Exhibit 10.1
PHARMACEUTICAL DEVELOPMENT AGREEMENT
This PHARMACEUTICAL DEVELOPMENT AGREEMENT (this "Development
Agreement") is dated as of June 10, 2003 (the "Effective Date"), and is by and
between FERRO PFANSTIEHL LABORATORIES, INC. ("Ferro Pfanstiehl"), a Delaware
corporation, and Bioenvision Inc. ("Bioenvision"), a Delaware corporation.
Recitals
A. Bioenvision is engaged in the clinical development, production, and
sale of Clofarabine, a purine based nucleoside.
▇. ▇▇▇▇▇ Pfanstiehl has specific expertise in the development, contained
handling, manufacture, and sale of nucleoside based Active
Pharmaceutical Ingredients ("API's").
C. Bioenvision uses Clofarabine as an ingredient in its purine-based
nucleoside drug products now under clinical investigation.
▇. ▇▇▇▇▇ Pfanstiehl and Bioenvision desire to enter into a relationship
for the scale up, final development, CTM supply and cGMP supplier
qualification of the API Clofarabine according to the terms and
conditions of this Development Agreement.
In consideration of the foregoing and for other good and valuable
consideration, and intending to be bound legally by this Development
Agreement, Ferro Pfanstiehl and Bioenvision hereby agree as follows:
Agreement
Article 1 - Definitions
1.1 Definitions. Appendix A to this Development Agreement sets forth the
definitions of certain terms used in this Development Agreement. Those
terms shall have the meanings set forth on Exhibit A where used in this
Development Agreement and identified with initial capital letters.
1.2 Construction. For purposes of this Development Agreement, except where
the context otherwise requires:
(A) The term "parties" means Bioenvision and Ferro Pfanstiehl.
(B) The term "person" includes any natural person, firm,
association, partnership, corporation, limited liability
company, limited liability partnership, governmental agency,
or other entity and the term "third party" means any person
other than the parties and their Affiliates.
(C) All currency amounts stated in this Development Agreement are
in United States Dollars.
(D) References to "days" mean calendar days. (If, however, an
action or obligation is due to be undertaken by or on a day
other than a business day, i.e., a Saturday, Sunday, or public
holiday, in New York, then that action or obligation will be
deemed to be due on the next following business day.)
(E) When introducing a series of items, the term "including" is
not intended to limit the more general description that
precedes the items listed.
(F) The headings of the Articles and Sections are included for
convenience of reference only and are not intended to affect
the meaning of the operative provisions to which they relate.
Article 2 - Development Program
2.1 Development Program. Attached to this Development Agreement as Exhibit
B is a description of a program (the "Development Program") to develop
Clofarabine API. The Development Program includes, but is not limited
to, the following:
(A) Transfer of validated analytical support methods,
(B Development and validation of a residue detection method,
(C) Verification of the current process chemistry,
(D) Generation of laboratory-based samples for analytical
comparison with existing API standards,
(E) Preparation of a technology transfer summary report,
(F) Pilot production of 0.5 Kgs of cGMP API suitable for US and EU
CTM use,
(G) An ICH-compliant stability study,
(H) cGMP compliant analytical, manufacturing, and cleaning
documentation, and
(I) An engineering response, with unit operations definition
consistent with a commercial 5 -10 Kg. scale-up, as part of
potential supplier qualification program.
2.2 Engagement. Bioenvision hereby engages Ferro to carry out the
Development Program, and Ferro Pfanstiehl agrees to use reasonable
commercial efforts to carry out, the Development Program under the
terms and conditions set forth in this Development Agreement. Ferro
Pfanstiehl will carry out the Development Program on Milestone basis
and will use its commercially reasonable efforts to perform each
Milestone Phase in accordance with the Development Program.
2.3 Ferro Pfanstiehl's Responsibilities. In carrying out the Development
Program, Ferro Pfanstiehl will be solely responsible for the following:
(A) The analytical development services described on Exhibit B,
(B) The process chemistry services described Exhibit B,
(C) The regulatory affairs and quality control activities
described on Exhibit B,
(D) The process engineering, project management, and manufacturing
support activities described on Exhibit B,
(E) Manufacture of intermediate protected fluoro-sugar coupling
reagent D-138,
(F) Manufacture of clinical trial material meeting all cGMP
requirements as described on Exhibit B, and
(G) Preparation of a suitable project ▇▇▇▇▇ Chart.
2.4 Bioenvision's Responsibilities. To assist Ferro Pfanstiehl in carrying
out the Development Program, Bioenvision will -
(A) Provide Ferro Pfanstiehl, in a timely fashion, with all
relevant documentation and data necessary or appropriate for
Ferro Pfanstiehl performance hereunder, including all
confidential Information, documentation and data relating to
product safety, stability, all analytical support methods,
analytical validation reports, drug substance stability data,
impurity profiles, reference standards, process development
reports, batch records and the like associated with
Clofarabine in Bioenvision's possession or in the possession
of a third party on behalf of Bioenvision,
(B) Ensure that all materials supplied to Ferro Pfanstiehl by or
on behalf of Bioenvision are suitable for use under this
Development Agreement, comply with all applicable laws and
regulations (including those relating to the import of such
materials) and have received all required governmental and
regulatory approvals, including customs and FDA approvals,
(C) Supply a fully characterized API reference standard and
selected impurity standards along with samples of the alpha &
beta anomers of the protected clofarabine coupling product.
and
(D) Identify an approved source of 2-chloroadenine.
Bioenvision will promptly provide such additional support, information,
and approvals as Ferro Pfanstiehl may reasonably request.
