DEVELOPMENT AND LICENSE AGREEMENT
BETWEEN
GENTA INCORPORATED
AND
EMISPHERE TECHNOLOGIES, INC.
March 22, 2006
DEVELOPMENT AND LICENSE AGREEMENT
THIS DEVELOPMENT AND LICENSE
AGREEMENT (the
“Agreement” ) is entered into as of March
22, 2006 (the “Effective Date” ) by and
between GENTA INCORPORATED , a Delaware corporation having a
place of business at 2 Connell Drive, Berkeley Heights, New Jersey
07922 ( “Genta” ), and EMISPHERE
TECHNOLOGIES, INC. , a Delaware corporation having an address
of 765 Old Saw Mill River Road, Tarrytown, NY 10591 (
“Emisphere” ).
Recitals
WHEREAS , Emisphere is a biopharmaceutical company
specializing in the oral delivery of therapeutic molecules and
compounds;
WHEREAS, Emisphere has developed a certain oral delivery
technology known as eligen™, and oral dosage formulations of
therapeutic compounds;
WHEREAS, Genta is a biopharmaceutical company engaged in
the research, development and commercialization of pharmaceutical
products;
WHEREAS, Genta has developed a gallium-nitrate compound
known as GANITE®, for which Genta has obtained FDA approval to
market and sell (and which Genta currently markets and sells) as an
intravenous treatment for patients with cancer-related
hypercalcemia;
WHEREAS, Genta desires to develop, and Emisphere is
willing to develop for Genta, a customized version of
Emisphere’s eligen™ technology for use with
gallium-nitrate to produce oral dosage formulations of gallium
nitrate and other gallium-containing compounds;
WHEREAS, Genta desires to obtain, and Emisphere is
willing to grant to Genta, an exclusive, worldwide right to develop
and commercialize oral dosage formulations of gallium nitrate and
other gallium-containing compounds based upon the eligen™
technology, subject to the terms and conditions set forth
herein.
NOW, THEREFORE, in consideration of the foregoing premises and
the mutual covenants contained herein and other good and valuable
consideration, the receipt and sufficiency of which are hereby
acknowledged, the parties agree as follows:
1. DEFINITIONS
1.1 “Active Pharmaceutical
Ingredient” or
“API” shall mean a compound (in bulk form)
having therapeutic activity, excluding any excipients and other
ingredients that do not have any therapeutic activity, and
excluding Carriers.
1.2 “Affiliate”
shall mean an individual, trust,
business trust, joint venture, partnership, corporation,
association or any other entity which (directly or indirectly) is
controlled by, controls or is under common control with a party to
this Agreement. For the purposes of this definition, the term
“control” (including, with correlative meanings, the
terms “controlled by” and “under common control
with”) as used with respect to a party, shall mean the
possession (directly or indirectly) of more than fifty percent
(50%) of the outstanding voting
1.
securities of a corporation or
comparable equity interest in any other type of entity, or
otherwise having the power to govern the financial and the
operating policies or to appoint the management of such
entity.
1.3 “Carrier”
shall mean any synthetic chemical
compound that enables a drug molecule to cross
membranes.
1.4 “Carrier A”
shall mean the Carrier set forth in
Exhibit A hereto that is designated as “Carrier
A.”
1.5 “Carrier B”
shall mean the Carrier set forth in
Exhibit A hereto that is designated as “Carrier
B.”
1.6 “Carrier Inventions”
shall have the meaning provided in
Section 9.1(b).
1.7 “Clinical Plan”
shall mean the plan agreed upon by
the parties for conducting the Clinical Program, as such plan may
be amended from time to time by the TLC.
1.8 “Clinical Program”
shall mean the program of clinical
development to be conducted during the Clinical Term, as more fully
described in the Clinical Plan. At least initially, the focus of
the Clinical Program will be the clinical development of a Product
in the * Field.
1.9 “Clinical Term”
shall mean the period of time
commencing upon the first dosing of the first subject in a Phase I
clinical trial of a Product and, unless terminated as provided in
this Agreement, ending upon the date upon which Genta has obtained
an initial Regulatory Approval of a Product in the * Field,
provided that, upon mutual written consent after the Effective Date
the parties may extend the Clinical Term to pursue additional
indications. After the Effective Date, the Clinical Term may only
be extended by mutual written agreement between the parties that
references this Section 1.9.
1.10 “Combination
Invention” shall
have the meaning provided in Section 9.1(b).
1.11 “Combination
Product” shall have
the meaning provided in Section 6.3(c).
1.12 “Confidential
Information” shall
have the meaning provided in Section 11.1.
1.13 “Control”
shall mean, with respect to any
Information or intellectual property right, possession by a party
of the ability (whether by ownership, license or otherwise) to
grant access, a license or a sublicense to such Information or
intellectual property right without violating the terms of any
agreement or other arrangement with any Third Party.
1.14 “Development Plan”
means collectively or individually,
as context requires, the Formulation-Development Plan and/or the
Clinical Development Plan.
1.15 “Development
Program” means
collectively or individually, as context requires, the
Formulation-Development Program and/or the Clinical Development
Program.
2.
1.16 “Development Term”
shall have the meaning provided in
Section 12.1.
1.17 “DMF” shall mean a drug master file (as such term is
defined in 21 C.F.R. Part 314.420).
1.18 “Emisphere
Inventions” shall
have the meaning provided in Section 9.1(c).
