Confidential Treatment Requested
EXHIBIT 10.54
BNP AGREEMENT (1995)
entered into as of November 17, 1995 by and between
SCIOS NOVA INC.
2450 Bayshore Parkway
Mountain View, CA 94043/USA
(hereinafter referred to as "SCIOS NOVA")
and
BIOCHEMIE GESELLSCHAFT M.B.H.
A-6250 Kundl/Austria
(hereinafter referred to as "BC")
WHEREAS, SCIOS NOVA is seeking to start Phase III clinical trials and obtain
regulatory approval of its NATRECOR(R) brand brain natriuretic peptide ("BNP")
for the treatment of acute congestive heart failure and is seeking a long-term
source of supply of BNP made by recombinant manufacture; and
WHEREAS, BC is in the business of the recombinant manufacture of peptides and
proteins and wishes to become SCIOS NOVA's supplier; and
WHEREAS, SCIOS NOVA has developed a 10 liter recombinant manufacturing process
for BNP and BC is willing to scale-up SCIOS NOVA's 10 liter manufacturing
process for BNP to the 150 liter scale so that the parties' can evaluate BC's
capability to become SCIOS NOVA's long-term supplier of BNP in bulk solution in
commercial quantities; and
WHEREAS, SCIOS NOVA wishes to ensure BC is willing and has the capacity to meet
SCIOS NOVA's requirements for bulk BNP during the term of this AGREEMENT, and BC
is willing to provide such assurance; and
WHEREAS, BC and SCIOS NOVA wish to set forth the principal terms and conditions
on which they will evaluate BC's capability to scale up the production of BNP in
BULK SOLUTION and on which the parties may thereafter agree to continue to work
together; and
WHEREAS, SCIOS NOVA is willing to purchase BULK SOLUTION from BC on a long-term
basis and BC is willing to sell BULK SOLUTION to SCIOS NOVA on a long-term
basis;
THE PARTTES HERETO AGREE AS FOLLOWS:
1. Definitions
Whenever written in capital letters throughout this Agreement the
following terms shall have the following meaning:
1.1 BC DELIVERABLES shall mean the following items to be delivered by
BC to SCIOS NOVA after Development Phase I:
(a) a written report of BC's complete results in Development
Phase I;
(b) samples of BULK SOLUTION that has been manufactured by BC
at the 150 liter fermentation volume;
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(c) results of the tests described in Annex 4;
(d) copies of the batch records for all of the
production runs performed by BC in Development Phase
I;
(e) BC's statement of its yield from fermentation at the
150 liter scale, including supporting data,
(f) BC's estimate of the quantity of BNP that will be
contained in the BULK SOLUTION to be produced in
Development Phase II; and
(g) BC's proposed revision of the TARGET PRICE.
1.2 BC KNOWHOW shall mean all know how, technology and trade
secrets developed by BC during the course of this Agreement
that relate or are useful to the manufacture of BULK
SOLUTION or BNP that are not included in BC PATENT RIGHTS.
1.3 BC PATENT RIGHTS shall mean all patent applications and
valid, issued and unexpired patents which are now or
hereafter owned or controlled by BC, including any
substitutions, extensions, reissues, renewals, divisions,
continuations, or continuations-in-part therefor or
thereof, and all foreign counterparts of the foregoing,
which cover the development or manufacture of BULK SOLUTION
or BNP.
1.4 BNP means brain natriuretic peptide produced by recombinant
DNA expression in E. coli which has the amino acid sequence
and meets the BNP SPECIFICATIONS set forth in Annex 1.
1.5 BNP COMPOUND shall mean BNP or any derivative thereof
containing [*****]
1.6 BNP SPECIFICATIONS shall mean the specifications set forth
in Annex 1. Annex 1 may be updated by mutual agreement of
the parties at the end of Development Phase I as provided
in Article 4.1 and at the end of Development Phase II as
provided in Article 5.3. All revisions shall take into
account the then current requirements of regulatory
authorities with regard to the acceptable characteristics
for proteins manufactured by recombinant means.
1.7 BULK SOLUTION means frozen bulk solution of BNP that meets
the SPECIFICATIONS FOR BULK SOLUTION.
1.8 COMMERCIAL PRICE shall mean the price per gram of BNP in
BULK SOLUTION that the parties establish in Article 5.5
will be charged by BC for deliveries under Article 6 during
the Commercial Phase, such price to be valid until December
31, 2002.