2.5 Reports. During the Development Program, Ferro Pfanstiehl will provide
Bioenvision with written reports on a periodic basis on Ferro
Pfanstiehl's work on the Development Program and otherwise endeavor to
keep Bioenvision reasonably apprised of Ferro Pfanstiehl's progress on
an informal basis. In addition, Ferro Pfanstiehl will respond to
Bioenvision's reasonable inquiries about the status of the Development
Program and, if requested, participate in periodic meetings at Ferro
Pfanstiehl's facility to discuss Development Program results and
progress. In addition, if requested by Bioenvision, Ferro Pfanstiehl
will package and ship to Bioenvision or its designee batches of
Clofarabine prepared during the Development Program. Ferro Pfanstiehl
will retain representative samples from each batch of Clofarabine for
record keeping, stability testing and other regulatory purposes.
2.6 Program Cost and Payment. Bioenvision will pay Ferro Pfanstiehl an
aggregate fee for the Development Work equal to:
(A) A non-refundable "Project Initiation Fee" of $50,000.00 (fully
creditable against Milestone Payments) plus
(B) Milestone Payments as set forth on Exhibit B.
Bioenvision is paying Ferro Pfanstiehl the Project Initiation
simultaneously with the execution and delivery of this Development
Agreement. Bioenvision will pay each of the Milestone Payments Net 30
days after the completion of each Milestone.
Article 3 - Intellectual Property
3.1 Ferro Pfanstiehl Intellectual Property. The parties anticipate that
Ferro Pfanstiehl will use its own intellectual property (the "Ferro
Pfanstiehl Intellectual Property") in developing Clofarabine for
purine-based nucleoside drug products under this Development Agreement.
Some of such Ferro Pfanstiehl Intellectual Property may be embodied in
patents owned by or assigned to Ferro Pfanstiehl (the "Ferro Pfanstiehl
Patents") and some of such technology may represent Ferro Pfanstiehl
trade secrets and know how (the "Ferro Pfanstiehl Trade Secrets and
Know How"). The following provisions will apply to Ferro Pfanstiehl
Intellectual Property:
(A) Generally. Ferro Pfanstiehl will retain its ownership of and
all of its rights in and to all Ferro Pfanstiehl Intellectual
Property, whether or not such Ferro Pfanstiehl Intellectual
Property is one of the resources used in developing
Clofarabine under this Development Agreement. Nothing in this
Development Agreement shall be deemed to be a conveyance of
any Ferro Pfanstiehl Intellectual Property to Bioenvision or
any other party.
(B) Use of Ferro Pfanstiehl Intellectual Property. Ferro
Pfanstiehl hereby grants Bioenvision a limited, royalty-free
right and license to use such Ferro Pfanstiehl Intellectual
Property as may be needed by Bioenvision to make use of the
Clofarabine API developed pursuant to the Development
Agreement, but such right and license shall not extend to any
use of Ferro Pfanstiehl Intellectual Property not necessary
for such use. Ferro Pfanstiehl hereby authorizes Bioenvision
to list (within the meaning of the FD&C Act) the Ferro
Pfanstiehl patents.
(C) Protection of Trade Secrets and Know-How. Ferro Pfanstiehl
will use its best efforts to identify technology to be used by
Ferro Pfanstiehl and/or Bioenvision in the development of
Clofarabine under this Development Agreement that Ferro
Pfanstiehl deems to be Ferro Pfanstiehl Trade Secrets and Know
How. With respect to Ferro Pfanstiehl Trade Secrets and Know
How,
(1) Bioenvision acknowledges that the Ferro Pfanstiehl
Trade Secrets and Know How are the property of Ferro
Pfanstiehl and are treated by Ferro Pfanstiehl as
confidential business information.
(2) Bioenvision will treat the Ferro Pfanstiehl Trade
Secrets and Know How as confidential and will protect
the Ferro Pfanstiehl Trade Secrets and Know How in
the same manner and with the same degree of care
Bioenvision protects its own trade secrets and other
confidential business information.
(3) Bioenvision will use the Ferro Pfanstiehl Trade
Secrets and Know How only for purposes of developing
applications of Clofarabine API.
(4) Except as required by law, Bioenvision will disclose
Ferro Pfanstiehl Trade Secrets and Know How only to
those of Bioenvision's employees who need access to
the Ferro Pfanstiehl Trade Secrets in order to carry
out Bioenvision's responsibilities with respect to
Bioenvision's application to Clofarabine, a
purine-based nucleoside drug product, and Bioenvision
will not disclose any of the Ferro Pfanstiehl Trade
Secrets and Know How to any other parties without
prior approval of Ferro Pfanstiehl for any other
purpose.
3.2 Bioenvision Intellectual Property. The parties anticipate that
Bioenvision may make available certain proprietary technology (the
"Bioenvision Intellectual Property") relating to the development of
Clofarabine API under this Development Agreement. Some of such
Bioenvision Intellectual Property may be embodied in patents owned by
or licensed to Bioenvision (the "Bioenvision Patents") or patents or
other Intellectual Property that is due to Bioenvision under existing
agreements with third parties and some of such technology may represent
Bioenvision trade secrets and know how (the "Bioenvision Trade Secrets
and Know How"). The following provisions will apply to Bioenvision
Intellectual Property:
(A) Generally. Bioenvision will retain its ownership of and all of
its rights in and to all Bioenvision Intellectual Property
whether or not such Bioenvision Intellectual Property is one
of the resources used by Ferro Pfanstiehl in the development
of of Clofarabine. Nothing in this Development Agreement shall
be deemed to be a conveyance of any Bioenvision Intellectual
Property to Ferro Pfanstiehl or any other person.
(B) Use of Bioenvision Intellectual Property. Bioenvision hereby
grants Ferro Pfanstiehl a limited, royalty-free right and
license to use Bioenvision Intellectual Property in the
development of Clofarabine under this Development Agreement,
but such right and license shall not extend to any other use
of Bioenvision Intellectual Property.
