Research Agreement - Children's Hospital and EntreMed Inc.
RESEARCH AGREEMENT
CHILDREN'S HOSPITAL RESEARCH AGREEMENT
This Agreement ("Agreement") entered into this 1st day of October,
1999 (the "Effective Date"), by and between Children's Hospital, 300 Longwood
Avenue, Boston, Massachusetts 02115-5737 ("Hospital"), and EntreMed, Inc., 9640
Medical Center Drive, Rockville, Maryland 20850 ("EntreMed").
WHEREAS, Hospital owns certain inventions that may be useful in the
treatment of diseases in humans or animals and is interested in having a
corporate sponsor and licensee to clinically develop these inventions;
WHEREAS, EntreMed is interested in funding and/or implementing the
clinical development of certain of the inventions in return for options for
licensing certain of the inventions;
WHEREAS, the research program contemplated by this Agreement is of
mutual interest and benefit to Hospital and to EntreMed and may further the
practice of medicine and the research agenda of the Hospital in the manner
consistent with its status as a non-profit, tax-exempt, teaching Hospital.
NOW, THEREFORE, the parties agree as follows:
1. SCOPE OF WORK
(a) Hospital agrees to use reasonable efforts to perform the
Research and Clinical Development Program entitled
"Angiogenesis Research Program" ("Program") in
accordance with Exhibit A, attached hereto and made a
part of this Agreement, as the same may be amended by
the parties from time to time.
(b) Any alteration in or amendment to the Program must be
approved in writing by both Hospital and EntreMed prior
to such alteration or amendment being effective.
2. PERIOD OF PERFORMANCE
(a) The Program shall be conducted during the period
beginning on the Effective Date, through September 29,
2002, and will be subject to renewal only by written
mutual agreement of EntreMed and Hospital.
3. PRINCIPAL INVESTIGATOR
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(a) The Principal Investigator for the Program will
be Robert D'Amato, M.D., Ph.D. ("Principal
Investigator") of the Department of Surgery. In
the event the Principal Investigator becomes
unable to complete the Program for any reason,
EntreMed and Hospital may mutually agree upon a
substitute Principal Investigator, in which event
this Agreement shall continue in full force and
effect. If EntreMed and Hospital cannot agree on
a substitute, either party may immediately
thereafter terminate this Agreement, subject to
the requirements of Section 11(f) of this
Agreement.
4. RESEARCH PROGRAM SUPPORT
(a) Primary Program Support. EntreMed agrees to pay Hospital
two million dollars (2,000,000.00) to fund the Program
in accordance with the conditions and terms of this
Agreement.
(b) Payments. On October 1, 1999, EntreMed will pay
Hospital the sum of six hundred fifty thousand
four hundred ninety-one dollars ($650,491) and
thereafter will make payments of six hundred
sixty-six thousand eight hundred eighty-five dollars
($666,885) on October 1, 2000 and six hundred
eighty-two thousand six hundred twenty four
dollars ($682,624) on October 1, 2001, in
accordance with the conditions and terms set
forth herein.
(c) Payments. Payments of all sums due hereunder shall be
made by check payable as follows:
Children's Hospital
Research Finance Office
300 Longwood Avenue
Boston, MA 02115-5737
(d) Late Payments. Late payments shall bear interest
from the due date until payment at a rate of the
lower of one and one-half percent (1 1/2%) per
month, or the maximum amount permitted by law.
The payment of such interest shall not foreclose
Hospital from exercising any other rights it may
have as a consequence of the lateness of any
payment, including without limitation termination
under Article 11(d).
5. EQUIPMENT
(a) Equipment purchased as part of the Program shall be
owned by the Hospital, shall be physically located at
the Hospital, and shall remain as property of the
Hospital following completion of the Program.
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6. PUBLICATIONS
(a) EntreMed acknowledges that Hospital is an academic
medical center and that Dr. D'Amato and his
collaborators shall be free to publish results of
their studies without restraint. Notwithstanding
this, Hospital agrees to send EntreMed copies of any
manuscripts resulting from the Program and submitted
for consideration for publication or any abstracts
that are submitted to a conference no later than the
same day the manuscript or abstract is submitted.
Hospital agrees to use reasonable efforts to notify
EntreMed at least one month in advance of any
instances where the results of the Program will be
presented at a conference by invitation and without
abstract. EntreMed will notify Hospital if any action
is necessary to secure patent protection for the
technology and Hospital agrees to take such action,
subject to the terms and conditions hereof. If
EntreMed so elects, Hospital agrees to include in any
publication of the results of the Program
acknowledgment of EntreMed's financial and technical
support.