1.9 COMPREHENSIVE AGREEMENT means any superseding agreement
that the parties may subsequently elect to create under
Article 6.10.
1.10 CONFIDENTIAL INFORMATION shall have the definition that is
set forth in the Confidential Disclosure Agreement between
the parties dated December 30, 1994.
1.11 DEVELOPMENT PHASE I means the development work to be
conducted by BC under Article 4.
1.12 DEVELOPMENT PHASE II means the development work to be
conducted by BC under
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Article 5.
1.13 NATRECOR is the United States trademark under which SCIOS NOVA
intends to market its BNP product. As used in this Agreement,
NATRECOR shall mean a synonym for BNP in finished form to be sold
to the trade, irrespective of whether such trademark shall be used
or not.
1.14 REVISED TARGET PRICE shall mean the revision of the TARGET PRICE
based on BC's results in DEVELOPMENT PHASE I that is established
by the parties according to Article 4.1.
1.15 SCIOS NOVA KNOWHOW shall mean the 10 liter PROCESS and other
know-how, technology and trade secrets that SCIOS NOVA may
disclose to BC related or useful to the manufacture of BULK
SOLUTION or BNP that are not included in the SCIOS NOVA PATENT
RIGHTS.
1.16 SCIOS NOVA PATENT RIGHTS shall mean all patent applications and
valid, issued and unexpired patents which are now or hereafter
owned or controlled by SCIOS NOVA, including any substitutions,
extensions, reissues, renewals, divisions, continuations, or
continuations-in-part therefor or thereof, and all foreign
counterparts of the foregoing, which cover the development or
manufacture of BULK SOLUTION or BNP or a derivative thereof.
1.17 SPECIFICATIONS FOR BULK SOLUTION shall mean the specifications in
Annex 2. Annex 2 may be updated by mutual agreement of the parties
at the end of DEVELOPMENT PHASE I as provided in Article 4.1 and
at the end of DEVELOPMENT PHASE II as provided in Article 5.3. All
revisions shall take into account the then current requirements of
regulatory authorities with regard to the acceptable
characteristics for proteins manufactured by recombinant means.
1.18 TARGET PRICE means a price per gram of BNP delivered to SCIOS NOVA
in BULK SOLUTION of [*****] calculated upon BC's knowledge before
DEVELOPMENT PHASE I for the supply of BULK SOLUTION in commercial
quantities.
1.19 10 liter PROCESS means SCIOS NOVA's current process to manufacture
BULK SOLUTION at a 10 liter fermentation volume including:
[*****]
details being listed in Annex 3.
1.20 150 liter PROCESS means a manufacturing process to produce BULK
SOLUTION at a 150 liter fermentation volume to be developed by BC
based on the 10 liter PROCESS.
1.21 3,000 liter PROCESS means a manufacturing process for BULK
SOLUTION at a 3,000 liter fermentation volume to be developed by
BC based on the 150 liter PROCESS.
2. Supply of information from SCIOS NOVA to BC, starting criteria
2.1 Delivery. Under a separate letter agreement, SCIOS NOVA has
provided BC with the 10 liter PROCESS so that BC could begin its
work on approximately November 1, 1995.
2.2 Response. Within 2 weeks of BC's receipt of the 10 liter PROCESS
under Article 2.1, BC
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shall advise SCIOS NOVA whether BC regards the information
provided to be adequate for BC's activities as per Article 3. In
the event BC shall regard the information provided by SCIOS NOVA
to be inadequate, SCIOS NOVA shall, to the extent SCIOS NOVA has
previously generated such information, provide upon BC's request
within 14 days such additional documents and research/development
results that SCIOS NOVA may possess.
Within 2 weeks of BC's receipt of the additional information, BC
shall advise SCIOS NOVA whether BC regards the additional
information so obtained to be adequate.
In the event BC shall have concluded that it does not have
adequate information, to perform DEVELOPMENT PHASE I for the price
indicated, BC shall so advise SCIOS NOVA and the parties shall
endeavor to reach an agreement on terms for proceeding. If the
parties are unable to reach such a revised agreement by December
1, 1995, then this Agreement shall be automatically terminated
with immediate effect (except Articles 11 and 12 which shall
continue in effect) and no party shall have a right for
compensation. Upon any termination under this Article, BC shall
return to SCIOS NOVA and cease to use all information and
materials provided by SCIOS NOVA as part of the 10 liter PROCESS.
