Exhibit 10.1
*** Text omitted and filed separately
Confidential Treatment Requested
under 17 C.F.R. §§200.80(b)(4) and
240.24b-2
COOPERATION AND SUPPLY
AGREEMENT
(“Agreement”)
between
Neurobiological Technologies,
Inc. and
NTI-Empire, Inc.
3260 Blume Drive – Suite
500
Richmond, California
94806
USA
(hereinafter collectively called
„NTI”)
and
Nordmark Arzneimittel GmbH &
Co. KG
Pinnauallee 4
25436 Uetersen
Germany
(hereinafter called
„Nordmark”)
(NTI and Nordmark are individually referred to
as “Party”
and collectively as
“Parties”)
Preamble
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1.
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Whereas,
Neurobiological Technologies, Inc. is an emerging drug development
company focused on the clinical development and regulatory approval
of neuroscience drugs.
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2.
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Whereas,
NTI-Empire, Inc., a wholly owned subsidiary and Related Company (as
defined in Art. 1.11 below) of Neurobiological Technologies, Inc.,
has acquired Empire Pharmaceuticals, Inc. of Greenville, NY
(hereinafter called “Empire”).
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3.
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Whereas, Empire
had acquired the exclusive worldwide rights to Viprinex
™
(INN Ancrod) on the basis of a
license agreement with Abbott Laboratories, parent company of its
German subsidiary Abbott GmbH & Co. KG in Ludwigshafen, Germany
in March 2002.
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4.
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Whereas,
Viprinex ™ is a medicinal product useful as a late stage
perfusion therapy for the treatment of acute ischemic
stroke.
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CONFIDENTIAL
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5.
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Whereas, the
active pharmaceutical ingredient of Viprinex
™ is Ancrod which is derived from the raw venom of
the Malayan pit viper and whereas, NTI is the owner of about 4 kg
of such raw venom.
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6.
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Whereas,
Nordmark develops, manufactures and places on the market medicinal
products and whereas, Nordmark is the holder of manufacturing
authorizations issued by the competent German authority on the
basis of which Nordmark is entitled to manufacture active
pharmaceutical ingredients as well as finished medicinal
products.
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7.
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Whereas,
Nordmark has comprehensive experience in the manufacture of active
pharmaceutical ingredients (hereinafter called “API”)
and whereas, Nordmark originally was part of Knoll.
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8.
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Whereas, Empire
and Nordmark have entered into a Nondisclosure Agreement on April
19, 2004.
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9.
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Whereas, NTI is
desirous of having Nordmark further develop and manufacture Ancrod
and is desirous to be supplied with Ancrod by Nordmark.
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10.
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Whereas, in
anticipation of the cooperation envisaged by the Parties NTI has
paid an amount of Euro 400.000 (VAT included), to Nordmark to
enable Nordmark to purchase certain equipment for the development
and manufacture of Ancrod; provided, however, that NTI shall own
all such purchased equipment.
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11.
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Whereas, NTI
intends to have manufactured by a contract manufacturer in the
United States a finished medicinal product containing Ancrod as
API.
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12.
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Whereas, NTI
furthermore intends to perform clinical trials with the finished
investigational medicinal product with the aim to apply for
registration of the finished pharmaceutical product containing
Ancrod in the United States and other markets.
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13.
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Whereas, the
Parties are desirous to cooperate, in accordance with the terms and
conditions of this Agreement, with the intention to achieve
registration of the finished pharmaceutical product containing
Ancrod.
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Now, therefore, the Parties agree as
follows:
Article 1
Definitions
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1.1
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“Ancrod”
(Viprinex ™ ) means an API (as further described in
Appendix 1 ) that is derived from API Starting Material,
wherein such API is intended: (a) to be used in the manufacture of
an Investigational Medicinal Product or a Medicinal Product
in
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accordance with this Agreement,
and (b) to furnish pharmacological activity or other direct effect
in the treatment of a disease.
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1.2
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“API” means an active pharmaceutical
ingredient.
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1.3
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“Manufacture” means the production
of Ancrod from API Starting Material, and the packaging and
labelling thereof, including without limitation the respective
in-process tests, analyses, final quality control and batch release
according to GMP.
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1.4
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“API
Starting Material” means the raw venom of the Malayan pit
viper, as described in Appendix 2 .
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1.5
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“Medicinal Product” means the
finished pharmaceutical form of an Ancrod API intended to be used
and marketed for treating or preventing disease in human
beings.
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1.6
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“Registration” means the
governmental approval (including marketing authorisation, pricing
and reimbursement approval) according to German, European or United
States law necessary to place a finished pharmaceutical product on
the market in those countries or jurisdictions.