1.19 “Emisphere Know-How”
shall mean, to the extent Controlled
by Emisphere or its Affiliates as of the Effective Date or at any
time during the Term, all Information not included in the Valid
Claims of Emisphere Patents or Joint Patents that is necessary or
useful for Genta for to perform its obligations under the
Formulation-Development Program or to manufacture, use, sell, offer
for sale or import Products, including, in each case, any
replication or any part of any of the foregoing
Information.
1.20 “Emisphere Patents”
shall mean, to the extent Controlled
by Emisphere or its Affiliates as of the Effective Date or at any
time during the Term, all Patents that claim inventions necessary
or useful for Genta to perform its obligations under the
Formulation-Development Program or to manufacture, use, sale, offer
for sale or import of Products, but excluding in each case the
Joint Patents. For clarity, Emisphere Patents includes all Patents
that claim Emisphere Inventions.
1.21 “Emisphere
Technology” shall
mean the Emisphere Patents and Emisphere Know-How.
1.22 “Existing MTA”
means the Material Transfer
Agreement between the parties dated July 8, 2004.
1.23 “FDA” shall mean the United States Food and Drug
Administration, or any successor agency thereto having the
administrative authority to regulate the marketing of human
pharmaceutical products or biological therapeutic products,
delivery systems and devices in the United States of
America.
1.24 “Field” shall mean all human and veterinary medical
uses.
1.25 “First Commercial
Sale” shall mean,
with respect to any Product, the first sale in a country after the
governing health regulatory authority of such country has granted
Regulatory Approval to market and sell the Product.
1.26 “Formulation-Development
Budget” means
budget agreed upon by the parties for Emisphere’s conduct of
its responsibilities under the Formulation-Development Program, as
such budget may be amended from time to time by the TLC. The
Formulation-Development Budget in effect as of the Effective Date
of this Agreement has been agreed upon by the parties in
writing.
1.27 “Formulation-Development
Plan” shall mean
the plan agreed upon by the parties for conducting the
Formulation-Development Program, as such plan may be amended from
time to time by the TLC. The Formulation-Development Plan in effect
as of the Effective Date of this Agreement has been agreed upon by
the parties in writing.
3.
1.28 “Formulation-Development
Program” shall
mean the program of formulation research and development of a
Product (including selection and incorporation of the Program
Carrier in connection therewith) to be conducted during the
Formulation-Development Term, as more fully described in the
Formulation-Development Plan. At least initially, the focus of the
Formulation-Development Program will be the research and
development of a Product for use within the * Field.
1.29 “Formulation-Development
Term” shall mean
the period of time commencing upon the Effective Date of this
Agreement and, unless earlier terminated as provided in this
Agreement, ending upon completion of the activities set forth in
the Formulation-Development Plan.
1.30 “Gallium Compound”
means a compound containing the
element gallium (including, without limitation, a Gallium Salt) as
its Active Pharmaceutical Ingredient.
1.31 “Gallium Inventions”
shall have the meaning provided in
Section 9.1(b).
1.32 “Gallium Salt”
means any salt form of gallium,
including without limitation gallium nitrate, gallium citrate,
gallium maltolate or gallium sulfate in anhydrous solvate or
hydrate forms.
1.33 “Genta Inventions”
shall have the meaning provided in
Section 9.1(c).
1.34 “Genta Know-How”
shall mean, to the extent Controlled
by Genta or its Affiliates as of the Effective Date or at any time
during the Term, all Information not included in the Genta Patents
or Joint Patents that is necessary or useful for Emisphere to
perform its obligations under the Formulation-Development Program
or the manufacture and supply of Products under Article 8. For
clarity, other than the Gallium Salt (in the form of gallium
nitrate or such other form as may be the subject of the
parties’ efforts under this Agreement) and the Materials (as
defined in Section 3.7) that Genta is required to provide under the
Formulation-Development Plan, no compositions of matter, cells,
cell lines, assays, animal models and physical, biological or
chemical materials owned or Controlled by Genta or its Affiliates
are included within the Genta Know-How to be provided
hereunder.
1.35 “Genta Patents”
shall mean, to the extent Controlled
by Genta or its Affiliates as of the Effective Date or at any time
during the Term, all Patents that claim inventions necessary or
useful for Emisphere to perform its obligations under the
Formulation-Development Program or under Article 8, but excluding
the Joint Patents. For clarity, Genta Patents includes all Patents
that claim Genta Inventions.
1.36 “Genta Technology”
shall mean the Genta Patents and the
Genta Know-How.
1.37 “* Field”
shall have the meaning provided in
Section 6.2(b)(i).
1.38 “Improvement”
shall mean, with respect to the
Program Carrier or a Potential Program Carrier, a Carrier that is
derived from or based upon the Program Carrier, any
Potential
4.
Program Carrier, or any other
Emisphere Technology, but that also incorporates or embodies
enhancements, modifications or improvements thereto.
1.39 “IND” shall mean an Investigational New Drug
Application filed with the FDA, or the equivalent application or
filing filed with any equivalent agency or governmental authority
outside the United States of America (including any supra-national
agency such as in the European Union) necessary under law to
commence human clinical trials in such jurisdiction.
1.40 “Information”
shall mean all tangible and
intangible (a) techniques, technology, practices, trade
secrets, inventions (whether patentable or not), methods,
knowledge, know-how, skill, experience, test and commercial data
and results (including pharmacological, toxicological, clinical and
pre-clinical test data and results), analytical and quality control
data, results or descriptions, software and algorithms and
(b) compounds, compositions of matter, cells, cell lines,
assays, animal models and physical, biological or chemical
materials.