(C) Protection of Trade Secrets. Bioenvision will use its best
efforts to identify technology to be used by Ferro Pfanstiehl
and/or Bioenvision in connection with the development of
Clofarabine under this Development Agreement that Bioenvision
deems to be Bioenvision Trade Secrets and Know How. With
respect to Bioenvision Trade Secrets and Know How,
(1) Ferro Pfanstiehl acknowledges that the Bioenvision
Trade Secrets and Know How are the property of
Bioenvision and are treated by Bioenvision as
confidential business information.
(2) Ferro Pfanstiehl will treat the Bioenvision Trade
Secrets and Know How as confidential and will protect
the Bioenvision Trade Secrets in the same manner and
with the same degree of care Ferro Pfanstiehl
protects its own trade secrets and other confidential
business information.
(3) Ferro Pfanstiehl will use the Bioenvision Trade
Secrets and Know How only for purposes of carrying
out Ferro Pfanstiehl's responsibilities relating to
Clofarabine API under this Development Agreement.
(4) Except as required by law, Ferro Pfanstiehl will
disclose Bioenvision Trade Secrets and Know How only
to those of Ferro Pfanstiehl employees who need
access to the Bioenvision Trade Secrets and Know How
in order for Ferro Pfanstiehl Pfanstiehl to carry out
its responsibilities with respect to the development
of Clofarabine and Ferro Pfanstiehl will not disclose
any of the Bioenvision Trade Secrets and Know How to
any other person or for any other purpose.
3.3 Jointly Developed Intellectual Property.
(A) FPL Property. Bioenvision acknowledges that FPL possesses
certain inventions, processes, know-how, trade secrets,
improvements, other intellectual properties and other assets,
including certain procedures and techniques, computer
technical expertise, software, and technical conceptual
expertise in the area of general drug development and
manufacturing, that have been independently developed by FPL
without the benefit of any information provided by, or
intellectual property owned or licensed by, Bioenvision
(collectively "FPL Property"). All FPL Property and all
improvements thereto which are used, improved, modified or
developed by FPL under or during the term of this Development
Agreement are, will be and will remain the sole and exclusive
property of FPL.
(B) Ownership and Rights to Inventions and Technology, All
inventions, technology and information, whether patentable
and/or licensable or not (other than those described under
Subsection 3.3(A) above that are the sole and exclusive
property of FPL pursuant to such Section) that are conceived,
reduced to practice or created solely by FPL and/or its agents
during the performance of this Agreement, or created by FPL
and/or its agents in conjunction with Bioenvision, shall, in
each case, be owned by Bioenvision; provided, however, that
Bioenvision shall grant and hereby grants to FPL a
royalty-free, non-exclusive, world-wide, irrevocable license
to practice any such Bioenvision owned technology to
manufacture clofarabine during the term of this Development
Agreement.
3.4 Protection of Trade Secrets and Know How. Each party will use its best
efforts to maintain the confidentiality of Jointly Developed Trade
Secrets and Know How and to preserve available trade secret protection
afforded to such
Jointly Developed Trade Secrets and Know How. Without limiting the
generality of the foregoing,
(A) Each party will treat the Jointly Developed Trade Secrets and
Know How as confidential and will protect the Jointly
Developed Trade Secrets and Know How in the same manner and
with the same degree of care such party protects its own trade
secrets and other confidential business information.
(B) Each party will use the Jointly Developed Trade Secrets and
Know How only as permitted under this Development Agreement.
(C) Except as required by law, each party will disclose Jointly
Developed Trade Secrets and Know How only to those of such
party's employees who need access to the Jointly Developed
Trade Secrets and Know How in order to use such Jointly
Developed Trade Secrets and Know How as permitted under this
Development Agreement and will not disclose any of the Jointly
Developed Trade Secrets to any other person for any other
purpose.
3.5 Warranties. The parties hereby represent and warrant to each other the
following:
(A) Bioenvision Warranty. Bioenvision hereby represents and
warrants to Ferro Pfanstiehl that Bioenvision, its Affiliates
and/or its licensee have unencumbered ownership of the
Bioenvision Intellectual Property (as defined above) and the
unrestricted right to disclose such Bioenvision Intellectual
Property to Ferro Pfanstiehl as provided in this Development
Agreement, and the full and unrestricted right to convey to
Ferro Pfanstiehl rights in the Bioenvision Intellectual
Property set forth in this Article 3.
(B) Ferro Pfanstiehl Warranty. Ferro Pfanstiehl hereby represents
and warrants to Bioenvision that Ferro Pfanstiehl has
unencumbered ownership of the Ferro Pfanstiehl Intellectual
Property (as defined above) and the unrestricted right to
disclose such Ferro Pfanstiehl Intellectual Property to
Bioenvision as provided in this Development Agreement, and the
full and unrestricted right to convey to Bioenvision rights in
the Ferro Pfanstiehl Intellectual Property set forth in this
Article 3.
Article 4 - Confidentiality
4.1 Confidential Information. For purposes of this Development Agreement,
the term "Confidential Information" means the information disclosed by
one party (the "Disclosing Party") to the other party (the "Receiving
Party") that the Disclosing Party identifies as confidential business
information in the ordinary course conduct of its business.
4.2 Exclusions. Notwithstanding Section 4.1 above, the term "Confidential
Information" does not include any information a Receiving Party can
demonstrate -
(A) Was already known by the Receiving Party when the Disclosing
Party disclosed it to the Receiving Party,
(B) Is publicly known or comes into the public domain without a
breach by the Receiving Party of the Receiving Party's duties
under this Development Agreement,
(C) Is subsequently independently conceived or discovered by the
Receiving Party or its employees without access to the
Confidential Information, or
(D) Is subsequently disclosed to the Receiving Party by another
person who is not under an obligation of confidence to the
Disclosing Party.