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1.7
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“Procedures” mean a description of
the operations to be carried out, the precautions to be taken and
the measures to be applied directly or indirectly to the
Manufacture of Ancrod or to the Services provided in connection
with this Agreement.
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1.8
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“Specifications” mean the
description in detail of the specifications and requirements for
Ancrod, as laid down in Appendix 1.
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1.9
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“Manufacturing Formulae and Processing
Instructions” mean information and documents that state all
API Starting Materials to be used by Nordmark hereunder, and that
lay down all processing operations to be used in the Manufacture of
Ancrod.
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1.10
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“Records” mean information and
documents that relate to or describe the Services or the
Manufacture of Ancrod, including without limitation a history of
each batch of Ancrod and of all other relevant circumstances
pertinent to the quality of Ancrod.
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1.11
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“Related
Company” means any corporation, association or legal entity
which is directly or indirectly controlling or controlled by NTI,
wherein the term “control” means the ownership of more
than 50% of the outstanding voting securities.
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1.12
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“Services” mean the services
performed by Nordmark under this Agreement, as more fully described
in Appendix 3 .
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1.13
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“Ancrod
Equipment” means any equipment that is purchased by Nordmark
using funds provided by NTI. Such equipment (as set forth in
Appendix 4 ) was, at the time of the commencement of the
Parties’ cooperation, not yet in Nordmark’s possession.
Before, during and after the term of this Agreement, all Ancrod
Equipment shall be owned by NTI.
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1.14
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“Investigational Medicinal Product”
means the pharmaceutical form of an Ancrod API intended to be
tested in a clinical trial.
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1.15
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“Milestone” means a specific goal to
be achieved by Nordmark, as described in Appendix 3
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Article 2
Subject of
Agreement
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2.1
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Subject of
Agreement is the performance of Services by Nordmark for NTI, the
Manufacture of Ancrod by Nordmark on behalf of NTI and the supply
of Ancrod to NTI, both prior to and after the Registration of the
Medicinal Product.
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2.2
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The purpose of
this Agreement is also to clearly establish and allocate the duties
and responsibilities of each Party hereunder ( Appendix 5
).
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2.3
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Except as
expressly set forth herein, no other rights or licenses are granted
by NTI to Nordmark hereunder with respect to Services to be
performed using API Starting Material or Ancrod, or with respect to
Nordmark’s use or exploitation of API Starting Material or
Ancrod.
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Article 3
Supply of API Starting
Material
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3.1
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NTI shall make
available free of charge to Nordmark in good time the API Starting
Material.
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Article 4
Performance of
Services
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4.1
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Nordmark
undertakes to buy without undue delay the Ancrod Equipment as
described in Appendix 4 . The Ancrod Equipment shall remain
the sole property of NTI.
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4.2
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Nordmark undertakes to perform
the Services in a professional and competent manner and in
accordance with the timescales set out in Appendix 3 , and
also to meet in person with NTI at least quarterly, and to provide
Records to NTI at least
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quarterly, regarding the progress
on the Services provided by Nordmark hereunder. Additionally,
Nordmark may update NTI on its progress regarding the Services
through weekly telephone conferences. During each quarterly meeting
between NTI and Nordmark pursuant to this Article 4.2, the Parties
shall discuss any changes, modifications or amendments to United
States federal laws and regulations that are pertinent to the
Services or the Manufacture of Ancrod hereunder and that are within
the knowledge of each Party.
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4.3
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NTI undertakes
to pay the Milestone amount allocated to each Milestone event laid
down in Appendix 3 . Fifty percent (50%) of each such
Milestone amount shall be paid by NTI within 30 days after NTI
receives written notice from Nordmark that Nordmark has initiated
work in connection with the corresponding Milestone event. The
remaining 50% of each such Milestone amount shall be paid by NTI to
Nordmark within 30 days after NTI receives written notice from
Nordmark that the corresponding Milestone event has been achieved;
provided, however, with respect to any Milestone payment that is
the subject of such written notice, NTI (in its sole discretion and
prior to the due date for the corresponding Milestone payment) may
request access to Nordmark’s Records (including without
limitation Nordmark’s raw data) related to Nordmark’s
achievement of such Milestone event, so that NTI may review such
Records in order to verify such achievement by Nordmark before
making the corresponding Milestone payment. If Nordmark and NTI
dispute in good faith Nordmark’s achievement of such
Milestone event, either Party may promptly notify the other Party
that it wishes to submit the dispute for resolution by designated
representatives of each Party (Stephen Petti, NTI’s Vice
President, Product Development, and Manfred Kurfürst,
Nordmark’s Head of Biological Products Production, Marketing
and Sales (or a person otherwise substituted or designated by a
Party)) (each a “Representative”). The Representatives
shall attempt to resolve the dispute through good faith
negotiations over a reasonable period, not to exceed thirty (30)
calendar days following one Party’s receipt of such notice
from the other Party, unless the Representatives mutually agree in
writing to extend such period of negotiation; provided, however,
that in no event shall such period of negotiation be longer than 45
days after the date of initiation of such good faith negotiations
by the Representatives. If the Representatives cannot resolve such
dispute within such 30-day (or mutually extended) period, the
dispute shall be resolved in accordance with Art. 17.2.