7. INTELLECTUAL PROPERTY
(a) Any invention conceived or first reduced to
practice by Hospital or Hospital personnel in the
performance of the Program shall be owned by
Hospital ("Invention"). Any invention conceived
or first reduced to practice by EntreMed or
EntreMed personnel at EntreMed's facilities
during the term of this Agreement shall be owned
by EntreMed. Any invention conceived or first
reduced to practice jointly by Hospital or
Hospital personnel and EntreMed or EntreMed
personnel shall be jointly owned by Hospital and
EntreMed; for jointly-owned inventions, Hospital
agrees to offer an option to license the
Hospital's interest in the invention according to
Section 7(c).
(b) Hospital agrees to notify EntreMed as soon as
possible when a new, potentially patentable
Invention has been identified and disclosed to
the Technology Transfer Office. EntreMed will
immediately order a patentability/6 and
infringement search and, if the Invention is
patentable, will be responsible, at EntreMed's
expense, for filing and prosecuting patent
applications on behalf of Hospital in Hospital's
name covering the new Inventions, with
appropriate and timely review and approval by
Hospital. EntreMed shall solicit Hospital's
comments prior to any significant actions
required during filing and prosecution and
provide Hospital with drafts of proposed actions
and responses sufficiently in advance to allow
time for comment and with file copies after the
action is completed. If EntreMed decides not to
file a patent application, EntreMed will notify
Hospital within [ninety] [90] days of receiving
disclosure of the new Invention; and if EntreMed
decides not to maintain prosecution of any patent
application, EntreMed will notify Hospital in a
timely fashion. Hospital may elect to file or
maintain prosecution of such patent rights at its
own expense; and Hospital shall be entitled to
dispose of such patent
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rights without limitation, and EntreMed shall have no
further option, license or other rights thereto.
(c) For inventions for which EntreMed shall elect to
file and maintain prosecution of a patent
application, Hospital grants to EntreMed an
exclusive nine-month option to decide whether or
not to negotiate an exclusive license. Such
option period shall begin at the date of filing
of a provisional patent application or a
non-provisional patent application. At the end of
the nine-month option period after filing of a
provisional patent application, EntreMed may
request an additional six-month option period.
In consideration for granting the additional
six-month period, EntreMed will agree to file a
non-provisional patent application at EntreMed's
expense. If EntreMed chooses to license such
patent rights during either option period,
EntreMed shall have an additional three-month
period in which to negotiate and enter into a
license on the terms and conditions of the model
license agreement (Exhibit B). During this
three-month period, EntreMed will provide a development
plan to Hospital which will include a time frame
for implementation of the development plan. This
development plan will be updated semiannually.
If EntreMed chooses not to license each patent
rights, Hospital shall have the right to license
to a third party; and EntreMed shall have no
further option, license or other rights thereto.
(d) Any license granted pursuant to this Agreement shall
conform to the terms and conditions of the License
attached as Exhibit B.
(e) Any license granted pursuant to this Article
shall be subject to a reservation of the
unrestricted right of Hospital and inventors
(while employed by Hospital or other non-profit
institution) to use subject matter claimed in the
licensed patent(s) or patent application(s) for
research purposes only at no cost to Hospital and
the right to license to non-profit institutions
for research purposes only.
(f) EntreMed shall retain all invention disclosures
submitted by Hospital in confidence and use its best
efforts to prevent their disclosure to third parties.
EntreMed shall be relieved of this obligation only when
this information becomes publicly available through no
fault of EntreMed.
8. INDEMNIFICATION
(a) EntreMed shall indemnify, defend and hold
harmless Hospital and its board members,
officers, medical staff, employees, and agents
from and against any and all liability, damage,
loss or expense (including reasonable attorneys'
fees and expenses of litigation) incurred by or
imposed upon it or any one of them in connection
with any claims, suits, actions, demands or
judgments arising out of, resulting from or
related to performance under this Agreement,
regardless of the theory of liability (including,
but not
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limited to, actions in the form of tort, warranty, or
strict liability), to the extent that such liability,
loss, damage or expense is the result of the acts or
omissions of EntreMed or any of its board members,
officers, agents, servants, and employees.
(b) EntreMed agrees, at its own expense, to provide
attorneys reasonably acceptable to the Hospital
to defend against any actions brought or filed
against any party indemnified hereunder with
respect to the subject of indemnity contained
herein, whether or not such actions are
rightfully brought. Hospital shall promptly
notify EntreMed if any such action shall be
brought or filed or claim made.
(c) This Article 8 shall survive expiration or termination
of this Agreement.