4.3. Protection of Confidential Information. Each party as a Receiving Party
acknowledges that the Confidential Information is the property of the
Disclosing Party and is treated by the Disclosing Party as confidential
business information. The Receiving Party will treat the Confidential
Information as confidential and will protect the Confidential
Information in the same manner and with the same degree of care the
Receiving Party protects its own trade secrets and other confidential
business information.
4.4 Disclosure of Confidential Information. Except as required by law, a
Receiving Party will disclose the Confidential Information only to
those of its employees who need access to the Confidential Information
in order for the Receiving Party to perform its obligations under this
Development Agreement. The Receiving Party will not disclose any of the
Confidential Information to any other person or entity without the
Disclosing Party's written permission.
4.5 Return or Destruction. At the end of the Term, unless the parties
otherwise agree in writing, the Receiving Party will immediately stop
using Confidential Information and, if the Disclosing Party so requests
in writing, promptly return to the Disclosing Party or destroy all
records (whether in written form or other media) containing
Confidential Information. The Receiving Party may, however, retain
records that demonstrate the Receiving Party's full compliance with
this Development Agreement if such retained records are used only for
that purpose.
Article 5 - Certain Representations and Warranties
5.1 Ferro Pfanstiehl's Respresentations and Warranties. Ferro Pfanstiehl
represents and warrants to Bioenvision that -
(A) Ferro Pfanstiehl has the full legal power and authority to
execute, deliver and perform its obligations under this
Development Agreement,
(B) Ferro Pfanstiehl will engage and employ professionally
qualified personnel to carry out the Development Program,
(C) Ferro Pfanstiehl will use its commercially reasonable efforts
to successfully complete the Development Program according to
the Development Program schedule, and
(D) Ferro Pfanstiehl will comply, in all material respects, with
all applicable laws in the performance of its obligations
under this Development Agreement.
Bioenvision acknowledges, however, that since the Development Program
is of a developmental or research nature, there can be no guarantee of
complete technical success, and Ferro Pfanstiehl has given no
guarantee, that the Development Program will be successfully completed,
or successfully completed within the contemplated time frame, despite
Ferro Pfanstiehl commercially reasonable efforts to do so. Accordingly,
Ferro Pfanstiehl will not be deemed to be in breach of this Development
Agreement solely because it fails to complete the Development Program.
5.2 Bioenvision's Respresentations and Warranties. Bioenvision represents
and warrants to Ferro Pfanstiehl that -
(A) Bioenvision has the full legal power and authority to execute,
deliver and perform its obligations under this Development
Agreement,
(B) Bioenvision has the unencumbered legal right to deliver the
Clofarabine Information and the Bioenvision Property to Ferro
Pfanstiehl as provided in this Development Agreement,
D) Bioenvision will comply, in all material respects, with all
applicable laws in the performance of its obligations under
this Development Agreement.
5.3 Disclaimer. The warranties provided in ARTICLE 3 AND this Article 5 are
the only warranties EITHER PARTY has given TO THE OTHER PARTY. Such
warranties are IN LIEU OF all other representations, or other
warranties INCLUDING IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS
FOR INTENDED USE AND/OR INFRINGEMENT, that EITHER PARTY might have
given or which might be provided or implied by law or commercial
practice, which other warranties ARE HEREBY EXCLUDED.
Article 6 - Term and Termination
6.1 Term. Unless earlier terminated or cancelled in accordance with the
provisions of this Article 6, the term of this Development Agreement
(the "Term") will begin the Effective Date and will end when Ferro
Pfanstiehl has completed the Development Program or, if earlier, the
date when this Development Agreement is terminated or cancelled
pursuant to this Article 6. If, however, Ferro Pfanstiehl has not
completed the Development Program by December 31, 2007, then this
Development Agreement will automatically terminate without further
action by either party.
6.2 Termination by Mutual Agreement. This Agreement may be terminated at
any time upon mutual written agreement between the parties provided
such termination is in a written document signed by both parties that
refers specifically to this Section 6.2.
6.3 Cancellation for Default. This Agreement may be cancelled by either
party in the event of a Default by the other party. A "Default" shall
be deemed to have occurred when:
(A) A party breaches its material obligations under this
Development Agreement,
(B) The other party gives the breaching party written notice of
breach in sufficient detail to apprise the breaching party of
the scope and extent of the alleged breach and specifically
referring to this Section 6.3,
(C) After having received such written breach notice, the
breaching party fails to cure such default within 10 days (in
the case of a failure by Bioenvision to pay any amounts
hereunder when due), 90 days (in the case of a breach of
Bioenvision's representation and warranty in Section 8.3), or
30 days (in the case of any other breach), provided, however,
if a breach is incapable of cure within 30 days and the
breaching party certifies to the other party in writing that
it is working diligently to cure such breach, such 30-day
period will be extended to for an additional 30 days, and
(D) The other party delivers a written notice of default to the
breaching party.
In such case, this Development Agreement will be deemed cancelled
effective with the delivery of a default notice under Section 8.3(D)
above. Cancellation of this Development Agreement pursuant to this
Section 8.3 shall not affect any other rights or remedies, which may be
available to either party.
6.4 Bankruptcy; Insolvency. Either party may terminate this Development
Agreement upon the occurrence of either of the following:
(A) The entry of a decree or order for relief by a court having
jurisdiction in the premises in respect of the other party in
an involuntary case under the Federal Bankruptcy Code, as now
constituted or hereafter amended, or any other applicable
Federal or state insolvency or other similar law and the
continuance of any such decree or order un-stayed and in
effect for a period of 60 consecutive days (other than any
such case which was initiated, directly or indirectly, by the
party attempting to cancel this Development Agreement or any
Affiliates thereof); or
(B) The filing by such party of a petition for relief under the
Federal Bankruptcy Code, as now constituted or hereafter
amended, or any other applicable federal or state insolvency
or other similar law.