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4.4
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The Parties are aware of the
necessity to expedite the Services and the Manufacture and supply
of GMP batches of Ancrod. To that end, the final Milestone event in
Appendix 3 requires delivery of three GMP batches of Ancrod
on or before July 29, 2005. If (a) Nordmark releases the first of
the three GMP batches prior to June 10, 2005, NTI undertakes to pay
to Nordmark an extra bonus of [***] of the total amount actually
paid or owed by NTI in connection with the Down Payment and
Milestone events set forth in Appendix 3 ; and (b) if
Nordmark releases the first of the three GMP batches on or before
June 6, 2005; NTI will pay an additional [***] (i.e., the [***]
bonus set forth in (a) above plus [***]);
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* Confidential Treatment Requested
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and (c) if Nordmark releases the
first of the three GMP batches on or before June 1, 2005; NTI will
pay an additional [***] (i.e., the [***] bonus set forth in (a)
above plus [***]).
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4.5
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Nordmark shall
maintain true and accurate Records, including all books, records,
test and laboratory data, reports and all other information
relating to the Services, and all information required to be
maintained by all applicable laws and regulations and
Nordmark’s standard operating procedures. Such Records shall
be maintained in forms, notebooks and records for a period of at
least three (3) years or longer if required by applicable laws or
regulations. Nordmark shall not dispose of any Records without
first providing at least sixty (60) days’ prior written
notice of its intent to dispose of any Records, and if NTI so
requests prior to such disposal, Nordmark shall transfer such
Records to NTI at NTI’s cost and expense.
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4.6
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If the Parties
mutually determine that, in addition to the Milestone events laid
down in Appendix 3 , other Milestone events would be
appropriate to achieve the cooperative endeavors and goals of the
Parties hereunder, the Parties may mutually agree to establish in
writing additional Milestone events (and the corresponding terms
and conditions related thereto). Any such additional Milestone
events (and related terms and conditions) shall be attached to this
Agreement as an addendum to Appendix 3 .
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Article 5
Obligations of
Nordmark
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5.1
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Nordmark
undertakes to strictly adhere to all applicable legal provisions,
and especially to the German Drug Law (AMG), to the regulation
governing the operations of pharmaceutical companies (PhBetrV) and
to the principles and guidelines of Good Manufacturing Practices,
as the laid down in the EC-Guide to good manufacturing practice for
medicinal products (GMP), including its annex 18 for API’s
(The Rules governing medicinal products in the European Union,
Volume 4), in Title 21 of the United States Code of Federal
Regulations, parts 210 and 211, and in applicable guidelines that
have been issued (or may be issued in the future) by the FDA, and
to NTI’s Specifications and commercially reasonable
Manufacturing and testing instructions.
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5.2
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Nordmark furthermore undertakes
to release Ancrod for shipment to NTI (or to a drug manufacturer in
the United States nominated by NTI) only if it meets all
Specifications, the Manufacturing Formulae and Processing
Instructions and any other requirements set forth in documents
relevant to Ancrod pursuant to Art. 6.1. On written request and
risk of NTI, Nordmark will “pre-release” the first of
the three GMP batches of Ancrod (as described in Article 4.4) for
shipment to NTI with a preliminary certificate of analysis with
respect to the Specifications. This first GMP batch will be shipped
to NTI or to a third party designated by NTI. This
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* Confidential Treatment Requested
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pre-released batch shall not be
used in humans before Nordmark has determined that such batch meets
all Specifications pursuant to Article 6.1 and is finally released
by Nordmark; provided, however, that such final release by Nordmark
shall be provided to NTI on or before the occurrence of the earlier
of: (a) the date that is four weeks after the date of pre-release
of such batch to NTI, or (b) July 14, 2005. As far as the shelf
life of Ancrod is concerned, Nordmark does not give a guarantee;
provided that, with respect to any Ancrod produced by Nordmark that
meets all Specifications, Nordmark shall store and ship such Ancrod
in accordance with industry standards and NTI’s
instructions.