1.41 “Inventions”
shall have the meaning provided in
Section 9.1(a).
1.42 “Joint Inventions”
shall have the meaning provided in
Section 9.1(c).
1.43 “Joint Patents”
shall mean all Patents that claim a
Joint Invention.
1.44 “Joint Technology”
shall mean the Joint Patents and
Joint Inventions.
1.45 “Milestones”
means, collectively, the First
Milestone (including the individual Formulation-Development Term
Milestones therein), Second Milestone, Third Milestone, Fourth
Milestone, Fifth Milestone, and Sixth Milestone, each of which
shall have the meaning provided in Section 6.2(a).
1.46 “NDA” shall mean a New Drug Application (as more fully
defined in 21 C.F.R. Part 314.5 et seq .) and all
amendments and supplements thereto filed with the FDA, or the
equivalent application filed with any equivalent agency or
governmental authority outside the United States of America
(including any supra-national agency such as in the European
Union), including all documents, data, and other information
concerning a pharmaceutical product which are necessary for gaining
Regulatory Approval to market and sell such pharmaceutical product
in the relevant jurisdiction.
1.47 “Net Sales”
shall mean the gross amounts
received by Genta or its Affiliates or Sublicensees for sales of
Products to Third Parties (it being understood that sales between
Genta, its Affiliates and Sublicensees are not included within Net
Sales, unless the buying party is the end user of such Product, in
which case the amount billed therefor shall be deemed to be the
amount that would be billed to a Third Party end user in an
arm’s-length transaction), less the following deductions: (i)
returns and return reserves (such reserves consistent with
generally accepted accounting principles (
“GAAP” )) (including allowances actually
given for spoiled, damaged, out-dated, rejected or returned Product
sold, withdrawals and recalls), (ii) rebates to the extent
consistently and reasonably applied by Genta or its Affiliates or
Sublicensees to its products, price reductions, rebates to welfare
systems, (iii) charge backs and charge back reserves (such reserves
consistent with GAAP), (iv) cash sales incentives (but only to the
extent it is a sales related deduction which is accounted for
within Genta or its Affiliates or
5.
Sublicensees on a
product-by-product basis), (v) government mandated rebates and
similar types of rebates (e.g., Medicaid), each as consistently and
reasonably applied by Genta or its Affiliates or Sublicensees to
its products, (vi) volume (quantity) discounts and cash discounts),
as consistently and reasonably applied by Genta or its Affiliates
or Sublicensees to its products, and (vii) taxes (value added or
sales taxes, government mandated exceptional taxes and other taxes
directly linked to the gross sales amount), it being understood
that income and capital gains taxes are not the type of taxes
contemplated as a deduction in this definition of Net
Sales.
1.48 “Oral Formulation”
shall mean a pharmaceutical product
containing on the one hand, a Gallium Compound, and on the other
hand, any Carrier, that is useful and is marketed only for oral
administration, including sublingual and buccal dosage
forms.
1.49 “Patents”
shall mean (a) United States
and foreign patents, re-examinations, reissues, renewals,
extensions and term restorations, and (b) pending applications
for United States and foreign patents, including, without
limitation, provisional applications, non-provisional applications,
continuations, continuations-in-part, divisional and substitute
applications, including, without limitation, inventors’
certificates.
1.50 “Potential Program
Carriers” shall
mean the two (2) Carriers set forth in Exhibit A hereto,
designated as “Carrier A” and “Carrier B,”
respectively, and such additional Carriers, if any, that the
Parties agree to add as Potential Program Carriers as set forth in
Section 3.8.
1.51 “Product”
shall mean any Oral Formulation
containing a Gallium Compound and the Program Carrier.
1.52 “Program Carrier”
shall mean the Carrier selected by
the parties to be incorporated into the Products pursuant to the
Formulation-Development Program in accordance with
Section 3.8.
1.53 “Regulatory
Approval” shall
mean any and all approvals (including price and reimbursement
approvals), licenses, registrations, or authorizations of any
country, federal, state or local regulatory agency, department,
bureau or other government entity that is necessary for the
manufacture, use, storage, import, transport and/or sale of a
Product in such jurisdiction.
1.54 “Regulatory
Authority” shall
mean any and all national, supra-national, regional, state or local
regulatory agency, department, bureau, commission, council or other
governmental entity, whose approval or authorization is necessary
for, or to whom notice must be given prior to, the manufacture,
distribution, use or sale of a Product.
1.55 “Sublicensee”
means a Third Party to whom Genta or
a Genta Affiliate has granted a sublicense under the Emisphere
Technology to manufacture and/or sell Products. A Sublicensee shall
be considered a “Domestic Sublicensee” to the
extent Genta or a Genta Affiliate has granted it a sublicense under
the Emisphere Technology to sell Products in the United States, and
a “Foreign Sublicensee” to the extent Genta or a
Genta Affiliate has granted it a sublicense under the Emisphere
Technology to sell Products outside the United States. For clarity,
(i) Net Sales of a Sublicensee who, under sublicense from Genta or
a Genta Affiliate, makes Products inside the United States and
sells them outside the United States are considered
6.