6.5 Rights and Duties on Termination or Cancellation. Upon termination or
cancellation of this Development Agreement -
(A) Ferro Pfanstiehl will, as promptly as practicable -
(1) Cease work on the Development Program, and
(2) Turn over to Bioenvision all results and information
obtained during the Development Program (whether in
written or electronic form) which are then in Ferro
Pfanstiehl's possession.
(B) Bioenvision will promptly pay or reimburse Ferro Pfanstiehl
for all undisputed fees, expenses and uncancellable
obligations incurred hereunder through the date of such
termination or cancellation.
(C) At Ferro Pfanstiehl option,
(1) The parties will promptly agree on a procedure by
which possession of any equipment located at Ferro
Pfanstiehl facility that is paid for by Bioenvision
is given to Bioenvision (with Bioenvision paying all
reasonable costs associated with the removal of such
equipment, including Ferro Pfanstiehl's facility
restoration costs), or
(2) Ferro Pfanstiehl may purchase all or any portion of
such equipment from Bioenvision by paying Bioenvision
the depreciated (calculated on a straight-line basis)
book value thereof.
(D) The obligations of confidentiality and restrictions on use of
Confidential Information in this Development Agreement will
survive.
Article 7 - Indemnification
7.1 Indemnification of Bioenvision. Ferro Pfanstiehl will indemnify and
defend Bioenvision, and hold Bioenvision harmless from and against, any
costs, expenses (including reasonable attorneys' fees), losses,
damages, or liabilities resulting from a claim of physical damage to
property of third parties or injury to persons ("Losses") proximately
caused by the gross negligence, recklessness, or intentional wrongdoing
of Ferro Pfanstiehl or its directors, officers, agents, representatives
or permitted assigns while engaged in activities under this Development
Agreement. Ferro Pfanstiehl will likewise indemnify and defend
Bioenvision,s directors, officers, agents, representatives or permitted
assigns, and hold the same harmless from and against, any Losses
proximately caused by the gross negligence, recklessness, or
intentional wrongdoing of Ferro Pfanstiehl or its directors, officers,
agents, representatives or permitted assigns while engaged in
activities under this Development Agreement.
7.2 Indemnification of Ferro Pfanstiehl. Bioenvision will indemnify and
defend Ferro Pfanstiehl, and hold Ferro Pfanstiehl harmless from and
against, any Losses proximately caused by the gross negligence,
recklessness, or intentional wrongdoing of Bioenvision or its
directors, officers, agents, representatives or permitted assigns while
engaged in activities under this Development Agreement. Bioenvision
will likewise indemnify and defend Ferro Pfanstiehl's directors,
officers, agents, representatives or permitted assigns, and hold the
same harmless from and against, any Losses proximately caused by the
gross negligence, recklessness, or intentional wrongdoing of
Bioenvision or its directors, officers, agents, representatives or
permitted assigns while engaged in activities under this Development
Agreement.
7.3 Special Indemnity. Bioenvision represents and warrants to Ferro
Pfanstiehl that the development, production, and sale of Clofarabine
will not infringe the rights of any third party, including, without
limitation, any rights of ILEX Oncology, Inc., Sourthern Research
Institute or their respective affiliates. Without limiting the
generality of the indemnity contained in Section 7.2 above, Bioenvision
will indemnify and defend Ferro Pfanstiehl, and hold Ferro Pfanstiehl
harmless from and against, any Losses proximately caused by the actual
or alleged infringement of any patent application, patent, trade
secret, or other intellectual property right of third parties arising
out of the development, manufacture, use, or sale by Ferro Pfanstiehl
of Clofarabine for Bioenvision under this Development Agreement.
Article 8 - Dispute Resolution
If the parties ever have a dispute involving their respective rights and
obligations under this Development Agreement, then the parties will attempt to
resolve such dispute as follows:
8.1 Dispute Notice. Either Ferro Pfanstiehl or Bioenvision may at any time
deliver to the other a written dispute notice setting forth a brief
description of the issues for which such notice initiates the dispute
resolution mechanism set forth in this Article 8. Such dispute notice
shall also specify the provision or provisions of this Development
Agreement and the facts or circumstances, in reasonable detail, that
are the subject matter of the dispute.
8.2 Informal Negotiations. During the 30-day period following delivery of a
dispute notice described in Section 8.1, the parties will cause their
representatives to meet and seek to resolve the disputed items
cordially through informal negotiations
8.3 Dispute Resolution Proceedings. If representatives of the parties are
unable to resolve disputed items through the informal negotiations
described in Section 8.3, then within 30 days after the informal
negotiation period the parties will refer the disputed issues to a
dispute resolution panel for final resolution as follows:
(A) Designation of Representatives. Within seven days after such
informal negotiation period, Ferro Pfanstiehl and Bioenvision
will each designate one representative to serve on the dispute
resolution panel. (If either party fails or refuses to
designate a representative, then the other party will be
entitled to have a representative appointed for such party by
the CPR Institute.)
(B) Selection of Neutral. Promptly after they have been
designated, the designated representatives will meet and
select a neutral person (the "Neutral") to serve as the third
member of the dispute resolution panel. If the designated
representatives of parties cannot agree on a Neutral, then
either representative may request the CPR Institute to select
the Neutral.