2.3 Support. Upon BC's request, SCIOS NOVA shall, without charge to
BC, provide BC with a maximum of two experts from SCIOS NOVA for a
period of up to three weeks each to support BC's development
activities in DEVELOPMENT PHASE I.
2.4 Essential Dates. The dates as per Articles 3, 4 and 5 shall depend
on SCIOS NOVA having provided the 10 liter PROCESS and additional
information under Article 2.2 so that BC can provide the positive
advice from BC to SCIOS NOVA by November 15. In the event delays
by SCIOS NOVA cause such advice to be given later, the dates as
mentioned in Articles 3, 4 and 5 shall be postponed by the period
of such delay.
2.5 Addition of Lyophilization. During DEVELOPMENT PHASE I the parties
shall decide whether BC shall also perform the lyophilization of
the BULK SOLUTION and ship BNP in a solid form. If the parties
determine that BC should perform such work, appropriate amendments
will be made by mutual agreement, including revisions of the
specifications, the references to the specifications, and setting
an additional charge for BC to perform the lyophilization.
3. DEVELOPMENT PHASE I (150 liter PROCESS)
3.1 General. In DEVELOPMENT PHASE I, BC shall use its best efforts and
provide the necessary resources to scale up the 10 liter PROCESS
to produce BULK SOLUTION by recombinant manufacturing methods at
the 150 liter fermentation volume so that the parties may fully
assess the feasibility of larger scale production. The goal of the
parties is to assess whether BC can produce BULK SOLUTION that
meets the SPECIFICATIONS FOR BULK SOLUTION at a price equal to or
less than the TARGET PRICE. DEVELOPMENT PHASE I shall begin
[*****]. SCIOS NOVA may, at its expense, have representatives
visit BC's facility and view BC's fermentation and product
recovery activities during DEVELOPMENT PHASE I.
3.2 DELIVERABLES. During DEVELOPMENT PHASE I BC shall develop the 150
liter PROCESS and define the yields and quantity of BNP in BULK
SOLUTION that BC is able to produce. On or about January 15, 1996,
BC shall provide to SCIOS NOVA a written interim report of BC's
activities and not later than March 1, 1996, BC shall deliver the
BC
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DELIVERABLES to SCIOS NOVA.
3.3 Charge. BC's work in DEVELOPMENT PHASE I is outlined in Annex 5.
SCIOS NOVA will be charged for BC's work in DEVELOPMENT PHASE I
based on [*****]. Regardless of the specific results achieved in
DEVELOPMENT PHASE I, SCIOS NOVA is obligated to [*****]; provided,
however, the aggregate charge to SCIOS NOVA for all of BC's work
under Articles 2 and 3 shall, in no event, exceed [*****] without
SCIOS NOVA's prior written consent.
3.4 Payment. In February 1996, BC shall invoice SCIOS NOVA for all of
BC's charges for DEVELOPMENT PHASE I, calculated per Article 3.3,
and such amount shall be paid by SCIOS NOVA within fourteen days
from the later of (a) SCIOS NOVA's receipt of the invoice or (b)
SCIOS NOVA's receipt of all of the BC DELIVERABLES.
4. Analysis of DEVELOPMENT PHASE I
4.1 Analysis and Discussion. Promptly following receipt of the BC
DELIVERABLES, SCIOS NOVA shall determine whether it believes the
samples and data indicate that BC will be able to meet the
SPECIFICATIONS FOR BULK SOLUTION, and promptly advise BC of the
results of its analysis. Not later than 30 days after receipt of
the BC DELIVERABLES, SCIOS NOVA shall notify BC whether SCIOS NOVA
wishes BC to conduct DEVELOPMENT PHASE II. If either party does
not wish to conduct DEVELOPMENT PHASE II, this Agreement shall be
discontinued per Article 10.2. If SCIOS NOVA notifies BC that it
wishes to have BC perform DEVELOPMENT PHASE II, then BC and SCIOS
NOVA shall meet to establish: (a) the Standard Operating Procedure
to be used for the 3,000 liter PROCESS in DEVELOPMENT PHASE II and
thereafter; (b) the BNP SPECIFICATIONS; (c) the SPECIFICATIONS FOR
BULK SOLUTION; and (d) the REVISED TARGET PRICE that will be
charged to SCIOS NOVA per gram of BNP in BULK SOLUTION that is
produced by BC in commercial runs after DEVELOPMENT PHASE II. Upon
mutual agreement of the parties, their decisions concerning these
four matters shall be memorialized in a written addendum to be
attached to and become a part of this Agreement.