Net Sales of a Foreign
Sublicensee, (ii) Net Sales of a Sublicensee who, under sublicense
from Genta or a Genta Affiliate, makes Products outside the United
States and sells them inside the United States are considered Net
Sales of a Domestic Sublicensee, and (iii) a Sublicensee who, under
sublicense from Genta or a Genta Affiliate, sells Products
globally, is considered a Domestic Sublicensee with respect to
sales made inside the United States and a Foreign Sublicensee with
respect to Net Sales made outside the United States.
1.56 “Supply Agreement”
shall have the meaning provided in
Article 8.
1.57 “Technical Liaison
Committee” or
“TLC” shall mean the committee formed pursuant
to Section 2.1.
1.58 “Term” shall have the meaning provided in
Section 12.1.
1.59 “Third Party”
shall mean any entity other than
Emisphere or Genta or an Affiliate of Emisphere or
Genta.
1.60 “Valid Claim”
shall mean any claim in an issued
Emisphere Patent that (i) has not expired, been cancelled, been
declared invalid, or been admitted to be invalid or unenforceable
by a decision of a court or government agency of competent
jurisdiction to which an appeal or other legal recourse is not, or
is no longer, possible, and (ii) has not been admitted to be
invalid by the patent’s owner or its successor or assigns
through reissue, re-examination, or disclaimer.
2. TECHNICAL LIAISON
COMMITTEE
2.1 Technical Liaison Committee.
Promptly after the Effective Date,
the parties will form a Technical Liaison Committee (the
“TLC” ) composed of three (3)
representatives of each of Genta and Emisphere. One (1)
representative of Genta on the TLC shall be selected to act as the
chairperson of the TLC. The TLC shall meet as needed, but at least
quarterly during the Development Term (and upon the termination or
expiration of the Development Term, the TLC shall dissolve and have
no further function under this Agreement). Such meetings may be
conducted by videoconference, teleconference or in person. A
reasonable number of additional representatives of either party may
attend meetings of the TLC, subject to Articles 9 and 11. Should
the additional representatives not be an employee of either party,
such individuals may attend TLC meetings provided they have
appropriate confidentiality agreements in place that are
commensurate with those set forth in Article 11 and have agreed to
assign inventions to either party to effect the intent of Article
9. The TLC shall have responsibility to (i) facilitate the exchange
of information between the parties, (ii) review progress on the
implementation and completion of the Development Plan, including
timelines and adherence to the Formulation-Development Budget, and
(iii) make such other decisions as are expressly allocated to the
TLC under this Agreement. The TLC shall not have the power to amend
or waive compliance with the terms of this Agreement.
2.2 Decision Making. Decisions of the TLC shall be made by majority
vote of all TLC members present either in person or by other means
(e.g., teleconference) at any meeting; provided that, if there is
not an equal number of TLC members who are representatives of each
party present at such meeting, then only an equal number of such
representatives of each party
7.
shall be entitled to vote at such
meeting. In the event that the votes required to approve a decision
cannot be reached, then either party may, by written notice to the
other, have such issue referred to the Chief Executive Officer of
Genta and the Chief Executive Officer of Emisphere, for attempted
resolution by good-faith negotiations within thirty (30) days after
such notice is received. For all matters that cannot be resolved by
such Chief Executive Officers upon request by a party, then neither
party shall have the deciding vote or the right to challenge the
results thereof, through arbitration or otherwise, provided that
the foregoing shall not limit either party’s right to submit
claims of breach of this Agreement for resolution by binding
arbitration pursuant to Section 14.3.
3. CONDUCT OF
FORMULATION-DEVELOPMENT PROGRAM
3.1 Objectives. Emisphere hereby agrees to establish and conduct
its responsibilities under the Formulation-Development Program
during the Formulation-Development Term in accordance with the
Formulation-Development Plan and the timelines set forth therein,
the Formulation-Development Budget, and with the terms of this
Agreement, to develop Products for further development and
commercialization by Genta.
3.2 Initial Technology Transfer.
Commencing promptly after the
Effective Date: (a) Genta shall disclose to Emisphere all existing
Genta Technology necessary to enable Emisphere to practice the
license granted to it under Article 5; and (b) Emisphere
shall disclose to Genta all existing Emisphere Technology necessary
to enable Genta to practice the license granted to it under
Article 5. During the Development Term, Emisphere shall
provide Genta with reasonable technical assistance relating to the
use of the Emisphere Technology, solely to the extent necessary to
enable Genta to practice the licenses granted to it under
Article 5.
3.3 Research Commitment. During the Formulation-Development Term,
Emisphere shall use commercially reasonable efforts to conduct its
responsibilities under the Formulation-Development Program in
accordance with the Formulation-Development Plan and
Formulation-Development Budget, as revised from time to time by the
TLC. Without limiting the generality of the foregoing, Emisphere
shall devote to the Formulation-Development Program such personnel
as is reasonably necessary to conduct all of Emisphere’s
responsibilities required under the Formulation-Development Plan,
it being understood that Genta is and will be responsible (a) under
the Formulation-Development Plan only for the supply of cGMP
quantities of Gallium Salt API (in the form of gallium nitrate or
such Gallium Salt(s) as may be mutually agreed by the parties) to
Emisphere in connection with formulation development, and
(b) for the conduct of the Clinical Program (as set forth in
greater detail in Article 4). Emisphere acknowledges that while the
Formulation-Development Plan describes the principal activities
that Emisphere is to perform under the Formulation-Development
Program, Emisphere’s responsibilities under the
Formulation-Development Program (and the reimbursement provided
under Section 6.1) include all such activities that would normally
be performed to perform such principal activities, including the
analysis and compilation of results from such activities in a form
appropriate for submission in an IND filing. Subject to the
foregoing Genta acknowledges that Emisphere’s
responsibilities under the Formulation-Development Program may not
constitute all activities that are necessary to develop a Product
for the * Field to the point of supporting the filing of an IND. In
addition, Emisphere shall promptly provide written reports of the
status of its activities under the Formulation-Development Plan and
the results from its
8.