(C) Procedures and Process. At the time the matter is referred to
the dispute resolution panel, Ferro Pfanstiehl and Bioenvision
will jointly establish the procedures to be followed with
respect to the presentation of the parties' respective
positions and the process by which the dispute resolution
panel will reach and render its decision on the disputed
issues. If Ferro Pfanstiehl and Bioenvision cannot agree on
such procedures and processes, then the Neutral will establish
such procedures and process, which will, in all events, be
consistent with the foregoing.
(D) Decision. The dispute resolution panel will act by majority
vote. The dispute resolution panel will base its decision on
applicable provisions of this Development Agreement or, if the
provisions of
this Development Agreement do not resolve the matter, on
general principles of substantive Delaware law. (The dispute
resolution panel may, if it so desires, seek the opinion of an
attorney licensed to practice law in the State of Delaware on
any matter of substantive Delaware law on which the panel
desires clarification.)
Article 9 - Force Majeure
9.1 Effect of an Event of Force Majeure. Neither party shall be held liable
or responsible for any loss or damages resulting from any failure or
delay in its performance due hereunder (other than the payment of
money) caused by an Event of Force Majeure.
9.2 Notice of Force Majeure. If either party is delayed or rendered unable
to perform due to an Event of Force Majeure, the affected party shall
give notice of the same and its expected duration to the other party
promptly after the occurrence of the cause relied upon, and upon the
giving of such notice the obligations of the party giving the notice
will be suspended during the continuance of the Force Majeure;
provided, however, such party shall take commercially reasonable steps
to remedy the Force Majeure with all reasonable dispatch. The
requirement that Force Majeure be remedied with all reasonable dispatch
shall not require the settlement of strikes or labor controversies by
acceding to the demands of the opposing party.
Article 10 - Notices
All notices, requests and other communications under this Development Agreement
shall be in writing and shall be deemed to have been duly given at the time of
receipt if delivered by hand or communicated by electronic transmission, or, if
mailed, three days after mailing registered or certified mail, return receipt
requested, with postage prepaid:
If to Bioenvision, to: Bioenvision, Inc.
▇▇▇ ▇▇▇▇▇▇▇ ▇▇▇▇▇▇, ▇▇▇▇▇ ▇▇▇
▇▇▇ ▇▇▇▇, ▇▇▇ ▇▇▇▇ ▇▇▇▇▇
Attention: CEO and
General Counsel
Telefax: ▇.▇▇▇.▇▇▇.▇▇▇▇
If to Ferro Pfanstiehl, to: Ferro Pfanstiehl Laboratories, Inc.
▇▇▇▇ ▇▇▇▇ ▇▇▇▇ ▇▇▇▇▇▇
▇▇▇▇▇▇▇▇, ▇▇▇▇▇▇▇▇ ▇▇▇▇▇
Attention: General Manager
Telefax: ▇.▇▇▇.▇▇▇.▇▇▇▇
With a copy to: Ferro Pfanstiehl Laboratories, Inc.
▇▇▇▇ ▇▇▇▇▇▇▇▇ ▇▇▇▇▇▇
▇▇▇▇▇▇▇▇▇, ▇▇▇▇ ▇▇▇▇▇
▇▇▇
Attention: General Counsel
Telefax: ▇.▇▇▇.▇▇▇.▇▇▇▇
Either party may change its notice address above to a different address
by giving the other party written notice of such change.
Article 11 - Miscellaneous
11.1 Independent Contractor. Ferro Pfanstiehl will perform services
hereunder only as an independent contractor, and nothing herein shall
be construed to be inconsistent with such relationship or status. Under
no circumstances shall Ferro Pfanstiehl be considered to be an employee
or agent of Bioenvision.
11.2 Publicity. Any press release, publicity or other form of public written
disclosure related to this Development Agreement prepared by one party
shall be submitted to the other party prior to release for approval,
which approval shall not be unreasonably withheld or delayed by such
other party.
11.3 Severability. If any provision of this Development Agreement shall
finally be determined to be unlawful, then such provision will be
deemed to be severed from this Development Agreement and replaced by a
lawful provision which carries out, as closely as possible, the
intention of the parties and preserves the economic bargain
contemplated by this Development Agreement and, in such case, each and
every other provision of this Development Agreement will remain in full
force and effect.
11.4 Assignment. Neither party may assign any right or delegate any duty
under this Development Agreement without the written approval of the
other party; provided, however, that Bioenvision may, without such
consent, assign this Development Agreement in connection with the
transfer or sale of all or substantially all of its assets or the
merger or other business combination with, to, or into another entity,
and either party may assign Development Agreement to it parent company
or a company under the common control of its parent company. Any
purported assignment in violation of the preceding sentence shall be
void. Any permitted assignee will be required to assume all obligations
of its assignor under this Development Agreement. No assignment shall
relieve either party of responsibility for the performance of any
obligation, which accrued prior to the effective date of such
assignment.
11.5 Subcontractors. Ferro Pfanstiehl may use subcontractors to perform any
part of this Development Agreement, provided such subcontractors are
bound by a confidentiality agreement with Ferro Pfanstiehl and meet
such other quality standards as may be imposed on Ferro Pfanstiehl
under this Development Agreement (for example, without limitation,
Ferro Pfanstiehl may, at its option, have cleaning verification/methods
validation performed by a CGMP compliant laboratory).
11.6 Governing Law. This Development Agreement will be governed by and
construed in accordance with the internal substantive laws of State of
Delaware, without giving effect to such state's principles of conflicts
of laws..
11.7 Headings. Paragraph headings and captions used herein are for
convenience of reference only and shall not be used in the construction
or interpretation of this agreement.
11.8 Waiver. Neither party's waiver of any breach or failure to enforce any
of the terms and conditions of this Development Agreement, at any time,
shall in any way affect, limit or waive such party's right thereafter
to enforce and compel strict compliance with every term and condition
of this Development Agreement.