4.2 Advance Work. In order to avoid delay in commencing DEVELOPMENT
PHASE II, BC agrees to perform the programming of its process
control computers and complete the installation of additional
equipment necessary for the manufacture of BULK SOLUTION by the
end of March 1996. SCIOS NOVA will reimburse BC at the rate
specified in Annex 5 for [*****] up to a maximum of [*****] within
30 days after invoice from BC following any termination under
Article 4.1 or, if SCIOS NOVA subsequently elects not to have BC
perform DEVELOPMENT PHASE II or the parties are unable to agree on
the four items for a long-term supply relationship per Article
4.1.
4.3 Use of 150 liter PROCESS. If the parties are unable to agree on
the four matters in Article 4.1 or SCIOS NOVA shall otherwise
elect not to proceed to DEVELOPMENT PHASE II then, in exchange for
having funded the development of such process, BC does hereby
grant to SCIOS NOVA a royalty-free, exclusive license to use, or
allow others to use, all or any part of the 150 liter PROCESS
solely for the manufacture of BNP. Such license shall be
irrevocable if SCIOS NOVA has made the payment specified in
Article 3.4 and in Article 10.2, if any is due, but may be revoked
by BC by written notice to SCIOS NOVA if such payments are not
made. BC shall have the right to use all or any part of the 150
liter
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PROCESS solely for any use other than the manufacture of BNP.
5. DEVELOPMENT PHASE II (3,000 liter PROCESS)
5.1 Timing. If the parties agree on the four items per Article 4.1,
then DEVELOPMENT PHASE II shall be conducted by BC according to
the terms of this Article 5. It is the parties' mutual goal,
assuming adequate results in DEVELOPMENT PHASE I, to begin
DEVELOPMENT PHASE II not later than [*****]. Once DEVELOPMENT
PHASE II is commenced, BC shall use its best efforts to complete
the work described below as quickly as reasonable.
5.2 Efforts. During DEVELOPMENT PHASE II, BC shall use its best
efforts and provide the necessary resources to perform the
following to manufacture BULK SOLUTION:
(a) complete the modification of its manufacturing plant by
investment in specific equipment necessary to manufacture
BULK SOLUTION at the 3,000 liter scale;
(b) develop the 3,000 liter PROCESS;
(c) manufacture, according to the Standard Operating Procedure
written by BC and approved by SCIOS NOVA under Article 4.1,
at least three batches using the 3,000 liter PROCESS;
(d) deliver to SCIOS NOVA the samples for DEVELOPMENT PHASE II
and results of tests described in Annex 4;
(e) deliver to SCIOS NOVA all BULK SOLUTION (except samples for
testing at BC) manufactured in DEVELOPMENT PHASE II,
together with a copy of the complete batch records for each
of the 3 batches to be produced;
(f) advise SCIOS NOVA of BC's yield from fermentation at the
3000 liter scale for each of the 3 batches, including
supporting data;
(g) advise SCIOS NOVA of the price per gram of BNP that BC
proposes to charge for production of BULK SOLUTION at
commercial scale under Article 6 based on results in
DEVELOPMENT PHASE II.