9. BIOLOGICAL MATERIALS TRANSFER
(a) Unique clones, chemicals, proteins or reagents
developed or discovered under the Program by
Hospital may be shared with scientists at
non-profit academic or governmental institutions upon
execution of Hospital's Materials Transfer
Agreement for commercially significant
materials. Requests for such materials that
originate from commercially entities will be
discussed with EntreMed, and Hospital will
consider the potential effect of such transfers
on the Program before deciding whether to
transfer such materials.
10. TIMELY PRE-CLINICAL AND CLINICAL DEVELOPMENT
(a) As a condition to obtaining a license to the
patent rights to Inventions under Section 7,
EntreMed agrees to support clinical development,
clinical trial and regulatory management of
licensed products. If EntreMed decides to
sublicense the licensed product and patent
rights, in whole or for a field of use, the
sublicenses must be acceptable to Hospital in
that such sublicensee can provide the resources
required to bring the Invention to the
marketplace. Such acceptance of a sublicensee by
Hospital will not be unreasonably withheld.
(b) EntreMed agrees to notify Hospital in a timely
way of its decision to discontinue preclinical or
clinical development of any licensed product and
its reasons for doing so. The license(s) held by
EntreMed to Patent Rights (as defined in the
license agreement for such licensed product) for
that Licensed Product (as defined in the license
agreement for such licensed product) will be
terminated upon notice from Hospital.
11. TERM AND TERMINATION
(a) The term of this Agreement begins on the Effective Date
and terminates on September 30, 2002, unless sooner
terminated as provided below.
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(b) Performance under this Agreement may be
terminated by EntreMed at any time with or
without cause, and by Hospital without cause,
upon one (1) year prior written notice to the
other party. If Hospital terminates this
Agreement under this Article 11(b), all options
and rights to Inventions and patent rights
granted in this Agreement to EntreMed shall
remain in effect under Article 7 and all licenses
granted prior to the effective date of
termination shall remain in effect subject to the
terms of the applicable license agreement entered
into between EntreMed and Hospital. EntreMed
shall continue to fund the Program for the
shorter of either one year following notice of
termination or the remainder of the term set
forth in Article 11(a).
(c) In the event of termination by EntreMed under
Article 11(b), all options and rights to
Inventions and patent rights granted in Article 7
shall immediately terminate this Agreement and
coincidentally with EntreMed's notice of
termination. Any license agreement granted to
EntreMed under Article 7 prior to such notice of
termination, shall survive, subject to the terms
of said license agreement.
(d) In the event of EntreMed's material breach of this
Agreement, including without limitation, failure to meet
its payment obligation under Article 4, Hospital shall
have the right to give notice of breach, and EntreMed
shall have ninety (90) days to cure such breach.
(e) In the event of termination by Hospital under
Article 11(b), and upon sending its notice of
termination, Hospital agrees to promptly take all
responsible steps to reduce the costs to
EntreMed, and Hospital shall return at
termination any unexpended funds to EntreMed less
any non-refundable costs including noncancelable
obligations Hospital has incurred in the
performance of the Program prior to the date of
notice of such termination. In no event shall
such deduction exceed the total support specified
in Article 4.
(f) In the event of termination under Article 3 and
upon the terminating party sending its notice of
termination, Hospital agrees to promptly take all
responsible steps to reduce the costs to
EntreMed, and Hospital shall return at
termination any unexpended funds to EntreMed less
any non-refundable costs including, but not
limited to non-cancelable obligations Hospital
has incurred in the performance of the Program
prior to the date of notice of such termination.
In no event shall such deduction exceed the total
support specified in Article 4. EntreMed agrees
to fund salaries of essential personnel for a
period of nine months from notice of
termination. All options and rights to
Inventions and patent rights granted in Article 7
to EntreMed shall remain in effect and all
licenses granted prior to the effective date of
termination shall remain in effect subject to the
terms of the applicable license agreement entered
into between EntreMed and Hospital.
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(g) The following provisions shall survive any expiration or
termination of this Agreement: 4(a) as to the Option,
5(a), 7(a), 8, 11(b), 11(c), 11(f), 11(g), 12(a), 15
(except (b) and (g)) and 16.
12. COMMUNICATIONS
(a) Notice. All medical/scientific and other communications,
reports, and notices shall be delivered by hand or sent
by first class mail postage prepaid and addressed as
follows:
If to EntreMed:
President
EntreMed, Inc.
9640 Medical Center Drive
Rockville, MD 20850
With a copy to:
James Dean Johnson, Ph.D.
