in
accordance with the applicable portions of the Federal Food, Drug, and Cosmetic
Act, 21 U.S.C. § 301 et. seq., and its implementing regulations and other
applicable federal regulations.

 
Amend Article 14.1 to read as follows:

14.1
Duration.  It is mutually recognized that the duration of this project cannot be
rigidly defined in advance, and that the contemplated time periods for various
phases of the RP are only good faith guidelines subject to adjustment by mutual
agreement to fit circumstances as the RP proceeds.  In no case will the term of
this CRADA extend beyond the term indicated in the RP unless it is revised in
accordance with Article 13.6.  The term of this CRADA is made retroactive to
expiration date of the original CRADA of December 14, 2006.

 
Add the following to Article 14.2 Survivability as follows:

Articles 3.5, 4.3, 8.9, 10.6, and the last sentence of Article 10.2 as
provisions that will survive termination of this CRADA.