performance of such activities,
in accordance with a schedule agreed upon by the parties, which
shall be in any event at least monthly. Each party shall be solely
responsible for the costs and expenses incurred in connection with
its performance of Development Plan activities, subject to Section
6.1. Genta shall be responsible for the conduct of toxicology
studies of Products that it deems appropriate, to the extent such
studies are not otherwise covered by the Formulation-Development
Plan. To the extent Genta conducts any toxicology studies of
Products, Emisphere shall have no right to utilize the data
generated from such studies without the prior written consent of
Genta, unless required by law; provided, however, that, at
Emisphere’s option, Emisphere shall have the right to
purchase such data solely for use in accordance with
Section 5.3, and Genta agrees, subject to Genta’s
consent not to be unreasonably withheld, to sell such data to
Emisphere solely for such purpose and as Confidential Information
of Genta subject to the confidentiality restrictions of this
Agreement, upon payment by Emisphere to Genta of an amount equal to
Genta’s cost of conducting the applicable toxicology
study(ies).
3.4 Continuing Information Exchange.
Without limiting its obligations
under Section 3.2, Emisphere shall promptly disclose and keep Genta
reasonably informed as of all Emisphere Technology developed or
obtained, including without limitation inventions, discoveries and
technical developments made in the course of performing its
activities under the Formulation-Development Program, and all
Inventions made by employees or independent contractors of
Emisphere related to Oral Formulations or otherwise necessary or
useful for the Formulation-Development Program, with any such
Inventions that are included in the Emisphere Technology and that
are directly relevant to the Formulation-Development Program being
communicated reasonably promptly after it is developed or obtained,
or its significance appreciated. Emisphere shall disclose to Genta,
in confidence, all reasonably requested toxicology and safety data
and other information Controlled by Emisphere relating to the
Potential Program Carriers, the Program Carrier or the Oral
Formulations; it being understood that (a) with respect to Carrier
A, Emisphere shall be required to disclose such information upon
the Effective Date of this Agreement and thereafter for so long as
Carrier A remains a Potential Program Carrier, and (b) with respect
to the Carrier B, Emisphere shall only be required to disclose such
information upon Genta’s selection of Carrier B *, and
thereafter for so long as Carrier B remains a Potential Program
Carrier. Emisphere shall also provide reasonable technical
assistance to enable Genta to utilize such information.
3.5 Subcontracts. Emisphere may perform some of its obligations
under the Formulation-Development Plan through one (1) or more
subcontractors, provided that (i) for any subcontractor involved in
activities that are not solely related to Carriers, Genta approves
of the subcontractor in advance in writing (such approval not to be
unreasonably withheld), (ii) none of the rights of Genta
hereunder are diminished or otherwise adversely affected as a
result of such subcontracting, and (iii) the subcontractor
undertakes in writing obligations of confidentiality and non-use
regarding Confidential Information which are substantially the same
as those undertaken by Emisphere pursuant to Articles 9 and 11
hereof. In the event that Emisphere performs any of its obligations
under the Formulation-Development Plan through a subcontractor,
then Emisphere will, at all times, be responsible for the
performance and payment of such subcontractor as if the obligations
performed by the subcontractor were performed by Emisphere. For
clarity, Emisphere shall have the right to use subcontractors to
perform its activities under the Formulation-Development Program
solely in connection with Carriers without first obtaining
Genta’s approval of such subcontractor.
9.
3.6 Compliance. All work conducted by either party in connection
with the Formulation-Development Program, shall be conducted in
accordance with applicable Good Laboratory Practices and, if
applicable, Good Manufacturing Practices, as such rules of practice
and regulations are amended from time to time.
3.7 Materials Transfer. In order to facilitate the
Formulation-Development Program, Genta has provided (under the
Existing MTA) and may continue to provide to Emisphere certain
biological materials or chemical compounds (collectively,
“Materials” ) Controlled by Genta (other
than under this Agreement) for use by Emisphere in furtherance of
the Formulation-Development Program. Except as otherwise provided
under this Agreement, all such Materials delivered to Emisphere are
and will remain the sole property of Genta, have been and will be
used by Emisphere only in furtherance of the
Formulation-Development Program in accordance with this Agreement,
have not been and will not be used or delivered to or for the
benefit of any Third Party (other than a permitted subcontractor of
Emisphere), and have been and will be used in compliance with all
applicable laws, rules and regulations. In particular, Genta has or
may supply Emisphere with Gallium Salt API as set forth in the
Formulation-Development Plan. The Materials supplied under this
Agreement must be used with prudence and appropriate caution in any
experimental work because not all of their characteristics may be
known. Except as expressly set forth herein, THE MATERIALS ARE
PROVIDED “AS IS” AND WITHOUT ANY REPRESENTATION OR
WARRANTY, EXPRESS OR IMPLIED, INCLUDING WITHOUT LIMITATION ANY
IMPLIED WARRANTY OF MERCHANTABILITY OR OF FITNESS FOR ANY
PARTICULAR PURPOSE.