Jones & Askew
2400 Monarch Tower
2434 Peachtree Road
Atlanta, GA 30326
If to Hospital:
For all medical/scientific communications:
Robert D'Amato, M.D., Ph.D.
Department of Surgery
Children's Hospital
300 Longwood Avenue
Boston, MA 02115-5737
With a copy to:
Director
Technology Transfer Office
Children's Hospital
300 Longwood Avenue
Boson, MA 02115-5737
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For all other communications, reports, and notices:
Director
Technology Transfer Office
Children's Hospital
300 Longwood Avenue
Boston, MA 02115-5737
(b) For the purpose of facilitating EntreMed's
understanding of the research activities
conducted by Hospital pursuant to the Program,
Hospital will permit duly authorized employees or
representatives of EntreMed to visit its
facilities where the research is conducted, or
attend restricted-access Hospital seminars on or
off site, at reasonable times and with prior
reasonable notice and approval by the Principal
Investigator. All such visits, seminars or other
communications, including without limitation,
informal conversations, email and the like
concerning research activities, will be subject
to the Mutual Nondisclosure Agreement between the
parties of even date as this Agreement.
(c) All communications regarding the business terms in this
Agreement shall be exclusively between EntreMed and the
Technology Transfer Office.
13. USE OF NAMES
(a) Each party agrees not to use or cite in any
manner the name of the other, its employees or
Principal Investigator in any commercial or
non-commercial advertising, article, press release or
in any other forms of writing or publication
medium, or orally to the extent practical,
without the prior written permission of the party
or individual whose name is to be used except as
required by law. Hospital agrees to respond to
any submission by EntreMed in a timely manner,
and EntreMed agrees to submit such writings, and
summarized oral comments to the extent practical,
for approval at least ten (10) days prior to
submission for public release. EntreMed agrees
that any such writings or publications or oral
comments or presentations, and any references in
its other communications to the public or third
parties, will accurately reflect the contractual
relationship between the parties and will not
misrepresent or mislead others as to the nature
of the relationship. The parties agree to meet
within thirty (30) days after the Effective Date
to establish a set of rules to assist them in
complying with this Article 13(a).
(b) EntreMed agrees not to disclose any of Hospital's
confidential or proprietary information in
Invention disclosures or reports, data concerning
scientific discoveries, data from evaluations,
research results and the like in any commercial
or non-commercial advertising, article, press
release or in any other forms of writing or
publication medium or to any third party without
the prior written permission of Hospital.
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14. REPRESENTATIONS AND WARRANTIES. HOSPITAL REPRESENTS
AND WARRANTS TO ENTREMED AS FOLLOWS:
(a) The execution and delivery of this Agreement by
Hospital have been duly and validly authorized
and this Agreement constitutes a legal, valid and
binding obligation of Hospital, enforceable in
accordance with its terms. The execution,
delivery and performance of this Agreement does
not conflict with or violate any charter document
or, to Hospital's knowledge, any contract binding
upon Hospital.
(b) Hospital has not received notice of any assertion that
any of the patents or subject Inventions infringe upon
any third party's know-how, patent or other intellectual
property rights.
(c) Hospital is and will be, during the term of this
Agreement and thereafter, the owner of all rights in and
to the inventions conceived or first reduced to practice
by Hospital or its employees or independent contractors
as a part of any of the projects which are included in
the Program.
EntreMed represents and warrants to Hospital as follows:
(a) The execution and delivery of this Agreement by
EntreMed have been duly and validly authorized
and this Agreement constitutes a legal, valid and
binding obligation of EntreMed enforceable in
accordance with its terms. The execution,
delivery and performance of this Agreement does
not conflict with or violate any charter document
or, to EntreMed's knowledge, any contract binding
upon EntreMed.
15. GENERAL PROVISIONS
(a) All rights and remedies hereunder will be cumulative and
not alternative, and this Agreement shall be construed
and governed by the laws of the Commonwealth of
Massachusetts.
(b) Neither party may assign, transfer or delegate
its rights, duties or obligations hereunder
without the prior written consent of the other,
and any assignment, transfer or delegation in
violation of this provision shall be void.
Subject to the terms of this provision, this
Agreement shall be binding upon and inure to the
benefit of the parties hereto and their
respective successors and assigns.