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5.3
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Nordmark shall
use Ancrod, API Starting Material and Ancrod Equipment solely and
exclusively for the purposes of this Agreement. For the sake of
clarity, Nordmark agrees that NTI shall own all side fractions and
unused portions of Ancrod in the possession of Nordmark, which
shall be used by Nordmark solely and exclusively for the purposes
of this Agreement. If Nordmark should desire to use an aliquot of
such side fractions and/or unused portions of Ancrod or API
Starting Material for its internal research use only, Nordmark
shall notify NTI in writing of such requested use. This written
request shall set forth a description and amount of such material
that Nordmark wishes to use, and a description of the intended use
of such material. NTI shall consider in good faith such request
(and the terms and conditions that may be attached to such
requested use), but the final approval or denial of such request
shall be in NTI’s sole discretion.
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Article 6
Making Available Technical
Information and Documents
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6.1
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NTI has made
and will make available to Nordmark relevant, up-to-date,
Ancrod-related technical information and other documents that are
necessary and/or appropriate with regard to the Manufacture,
quality control, handling and storage of Ancrod and API Starting
Material, and in particular NTI shall provide the Specifications,
Manufacturing Formulae and Processing Instructions, packaging
instructions, sampling Procedures and testing Procedures, as listed
in Appendix 6 . Furthermore NTI shall supply to Nordmark any
additional information relating to Ancrod or API Starting Material
in NTI’s possession which Nordmark may reasonably request
during the term of this Agreement for the fulfillment of
Nordmark’s obligations under this Agreement.
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6.2
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Within two
months after completion of any Ancrod production run, Nordmark
undertakes to make available to NTI the necessary and useful
documents (including without limitation lot release testing
documentation) that a drug manufacturer may reasonably request in
order to use Ancrod for the Manufacture of the finished
Investigational Medicinal Product.
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6.3
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In the case of
any deviation from or change of the technical information,
Specifications or Manufacturing Formulae and Processing
Instructions, such deviation or change may be executed by Nordmark
only after written consent of NTI. Should the technical
information, Specifications or Manufacturing Formulae and
Processing Instructions violate any legal rules or orders, as
applicable at the site of production, Nordmark shall inform NTI in
writing without undue delay after having received knowledge thereof
in order to enable the Parties to jointly find a solution of such
problems.
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6.4
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Nordmark shall
carry out all necessary and relevant tests (including without
limitation specified lot release tests) in order to ensure the
quality of each lot and batch of Ancrod Manufactured for NTI, and
shall release Ancrod for delivery only if it meets all
Specifications (in accordance with Art. 5.2). Nordmark shall, on
request, supply to NTI’s representative adequate test samples
of materials obtained, generated or provided by Nordmark hereunder,
and copies of information and documents relating to the Services,
Ancrod or API Starting Material, including without limitation
Manufacturing and quality control documents and further information
on in-process control and the Manufacturing process.
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6.5
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Nordmark shall
pass on to NTI, simultaneously with the shipment of each batch of
Ancrod, the corresponding certificate of analysis and copies of
related raw data relevant to such batch (including without
limitation raw data pertaining to lot release tests), as well as,
on NTI’s request, other information related to the in-process
control and the Manufacturing control. The certificate of analysis
shall be signed by Nordmark’s qualified person with regard to
quality control, and shall serve as evidence for the proper release
of such batch of Ancrod by Nordmark.
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Article 7
Documentation and Defective
Products
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7.1
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Nordmark shall
keep all Records, including without limitation Manufacturing and
quality control documentation, as required by the applicable law
pursuant to Art. 5.1. If required by applicable law or regulation,
and upon prior written notice to NTI, Nordmark may retain a
sufficient and representative amount of samples of Ancrod and of
the API Starting Material. Nordmark shall at all times use all
reasonable endeavors to keep the NTI materials secure and safe from
loss and damage, in such manner as Nordmark stores its own or its
other customers’ material of similar nature, but in no event
shall Nordmark use less than reasonable care; nor shall Nordmark
disclose to any third party or otherwise part with possession of
the materials or information provided by NTI hereunder.
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7.2
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NTI shall be entitled to inspect
- at any time during normal business hours - the facilities of
Nordmark where the Manufacturing of Ancrod takes place and where
the API Starting Material, intermediate products and the Ancrod API
are stored
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(“GMP Compliance
Audit”). Such GMP Compliance Audit shall also include the
right of NTI to inspect the relevant Records (including without
limitation Manufacturing and quality control documentation) and to
take samples of materials obtained, generated or provided by
Nordmark hereunder. Nordmark undertakes to give NTI all necessary
or reasonably requested support
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