5.3 Assessment of DEVELOPMENT PHASE II and Payment. SCIOS NOVA shall
promptly assay the BULK SOLUTION produced in DEVELOPMENT PHASE II
for conformity with the SPECIFICATIONS FOR BULK SOLUTION, (as
established by the parties under Article 4.1) and provide the
results of its analysis to BC. If three batch runs produce BULK
SOLUTION that satisfies the SPECIFICATIONS FOR BULK SOLUTION and
have a yield of at least 125 grams each, then SCIOS NOVA shall
make one of the following payments to BC based on when SCIOS NOVA
received the final shipment of the three batches from DEVELOPMENT
PHASE II:
[*****]
Recognizing that delivery of BULK SOLUTION from DEVELOPMENT PHASE
II and batch records to SCIOS NOVA after [*****] will prevent
SCIOS NOVA from achieving its development timelines, the parties
agree that SCIOS NOVA shall have the option whether to accept and
pay [*****] for any batch that is delivered after [*****]. In
addition, if the COMMERCIAL PRICE proposed by BC under Article 5.5
is more than
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the REVISED TARGET PRICE, then the amount otherwise payable by
SCIOS NOVA under this Article 5.3 shall be [*****]; provided,
however, that such reduction shall not apply if the COMMERCIAL
PRICE is higher than the REVISED TARGET PRICE due to the fact that
the average fermentation yield of the 3 batches (each yielding at
least 125 grams) at the 3000 liter scale (as provided in Article
5.2(f)) is less than the fermentation yield from the 150 liter
scale provided by BC under Article 1.1(e).
5.4 Third Party Testing. If SCIOS NOVA rejects the material from any
of the three batches as not meeting the SPECIFICATIONS FOR BULK
SOLUTION, and if the first results of BC conflict, a sample of
such shipment shall be submitted for testing to a qualified
independent laboratory mutually agreed on by the parties, and such
test results shall control. Fees and expenses of the laboratory
will be paid by the party against whom the finding is made.
5.5 Setting Commercial Price. Within 60 days of delivery of the final
DEVELOPMENT PHASE II shipment to SCIOS NOVA in accordance with
Article 5.3, the parties shall endeavor to establish by mutual
agreement (a) the COMMERCIAL PRICE to be charged for BULK SOLUTION
produced under Article 6 by BC for SCIOS NOVA and (b) any revision
to the SPECIFICATIONS FOR BULK SOLUTION and to the Standard
Operating Procedure for the 3,000 liter PROCESS. The agreement of
the parties concerning these matters shall be memorialized in a
written addendum to be attached to and become part of this
Agreement. The agreement on these matters shall thereafter apply
between the parties for the duration of this Agreement or until
revised by mutual agreement.
5.6 Regulatory Documents. If the BULK SOLUTION manufactured in
DEVELOPMENT PHASE II has been found by SCIOS NOVA to meet the
SPECIFICATIONS FOR BULK SOLUTION, yield the minimum quantity of
BNP, and the parties have agreed on the COMMERCIAL PRICE and
SPECIFICATIONS as per Article 5.5, then BC shall also use its best
efforts and provide the necessary resources to prepare and either
deliver to SCIOS NOVA or file directly, as appropriate, the
following materials written in the English language concerning the
manufacture of BULK SOLUTION for use by SCIOS NOVA in seeking
regulatory approval for NATRECOR:
. all site relevant documents necessary to the filing of an
IND amendment by SCIOS NOVA to support the testing of BNP
produced by BC in human clinical trials shall be filed or
delivered to SCIOS NOVA within 30 days of the setting of
the COMMERCIAL PRICE under Article 5.5.
. all site relevant documents necessary to support an
Establishment License Application (ELA) (which may include
BC filing a PLA concurrently with SCIOS NOVA). The parties
shall coordinate their efforts with the other regulatory
filings that will be necessary to determine in which
countries an ELA (or equivalent filing or PLA by BC) shall
be filed in addition to filings with the United States FDA,
and consult with each fully concerning the content and
scope of all filings to be made related to BC's manufacture
of BULK SOLUTION. If the parties determine that BC should
make any filing directly, then a full copy of each such
filing and any subsequent amendments shall be provided to
SCIOS NOVA simultaneous with its filing by BC.
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. all relevant information and documents relating to the
process for the production of BULK SOLUTION that is needed
for SCIOS NOVA to prepare the Chemical Manufacturing
Control section of the Product License Application or New
Drug Application (PLA/NDA), whichever is required to be
filed with, and meeting the standards of the United States
FDA.
5.7 Payment for Regulatory Documents. Upon the complete delivery to
SCIOS NOVA of all documentation described in Article 5.6 necessary
for filings with, and meeting the standards of, the United States
FDA for an ELA, and PLA/NDA for NATRECOR, SCIOS NOVA shall pay
[*****] to BC.
5.8 Timing. The payments specified in Articles 5.3 and 5.6 shall be
made within 30 days of completion of the delivery to SCIOS NOVA of
the specified items by BC and confirmation that the relevant
specifications have been met.