3.8 Selection of the Program Carrier.
Under the Formulation-Development
Program, Emisphere shall perform pre-clinical studies and other
activities to generate such data and information as is necessary to
evaluate the suitability of each of the two (2) Potential Program
Carriers identified in Exhibit A hereto for incorporation
into the Product to be developed under the Formulation-Development
Program. The selection of the Program Carrier shall be conducted in
a * .
4. DEVELOPMENT AND
COMMERCIALIZATION OF PRODUCTS BY GENTA
4.1 Development and Commercialization of
Products. Subject to the
terms and conditions of this Agreement, and except as otherwise
provided with respect to Emisphere’s performance of its
responsibilities under the Formulation-Development Program under
Article 3, its preparation and maintenance of certain regulatory
filings under Article 4, and its manufacturing
responsibilities under Article 8, Genta shall control and be solely
responsible for the worldwide development and commercialization of
Products, at its sole cost and expense. Genta hereby agrees to
establish and conduct the Clinical Program during the Clinical Term
in accordance with the Clinical Plan and the timelines set forth
therein. Genta shall own all data generated in the development
and/or commercialization of Products other than data solely
relating to Carriers (provided Genta shall have the right to access
and use such Carrier-specific data as necessary to carry out the
purposes of this Agreement).
4.2 Disclosure and Use of Data Relating to
Program Carriers. Genta
shall during the Term of this Agreement promptly and fully disclose
to Emisphere in writing all data generated by or on behalf of Genta
or its Affiliates (or Sublicensees, to the extent provided
to
10.
and Controlled by Genta) with
respect to the Program Carrier. Emisphere shall be free to use all
such data disclosed to it by Genta for any purpose (including,
without limitation, in support of patent filings), other than the
development, manufacture or commercialization of Oral Formulations.
Without limiting the generality of the foregoing, Emisphere shall
be free to use such data for the purpose of researching,
developing, manufacturing or commercializing the Program Carrier
pursuant to Article 8 hereof and/or for use of any Carrier in
combination with any compound that is not a Gallium
Compound.
4.3 Clinical Trials and Clinical
Data. Genta shall have
the sole right to conduct clinical trials of Products in the Field.
Genta shall establish and conduct the clinical trials of the
Product developed under the Formulation-Development Program for the
* Field in accordance with the Clinical Plan. As between the
parties, Genta shall own all clinical data and reports related to
any Product clinical trials (including, but not limited to, the
clinical trials for the Product developed under the
Formulation-Development Program for the * Field). All clinical data
relating to Products, including safety reports from such clinical
trials, shall be maintained by Genta in a centralized database.
Genta shall be the sole IND holder and will solely own all NDAs for
all Products as further specified in Section 4.10. Emisphere shall
have the right to cross file and reference data from Product INDs
or NDAs with respect to obtaining Regulatory Approval for any
Program Carrier for use in combination with drugs that do not
include a Gallium Compound. R
4.4 DMFs and Information Relating to
Carriers. Without
limiting its obligations under Sections 3.2 and 3.4, * Emisphere
shall provide Genta with true and complete copies of its DMFs (if
any exist) for each Potential Program Carrier. During the Term of
this Agreement, Emisphere shall promptly provide Genta with true
and complete copies of any additions that are made to such DMFs,
along with any additional Program Carrier-related regulatory and
scientific documents that Genta reasonably requests that are
Controlled by Emisphere. Genta, its Affiliates and Sublicensees
hereunder shall have the right to cross file and reference data
from the Program Carrier regulatory filings that are Controlled by
Emisphere solely in connection with obtaining Regulatory Approval
for Products.
4.5 CMC Section. Emisphere and Genta will together develop the
Chemistry, Manufacturing and Controls section of the NDA for
Products.
4.6 Communications with Regulatory
Authorities. Except as
required by applicable law, Genta shall have the sole right to
communicate with Regulatory Authorities concerning Products,
including conducting meetings and holding telephone discussions
with such Regulatory Authorities, provided that the foregoing
prohibition shall not apply to Emisphere’s filings and
filing-related communications with Regulatory Authorities relating
solely to the Program Carrier (in which event Emisphere shall
consult with Genta prior to such communication and consider
Genta’s input in good faith) or to combinations of the
Program Carrier with any API other than a Gallium Compound (in
which event no consultation with Genta will be required). During
the Development Term, Emisphere will assist Genta, at Genta’s
reasonable request, in preparing for any such communications or
meetings, Genta shall notify Emisphere prior to scheduling any such
meetings with the FDA to enable Emisphere to participate in such
meetings, and Emisphere shall have the right to have a
representative of Emisphere attend with Genta to observe any
meeting with the FDA pertaining to Products,
11.
provided Emisphere gives Genta
reasonable advance notice of its desire to attend such meeting,
Emisphere participates with Genta in Genta’s preparation for
the meeting, and the FDA does not object to Emisphere’s
attendance or participation. Emisphere’s participation in
communications with Regulatory Authorities concerning Products
shall be subject to Genta’s reasonable discretion. Genta
shall also provide to Emisphere copies of all meeting minutes that
are kept for Genta interactions during the Development Term with
the FDA in respect of Products.
4.7 Assistance with NDA. Emisphere shall compile all data and information
Controlled by Emisphere from any studies conducted by or on behalf
of Emisphere involving the Program Carrier in a format appropriate
for NDA filings for the Product as necessary to support an NDA
submission, as determined by the TLC. Emisphere shall provide Genta
with such data and information (including all research and clinical
study reports) at a time agreed upon by the TLC, and in any event
within a reasonable time.