11.9 Construction. This Devleopment Agreement has been jointly prepared on
the basis of the mutual understanding of the parties and shall not be
construed against either party by reason of such party's being the
drafter hereof or thereof.
11.10 Exhibits. The Exhibits to this Development Agreement form an integral
part of this Development Agreement and are hereby incorporated into
this Development Agreement by this reference.
11.11 Counterparts. More than one counterpart of this Development Agreement
may be executed by the parties hereto, and each fully executed
counterpart shall be deemed an original without production of the
others.
11.12 Complete Agreement. This Development Agreement and the Pharmaceutical
Supply Agreement between the parties, dated thedate hereof, together
set forth the entire understanding of the parties hereto with respect
to the subject matter hereof and thereof and supercede all prior
letters of intent, agreements, undertakes, arrangements,
communications, representations, or warranties, whether oral or
written, by any officer, employee, or representative of either party
relating thereto.
To evidence their agreement as stated above, BIOENVISION, INC. and
FERRO PFANSTIEHL LABORATORIES, INC., have each caused their respective duly
authorized directors, officers, or attorneys to execute this PHARMACEUTICAL
DEVELOPMENT AGREEMENT as of the date first above written.
BIOENVISION, INC. FERRO PFANSTIEHL LABORATORIES, INC.
/S/ ▇▇▇▇▇ ▇▇▇▇▇▇
/S/ ▇▇▇▇▇ ▇▇▇▇
By: By:
---------------------------------------------- ------------------------------------------------
▇▇▇▇▇ ▇▇▇▇ ▇▇▇▇▇ ▇▇▇▇▇▇
Director of Finance, Worldwide Business Director
General Counsel Pharmaceuticals & Fine Chemicals
EXHIBIT A
---------
Definitions
-----------
The following terms identified with initial capital letters are defined
in the following Sections of this Development Agreement:
Term Cross Reference
API's ...................................................Recital B
Bioenvision ................................................Preamble
Bioenvision Field of Use ...................................Section 3.3(B)(5)(a)
Bioenvision Intellectual Property ..........................Recital 3.2
Bioenvision Patents ........................................Section 3.2
Bioenvision Trade Secrets and Know How .....................Recital 3.2
Confidential Information ...................................Section 4.1
Development Agreement ......................................Preamble
Development Program ........................................Section 2.1
Disclosing Party ...........................................Section 4.1
Effective Date .............................................Preamble
Event of Force Majeure......................................Section 9.3
Ferro Pfanstiehl ...........................................Preamble
Ferro Pfanstiehl Field of Use ..............................Section 3.3(B)(5)(b)
Ferro Pfanstiehl Intellectual Property .....................Section 3.1
Ferro Pfanstiehl Patents ...................................Section 3.1
Ferro Pfanstiehl Trade Secrets and Know How ................Section 3.1
Joint Development Trade Secrets and Know How ...............Section 3.3
Jointly Developed Intellectual Property ....................Section 3.3
Jointly Developed Patentable Inventions ...................Section 3.3
Jointly Developed Patents ..................................Section 3.3(B)(4)
Milestone Payments .........................................Section 2.6(B)
Neutral ....................................................Sectopm 8.3(B)
Project Initiation Fee .....................................Section 2.6(A)
Receiving Party ............................................Section 4.1
Term .......................................................Section 6.1
In addition the following term or terms shall have the meanings set
forth below where used in this Development Agreement and identified with initial
capital letters:
Term Meaning
Event of Force Majeure Any event beyond the reasonable
control of the party assert such
an event, including events such as
wars, insurrection, acts of
terrorism, lightening,
earthquakes, fires, floods,
strikes, lockouts and other
similar or dissimilar causes.
EXHIBIT B
---------
1. Background: Bioenvision is developing Clofarabine as a potential New
Chemical Entity (NCE). Bioenvision has indicated that the Clofarabine
drug product, both alone and in combination with other oncolytics and
adjuvants, is currently undergoing extensive clinical trials as an
oncolytic for the treatment of various cancer-related disease states.
2. Technical Package: Under a secrecy agreement with Bioenvision, Ferro
Pfanstiehl has received and reviewed an extensive technical package
provided to Ferro Pfanstiehl by Ilex on behalf of Bioenvision on
November 19, 2002. The scope of required activities included in that
technical package included the following:
a. Transfer of developmental & validated analytical support methods,
b. Development and validation of a residue detection method,
c. Verification of the current process chemistry & further
process development per i. below,
d. Generation of laboratory-based samples for analytical
comparison with existing API standards,
e. Preparation of a technology transfer summary report,
f. Pilot production of approximately 0.5 Kgs of cGMP API suitable
for US and EU CTM use,
g. An ICH-compliant stability study,
h. cGMP compliant analytical, manufacturing, and cleaning
documentation, and
i. An engineering response, with unit operations definition
consistent with a commercial 5 -10 Kg. scale-up, as part of
potential supplier qualification program.
j. Prepare and submit DMF or EU equivalent supporting
Bioenvision IND's
3. Development Goals: The project development goals for the scope of
process development work include the following:
a. Assessment of solvent exchange during preparation of crude
protected Clofarabine intermediate with avoidance of the use
of solid drying agents,
b. Application of solvent exchange concepts elsewhere in the
process,
c. Minimization or complete avoidance of solids drying steps
throughout the process,
d. Substitution of heptane for petroleum ether.
e. General unit operation improvements throughout the process.
▇. ▇▇▇▇▇ Pfanstiehl is to produce approximately 0.5 Kgs of CGMP
material suitable for human use in clinical trials.
4. Key Assumptions: The key project assumptions are as follows:
▇. ▇▇▇▇▇ Pfanstiehl will manufacture and supply D-138, the key
protected fluoro-sugar essential to the convergent synthesis
of Clofarabine.