Notwithstanding anything herein to the contrary,
in the event EntreMed merges with another entity,
is acquired by another entity, or sells all or
substantially all of its assets to another
entity, EntreMed may assign its rights and
obligations hereunder to, in the event of a
merger or acquisition, the surviving entity, and
in the event of a sale, the acquiring entity,
without Hospital's consent so long as: (i)
EntreMed is not then in breach of this Agreement;
(ii) the proposed assignee has a net worth at
least equivalent to the net worth EntreMed had as
of the date
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of this Agreement; (iii) the proposed assignee has
available resources and sufficient scientific business
and other expertise to satisfy EntreMed's obligations
hereunder; (iv) EntreMed provides written notice of the
assignment to Hospital, together with documentation
sufficient to demonstrate the requirements set forth in
subparagraphs (i) through (iii) above, at least twenty
(20) days prior to the effective date of the proposed
assignment; and (v) Hospital receives from the proposed
assignee, in writing, at least twenty (20) days prior to
the effective date of the assignment: (aa) reaffirmation
of the terms of this Agreement; (bb) an agreement to be
bound by the terms of this Agreement; and (cc) an
agreement to perform the obligations of EntreMed under
this Agreement.
(c) This Agreement may be amended only by written agreement
signed by both parties.
(d) It is expressly agreed by the parties hereto that the
Hospital and EntreMed are independent contractors and
nothing in this Agreement is intended to create an
employer relationship, joint venture, or partnership
between the parties. Neither party has the authority to
bind the other.
(e) This Agreement and its Exhibits constitute the
entire agreement between the parties with respect to the
subject matter hereof and supersedes all proposals,
negotiations and other communications between the
parties, whether written or oral, with respect to the
subject matter hereof.
(f) If any provisions of this Agreement shall be held to be
invalid, illegal or unenforceable, the validity,
legality and enforceability of the remaining provisions
of this Agreement shall not be impaired thereby.
(g) The use of vertebrate animals in the conduct of
work under this Agreement shall comply with
applicable portions of the Animal Welfare Act
(P.L. 89-544 as amended) and will follow the
guidelines prescribed in DHEW, NIH Publication
No. 78-23, "Guide for the Care and Use of
Laboratory Animals," as amended, and in any
applicable state or local regulations.
(h) EXCEPT AS PROVIDED IN ARTICLE 14, AND TO THE
EXTENT PERMITTED BY APPLICABLE LAW, HOSPITAL
MAKES NO WARRANTY, EXPRESS OR IMPLIED, INCLUDING,
WITHOUT LIMITATION, ANY IMPLIED WARRANTIES OF
MERCHANTABILITY, FITNESS FOR A PARTICULAR
PURPOSE, TITLE OR NONINFRINGEMENT, WITH RESPECT
TO ANY PATENT, TRADEMARK, COPYRIGHT, SOFTWARE,
TRADE SECRET, TANGIBLE RESEARCH PROPERTY,
INVENTION, RESEARCH RESULTS, INFORMATION OR DATA
PROVIDED OR UNDER OPTION TO ENTREMED HEREUNDER
AND HEREBY DISCLAIMS THE SAME, AND HOSPITAL SHALL
NOT BE LIABLE
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FOR ANY DIRECT, CONSEQUENTIAL OR OTHER DAMAGES SUFFERED
BY ENTREMED OR ANY LICENSEE OR OTHERS RESULTING FROM USE
OF THE SAME OR ANY RESULTING PRODUCT OR PROCESS.
IN WITNESS WHEREOF, the parties have executed this Agreement as of
the date first written above.
Children's Hospital EntreMed, Inc.
By: /s/ William New By: /s/ John W. Holaday, Ph.D.
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Vice President
Research Administration President and CEO
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Title
10/19/99 9/22/99
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Date Date
/s/ Robert D'Amato 10/22/99
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Robert D'Amato, M.D., Ph.D. Date
Principal Investigator
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Overview of EntreMed funded projects in D'Amato Laboratory
Continuing collaborative projects:
1. Thalidomide and analogs
Testing of analogs and isomers with the phthalimide skeleton
2. Methoxyestradiol and analogs
Testing of analogs with substitutions at 2 position on A ring
3. Epoxide angiogenesis inhibitors such as arglabin
Testing of thalidomide and arglabin analogs with epoxides
New projects:
4. Purification of potent secreted angiogenesis inhibitors from human
tumors
A. MG63 osteosarcoma
B. A375 melanoma
C. ST2 gastric carcinoma
5. Testing of angiogenesis inhibitors on the RPE/VEGF transgenic mouse
(Inducible choroidal neovascularization as a model of macular
degeneration)
Treatment with angiogenesis inhibitors-angiostatin/
endostatin
6. Female reproductive system
Endometriosis model-Uterine explants in mice
Treatment with angiogenesis
inhibitors-angiostation/endostatin
7. Testing of novel inhibitors including new EntreMed compounds and
gene therapy.