4.8 Clinical Efforts. Genta shall use commercially reasonable efforts
to conduct the Clinical Program during the Clinical Term in
accordance with the Clinical Plan, as revised from time to time by
the TLC. Without limiting the generality of the foregoing, but
subject to Section 5.4, Genta shall devote to the Clinical
Program such personnel as is consistent with the use of
commercially reasonable efforts to conduct Genta’s activities
under the Clinical Plan, it being understood that Emisphere is and
will be responsible under the Clinical Plan to supply cGMP
quantities of Product to Genta in connection with clinical
development, provided that Genta has first provided cGMP quantities
of Gallium Salt API to Emisphere for the purpose of making such
Product, as provided in the Clinical Plan. In addition, during the
Clinical Term, Genta shall promptly provide written reports of the
status of its activities under the Clinical Plan and the results
from its performance of such activities, in accordance with a
schedule agreed upon by the parties, which shall be in any event at
least monthly. Each party shall be solely responsible for the costs
and expenses incurred in connection with its performance of
Clinical Plan activities, subject to Section 6.1. As used in this
Section 4.8, “commercially reasonable efforts” shall
mean those efforts, consistent with the exercise of prudent
scientific and business judgment, as applied in the pharmaceutical
industry to development and commercialization activities conducted
with respect to other products of similar potential and market
size. It is understood that such potential may change from time to
time based upon changing scientific, business, marketing and return
on investment considerations.
4.9 Pharmacovigilance. Each party shall fully and timely disclose to
the other all clinical safety data and information on products
containing the Program Carrier to the extent required by regulatory
authorities or applicable law.
4.10 Regulatory Approvals.
As between the parties, except as
otherwise provided in this Agreement, Genta shall be responsible
for and shall own all filings (including INDs, CTAs, NDAs and MAAs)
necessary for Regulatory Approval of Products and for obtaining and
maintaining such Regulatory Approvals, at Genta’s expense,
provided that Genta shall provide Emisphere with a reasonable
opportunity to review and comment on those portions of any such
proposed filing regarding the Program Carrier prior to submission
to the applicable Regulatory Authority. Such regulatory documents
shall be maintained and held by Genta. Emisphere agrees to use its
commercially reasonable efforts to assist Genta in obtaining FDA
approval of an NDA for any Product developed pursuant to this
Agreement, as well as Regulatory Approvals from
12.
any other Governmental Authority
that may be required for the marketing of Products in any other
country. Genta will compensate Emisphere for any such assistance as
provided in Section 6.1. Emisphere specifically agrees to cooperate
with any inspection by the FDA or other regulatory agency,
including, but not limited to, any inspection prior to approval of
the NDA for any Product. Emisphere shall have the right to receive
copies of all Regulatory Approvals and other filings with
Regulatory Authorities with respect to Products, subject to the
provisions of Article 11.
4.11 Post-Development Term Development and
Commercialization. After
the end of the Development Term, Emisphere shall have no obligation
to perform any further Development Plan activities, and Genta shall
have the sole right to control development and commercialization of
the Products. Notwithstanding the foregoing, during the Term of
this Agreement (including after the end of the Development
Term):
(a) Genta will keep Emisphere informed regarding the
worldwide development of Products by Genta, its Affiliates and
Sublicensees on a quarterly basis;
(b) Genta and Emisphere will coordinate their
efforts with respect to development activities that would
reasonably be considered to materially affect the other
Party’s ability to market and commercialize Products (in the
case of Genta) or the Program Carriers or products (other than the
Products) containing Program Carriers (in the case of Emisphere),
such as the design and conduct of any long-term toxicology study
for the Program Carrier;
(c) if Emisphere receives any written or oral
communications from a Regulatory Authority relating to a Product or
solely to the Program Carrier, then Emisphere shall provide Genta
with a copy of any such written communication or a summary of any
such oral communication as soon as practicable but no later than
ten (10) business days after receipt of such communication, or
sooner if mandated by law; and
(d) each of the parties’ rights and
obligations under Section 4.10 (Regulatory Approvals) shall
continue in effect.
4.12 Compliance. All work conducted by either party in connection
with the Clinical Program shall be conducted in accordance with
applicable Good Clinical Practices, as such rules of practice and
regulations are amended from time to time, and other applicable
laws, rules and regulations. Genta and its Affiliates shall
conduct, and shall use commercially reasonable efforts to cause its
Sublicensees to conduct, all commercialization activities with
respect to the Products in accordance with applicable laws, rules
and regulations.
5. LICENSE
GRANTS
5.1 License Grants.
(a) Exclusive Development and
Commercialization License By Emisphere. Subject to the terms and conditions of this
Agreement (including, without limitation, Article 6 hereof),
Emisphere hereby grants to Genta and its Affiliates an exclusive
(even as to Emisphere, but subject to Section 5.3), worldwide,
royalty-bearing (under Section 6.3) license, with the right to
sublicense through multiple tiers of sublicense, under
the
13.