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6. Commercial Phase
6.1 Terms. As provided in Article 5.5, at the conclusion of
DEVELOPMENT PHASE II the parties shall have established and
documented by mutual agreement certain key matters, including, (a)
the Standard Operating Procedure for the 3,000 liter PROCESS, (b)
any revision to the SPECIFICATIONS FOR BULK SOLUTION, (c) any
revision to the BNP SPECIFICATIONS, and (d) the COMMERCIAL PRICE.
6.2 Future Orders. After DEVELOPMENT PHASE II, future orders will be
initiated by written purchase order from SCIOS NOVA and the
manufacture, delivery, acceptance and purchase of all such orders
shall be governed by the provisions of this Article 6, and the
other applicable provisions of this Agreement. Process validation
shall be fully performed by BC with SCIOS NOVA's input prior to
regulatory approval. Assuming successful clinical trials, SCIOS
NOVA's current goal is to file prior to [*****] an NDA application
with the United States FDA for approval to market BNP in the
United States.
6.3 Price. Subject to Article 6.9(e), (which applies after regulatory
approval has been obtained), the price to SCIOS NOVA for BULK
SOLUTION produced by BC after DEVELOPMENT PHASE II shall be the
COMMERCIAL PRICE that the parties established under Article 5.5.
Such price shall be valid until [*****]. In the event the [*****]
as per Article 10.1 shall not have ended at that time, the
COMMERCIAL PRICE shall be revised by mutual agreement of both
parties for the remaining term of this Agreement taking into
consideration BC's cost development, and BC's and SCIOS NOVA's
respective profitability related to BNP. If the parties are unable
to agree on a revision to the COMMERCIAL PRICE, shipments shall
nonetheless continue and initially be paid for at the COMMERCIAL
PRICE, with a retroactive adjustment upon a determination by the
arbitrators under Article 13.3 setting the revised COMMERCIAL
PRICE to apply for the remainder of [*****]. Payment for
deliveries of BNP shall be based on the net quantity of BNP
meeting the BNP SPECIFICATIONS that is contained in a shipment of
BULK SOLUTION as determined initially by BC using methods
consistent with applicable regulatory requirements and guidelines,
and with the methods described in the then current ELA and PLA/NDA
filings related to NATRECOR. The quantity shipped shall be subject
to confirmation by SCIOS NOVA under Article 6.5. If there is a
disagreement about the quantity shipped of [*****], then the
parties shall confer and attempt to resolve the matter. If the
parties are unable to resolve the matter, then it will be
submitted to a qualified independent laboratory mutually agreed by
the parties, and the determination of such laboratory shall
control. Fees and expenses of such laboratory will be paid by the
party against whom the finding is made.
6.4 Forecasts and Coordination. In order to assist BC in planning for
and meeting SCIOS NOVA's requirements for BULK SOLUTION, SCIOS
NOVA agrees to: (a) keep BC informed on a regular basis with
respect to its long-range development plans for NATRECOR, and
notify BC promptly of any developments expected to substantially
impact SCIOS NOVA's future BULK SOLUTION requirements; (b) provide
BC on a quarterly basis, beginning in [*****], with non-binding,
good faith, rolling forecasts of its supply requirements and dates
it anticipates requiring delivery in the ensuing twelve months;
and (c) provide BC with firm orders at least [*****] prior to
scheduled delivery date.
In addition, in order to ensure a high level of communication
between the parties, SCIOS
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NOVA and BC agree, beginning after completion of DEVELOPMENT PHASE
II, to meet not less frequently than bi-annually during the term
of this Agreement to discuss issues relating to the supply of BULK
SOLUTION. Subject to SCIOS NOVA's compliance with the foregoing
lead times, during the term of this Agreement BC is committed and
prepared to supply up to [*****] of SCIOS NOVA's forecasted
purchases of BNP in BULK SOLUTION.
6.5 Acceptance and Payment. Acceptance of delivery and payment for all
orders will be subject to release testing and acceptance by SCIOS
NOVA for conformity with the then current SPECIFICATIONS FOR BULK
SOLUTION. SCIOS NOVA will be invoiced upon shipment of BULK
SOLUTION, with a summary of BC's results of analysis against the
SPECIFICATIONS FOR BULK SOLUTION, and [*****] after receipt of
such items (in order to allow time for release testing of each
batch by SCIOS NOVA). SCIOS NOVA may reject within [*****] after
receipt of any batch of BULK SOLUTION that fails to meet the then
current SPECIFICATIONS FOR BULK SOLUTION. If test results of BC
and SCIOS NOVA conflict with respect to a given shipment, a sample
of such shipment shall be submitted for testing to a qualified
independent laboratory, mutually agreed upon by the parties, and
such test results will control. Fees and expenses of the
laboratory will be paid by the party against whom the findings
were made.