▇. ▇▇▇▇▇ Pfanstiehl will purchase 2-chloroadenine from the
existing Bioenvision supplier at the assumed price of
$2000.00/kg delivered. If this price changes, the COGS will be
adjusted appropriately.
c. Bioenvision will supply a fully characterized reference
standard of the Product and selected impurity standards of the
alpha and beta anomers of the protected Clofarabine convergent
coupling product.
d. Bioenvision will provide reasonable site support Ferro
Pfanstiehl desires to ensure successful technology transfer
during the course of the anticipated activities.
e. Yields will be consistent with those previously reported in
technical transfer documents in the possession of Ferro
Pfanstiehl.
5. Deliverables and Pricing:
Analytical Services
-------------------
Transfer in Release/Stability Methods $12,000.00
Analytical Support to Development $10,500.00
Validate Method for Cleaning/Swab Recovery $14,000.00
Transfer in of In-Process Methods $4,000.00
In-Process HPLC Bromo Intermediate $7,000.00
GC Method Support to Solvent Use on Regulated
Intermediate Release 3,500.00
Support to Process Development and Manufacturing $7,000.00
Analytical Supplies $1,500.00
Process Chemistry
Verify Chemistry & Produce 20 & 50 Gm Samples $21,000.00
Preparation of a Technology Transfer Report $3,500.00
Preparation of Manufacturing Summary Report $3,500.00
Process Development Supplies and Dedicated Glassware $11,000.00
Unit Operations Based Process Development Program $74,000.00
Regulatory Affairs
Batch Record, Cleaning Record Reviews & RA Releases $3,500.00
DMF/EUDMF Preparation & Submission $35,000.00
Quality Control
External Testing $500.00
ICH Stability Studies (Assay, Related Impurities, KF
& Appearance: One lot at Two Conditions) $21,000.00
Process Engineering
Setup/Process Flow Diagram/Operability Reviews $3,500.00
Manufacturing
Process Batch Record Development $10,500.00
Cleaning Record Generation $3,500.00
Project Management
Client Updates $7,000.00
Subtotal Development Activities $257,000.00
Manufacture of CTM API
Approx. 0.5 Kgs of CLOFARABINE Suitable for Human Use $165,430.00 Total
Program Costs $422,430.00
6. Product Specifications: Attached as Exhibit C are the "Tentative
Purchase Specifications" Exhibit C, The parties will negotiate the
final purchase specifications in good faith before release following
Method Suitability Testing of all appropriate assay procedures by Ferro
Pfanstiehl.
7. Terms: $50,000.00 Non-Cancelable Project Initiation Fee, creditable
against Milestone Invoicing, Deliverables Invoicing: Net 30 Days, FOB
Waukegan, IL. Bioenvision will supply
a. All available written and validated analytical methods as well
as a validated stability indicating assay,
b. Fully characterized API reference sample and selected impurity
standards and samples of the alpha and beta anomers of the
protected Clofarabine coupling product.,
c. The latest process improvement technology reports, and
d. Approved source information for Ferro Pfanstiehl purchase of
2-chloroadenine.
8. Timing: A Project ▇▇▇▇▇ Chart is attached as Exhibit D dated 5/30/03
based on a Mid June Project Initiation. The ▇▇▇▇▇ indicates delivery of
API for CTM material upon timely Bioenvision submission of suitable
analytical support methodology, release method reports, reference and
impurity standards, and characterization reports. Completion is expected
on or about late December, 2003 per attached ▇▇▇▇▇ Chart.
9. Commercial Pricing Indication: $60,000.00/Kg for 5 Kg lots, $50,000/kg
for 10 kg lots (Pricing Indications Subject to Change upon a more
thorough definition of a commercially viable process description)
EXHIBIT C
---------
Tentative Purchase Specifications
---------------------------------
1.0 Compound Name: Clofarabine
2.0 References: Current USP
3.0 Specifications:
---------------------------------------- --------------------------------------------------------------------
TEST SPECIFICATIONS
---- --------------
---------------------------------------- --------------------------------------------------------------------
3.1 Physical Examination White to off-white solid
--------- ------------------------------ --------------------------------------------------------------------
3.2 Identification Conforms to reference spectra
(FTIR)
--------- ------------------------------ --------------------------------------------------------------------
3.3 Identification The retention time of the principal peak in the chromatogram
(HPLC) corresponds with the
Clofarabine peak in the reference chromatogram
--------- ------------------------------ --------------------------------------------------------------------
3.4 Assay (HPLC) 97.0% - 103.0% w/w
Calculated on the anhydrous and solvent-free basis
--------- ------------------------------ --------------------------------------------------------------------
3.5 Impurities (HPLC) Total <= 2.0%, Clofarabine (alpha) anomer <= 1.0%,
and individual un-named <=0.75%.
Report all impurities =>0.05% AUC
--------- ------------------------------ --------------------------------------------------------------------
3.6 Water Determination USP (921)
(▇▇▇▇ ▇▇▇▇▇▇) Report Results
--------- ------------------------------ --------------------------------------------------------------------
3.7 Loss on Drying <=2.0% corrected for water content
(LOD), USP (731)
--------- ------------------------------ --------------------------------------------------------------------
3.8 Residue on Ignition <=0.2%
(ROI), USP (281)
--------- ------------------------------ --------------------------------------------------------------------
3.9 Container / Closure Double-bagged in polyethylene bags inside an HDPE drum
--------- ------------------------------ --------------------------------------------------------------------
4.0 Storage and Handling: Refer to MSDS for additional information
4.1 Store at controlled room temperature (15-30(Degree)C)
4.2 Observe appropriate MSDS safety precautions when handling.