Emisphere Technology and the
Joint Technology, solely to develop, make, have made, use, sell,
offer for sale, have sold and import Products in the Field. For
purposes of clarification, in no event shall Genta have any right
or license under this Agreement to make, have made, use, sell, have
sold, offer for sale or import (A) any pharmaceutical product
containing any formulation of a Gallium Compound and a Program
Carrier that is not an Oral Formulation, or (B) any
pharmaceutical product containing the Program Carrier and any drug
other than a Gallium Compound. Further, for purposes of
clarification, in no event shall Genta have the right to practice
the Emisphere Technology for any purpose other than to develop,
make, have made, use, sell, offer for sale, have sold and import
Products in the Field. Genta shall be responsible for negotiating
all Third-Party sublicenses that may be desirable under this
Section 5.1 and shall periodically report on such activities to the
Emisphere. With respect to Third Parties to whom Genta proposes to
enter into a sublicense under the foregoing license, Genta shall
notify Emisphere in writing of the name of the proposed Sublicensee
and the general nature of the proposed sublicense at least eleven
(11) business days prior to entering into such sublicense. No
Third-Party sublicense shall be effective unless approved in
writing by Emisphere, such approval not to be unreasonably withheld
or delayed, and any Emisphere failure to notify Genta whether or
not Emisphere approves such sublicense prior to the expiration of
such eleven (11) business day period shall be considered
approval.
(b) Development License By
Genta. Subject to the
terms and conditions of this Agreement, Genta hereby grants to
Emisphere and its Affiliates, during the Term, a non-exclusive,
worldwide, royalty-free license, with the right to sublicense only
to subcontractors permitted under Section 3.5, under the Genta
Technology solely to perform Emisphere’s obligations under
the Formulation-Development Plan, its preparation and maintenance
of certain regulatory filings under Article 4, and its supply
obligations under Article 8.
5.2 Exclusivity; Restricted
Activities. Without
limiting the exclusivity of the license granted to Genta under
Section 5.1(a), Emisphere hereby agrees that, during the Term and
the Post-Termination Exclusive Period (defined below), Emisphere
and its Affiliates shall not develop or commercialize, or
collaborate with or grant any Third Party any license or right to
develop or commercialize, any Oral Formulations. For purposes of
this Section 5.2, “Post-Termination Exclusive
Period” shall mean the period of time beginning upon
expiration or any termination of this Agreement (other than
termination by Emisphere under Section 12.3, in which case there
will be no Post-Termination Exclusive Period) and continuing
thereafter for:
(a) *, if this Agreement expires or terminates prior
to the *-year anniversary of the Effective Date, or
(b) if this Agreement expires or terminates upon or
after the *-year anniversary of the Effective Date, the lesser of
the following:
(i) *; or
(ii) a number of days equal to the product of
(i) the number of successive full calendar days elapsed from
the Effective Date to the date of such expiration or termination,
and (ii) *.
14.
5.3 Permitted Activities.
For purposes of clarification,
Emisphere shall at all times retain the right to use the Carriers
(including without limitation the Program Carrier) for the
research, development, manufacture and/or commercialization of any
product, other than an Oral Formulation. Emisphere shall at all
times be free to use the Carriers with products other than those
containing a Gallium Compound. For purposes of clarification and
notwithstanding anything to the contrary contained in this
Agreement, Genta shall at all times retain the right to develop or
commercialize any formulations of Gallium Compounds that do not use
Emisphere Technology, and any oral-delivery formulations and
technologies that do not use Emisphere Technology, either alone,
through Affiliates or sublicensees, or in collaboration with third
parties, and such activities shall be considered outside the scope
of the Development Program and this Agreement.
5.4 Diligence. Genta shall use commercially reasonable efforts
to commercialize the Product developed under the Development
Program in the * Field in the United States, and to maximize sales
of such Product, either alone, or through Affiliates or
sublicensees, in the * Field in the United States. As used herein,
“commercially reasonable efforts” shall mean those
efforts, consistent with the exercise of prudent scientific and
business judgment, as applied in the pharmaceutical industry to
development and commercialization activities conducted with respect
to other products of similar potential and market size. It is
understood that such potential may change from time to time based
upon changing scientific, business, marketing and return on
investment considerations.
5.5 No Implied Licenses. No right or license under any Patents or
Information is granted or shall be granted by implication. All such
rights or licenses are or shall be granted only as expressly
provided in the terms of this Agreement.
6. FEES AND
PAYMENTS
6.1 Reimbursement : Genta shall reimburse Emisphere for all costs
(at the rates set forth in Section 6.1(d)) incurred by Emisphere in
conducting its responsibilities under the Development Program, as
outlined in the Development Plan; subject to the
following:
(a) The total amount set forth in the
Formulation-Development Budget for Emisphere’s performance of
its responsibilities set forth in the Formulation-Development Plan
is *. Subject to Section 6.1(c), Genta shall have no obligation to
reimburse, and Emisphere shall be solely responsible for, any costs
and expenses it incurs in excess of * in performing its
responsibilities set forth in the Formulation-Development
Plan.
(b) In addition to the total amount budgeted, the
Formulation-Development Budget includes a separate break out of
distinct Development Program activities that Emisphere is to
perform and the amounts budgeted for these distinct activities (to
the extent highlighted in bold in the Formulation-Development
Budget, the “ Budgeted Activities ”). Subject to
Section 6.1(a) and 6.1(c), Genta shall have no obligation to
reimburse, and Emisphere shall be solely responsible for, any costs
and expenses it incurs in the performance of any individual
Budgeted Activity in excess of *% of the amount budgeted for that
Budgeted Activity. However, if an IND for a Product is filed, and
the total cost of performing all activities set forth in the
Formulation-Development Plan was less than *, then Emisphere shall
be entitled to
15.
reimbursement from Genta up to a
total of * to