6.6 Risk of Loss. Deliveries of each lot or portion thereof will be
CIP SCIOS NOVA's facility in Mountain View, CA, or if directed by
SCIOS NOVA, its third party fill and finish contractor or
marketing partner.
6.7 Marketing Partner(s). SCIOS NOVA currently intends to market
NATRECOR in territories outside the United States and Canada
through partners. BC agrees to supply BULK SOLUTION to such
partner(s) on terms comparable to those set forth herein if SCIOS
NOVA determines not to supply NATRECOR to such partner(s) via
SCIOS NOVA.
6.8 Access to Plant. SCIOS NOVA shall have reasonable access to BC's
facility at all times that BC is manufacturing BULK SOLUTION for
the purpose of monitoring BC's activities under this Agreement.
During such visits SCIOS NOVA personnel shall be observers and
shall not have the authority to direct the operations of BC's
personnel. BC shall keep SCIOS NOVA reasonably informed concerning
BC's manufacturing schedule and facilitate such access. Following
the agreement of the parties under Article 4.1, changes to the
3,000 liter PROCESS are to be agreed upon in writing by both
parties prior to implementation.
6.9 Understanding on Quantity and Shipment. In the commercial
production phase under this Article 6, the following shall apply
unless otherwise agreed by the parties:
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[*****]
6.10 Comprehensive Agreement. After DEVELOPMENT PHASE II the parties may
elect to enter into the COMPREHENSIVE AGREEMENT as an updated
statement reflecting the terms of this Agreement, including Article
6.1 through 6.9, Article 7, Article 8, and Article 10, and such
additional terms as they may then deem to be reasonable and customary
in such agreements. The COMPREHENSIVE AGREEMENT would consolidate in
one document all of the aspects of the parties' relationship, perhaps
to make it easier for a SCIOS NOVA marketing partner or various
regulatory authorities to more easily understand the commitments of
the parties. However, if the parties elect to conduct DEVELOPMENT
PHASE II and have agreed on the items described in Article 4.1, then
this current Agreement is intended by the parties as their binding
commitment to one another until such time, if ever, as the
COMPREHENSIVE AGREEMENT is finalized, at which time the COMPREHENSIVE
AGREEMENT will supersede this Agreement. Each of BC and SCIOS NOVA
will exercise good faith and reasonable best efforts to conclude the
COMPREHENSIVE AGREEMENT within 90 days after SCIOS NOVA gives notice
that it believes the COMPREHENSIVE AGREEMENT is needed to secure a
marketing partner for NATRECOR or to clarify matters for any
regulatory authority. In specific reliance upon the understandings
indicated above, SCIOS NOVA has engaged BC to conduct DEVELOPMENT
PHASE I which in turn may lead to DEVELOPMENT PHASE II as per Article
5.
7. Regulatory
7.1 Compliance. SCIOS NOVA intends to use BULK SOLUTION produced in
DEVELOPMENT PHASE II to produce its product NATRECOR for large-scale,
pivotal clinical trials in humans. BULK SOLUTION produced in the
commercial phase will be used to produce NATRECOR for sale as a
pharmaceutical agent throughout the world, wherever regulatory
approval has been obtained. Accordingly, BC agrees that beginning with
the three production runs to be performed using the 3,000 liter
PROCESS in DEVELOPMENT PHASE II and for all production runs
thereafter, all BULK SOLUTION will be manufactured, tested, stored,
and shipped by BC in accordance with the then current Good
Manufacturing Practices Regulations as interpreted by the United
States FDA and relevant regulatory agencies in other major countries,
as well as other applicable regulatory requirements of the United
States FDA, which are not otherwise specifically described in the Good
Manufacturing Practices. Once the ELA, BC's PLA (if any), and/or SCIOS
NOVA's PLA/NDA have been filed, then BC agrees that all BULK SOLUTION
shall also be manufactured, tested, stored and shipped in accordance
with the then current version of such regulatory documents. As
manufacturer of BULK SOLUTION, BC will promptly provide all assistance
reasonably requested by SCIOS NOVA to secure and maintain regulatory
approval for NATRECOR, and BC shall make all regulatory filings and
provide to SCIOS NOVA all information concerning the manufacture of
BULK SOLUTION by BC, that may be necessary or advisable in order for
SCIOS NOVA or its licensees to obtain approval to market BNP in any
country, and SCIOS NOVA shall have full access, and the right to
review and copy all such filings, including, but not limited to, the
following:
(i) BC will prepare, maintain and give SCIOS NOVA's regulatory
and quality personnel access to all batch records, and provide
copies to SCIOS NOVA upon reasonable request;
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
11
(ii) BC will file and keep current (including filing of all
annual updates) the portions of the ELA or DMF relating to the
manufacturing of BULK SOLUTION being performed by BC (the filing
date will be agreed upon by BC and SCIOS NOVA based on the
schedule for the PLA/NDA filing);
(iii) BC will cooperate with SCIOS NOVA regarding product
marketing application requirements to demonstrate the consistency
of the characteristics of BULK SOLUTION, from lot to lot, and of
the purity profile of the BULK SOLUTION from lot to lot. BC will
also cooperate with SCIOS NOVA and perform the activities
necessary to assure that all validation requirements are met on a
timely basis;
(iv) SCIOS NOVA will be permitted to inspect BC's facility, at
reasonable times and at least annually, and, upon advance notice,
to be present during manufacture and to be present during
regulatory inspections;
(v) BC will notify SCIOS NOVA of all regulatory inspections and
provide SCIOS NOVA with copies of all significant correspondence
to or from the United States FDA (e.g., Section 483 letters,
warning letters and BC's responses) and with any comparable
regulatory agency in another country; and
(vi) BC will notify SCIOS NOVA in writing at least 30 days in
advance of any proposed modification to those portions of its
facility or organization that are involved in the manufacture of
BULK SOLUTION, consider all concerns that SCIOS NOVA may express
in writing about the impact of such changes on regulatory
compliance and production timing, minimize the negative impact of
such changes on BC's methods and schedule for production of BULK
SOLUTION (including obtaining advance regulatory approval of the
change), and promptly prepare and file any such amendments to the
regulatory filings related to the BULK SOLUTION which need to be
amended.
Compensation for all such services is included in the price to be
charged by BC under Article 6.3.
8. Back-up Supplier: Licenses
8.1 Alternate Supplier. In order that SCIOS NOVA is not dependent on a
single supplier of BULK SOLUTION and recognizing that regulatory
requirements dictate that all BULK SOLUTION utilized by SCIOS NOVA
should be manufactured by the same process, BC agrees that beginning
in 1998 and pursuant to Article 8.2, SCIOS NOVA may itself use, or
have another supplier use, the 150 liter PROCESS or the 3,000 liter
PROCESS to produce annually the quantity of BULK SOLUTION that is
necessary to yield [*****] of BNP. In addition to the foregoing, in
the event BC fails for any reason, including without limitation, a
force majeure event described in Article 14.6, to deliver BULK
SOLUTION to SCIOS NOVA for a continuous period of 120 days, then SCIOS
NOVA shall have the right to make or have made all of its requirements
of BULK SOLUTION for the duration of BC's inability to supply.
8.2 Access to Process; Royalties. To permit SCIOS NOVA to manufacture BULK
SOLUTION itself or arrange for such an alternate supplier, BC does
hereby grant to SCIOS NOVA a license to use and to allow such
alternate supplier to use the 3,000 liter PROCESS and the 150 liter
PROCESS solely to make or have made BULK SOLUTION. Such license shall
be
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
12
royalty-free when it is exercised under Article 8.1 due to BC's
inability to supply. When exercised under Article 8.2 or when
exercised under Article 8.1 so that SCIOS NOVA may establish an
alternate supplier even though BC is able to supply SCIOS NOVA's
needs, such license shall bear a royalty of [*****] of SCIOS NOVA's
net sales of NATRECOR that has been produced by using BC KNOWHOW or BC
PATENT RIGHTS. The license shall be irrevocable except for a
termination under Article 10.5 based on SCIOS NOVA's material breach
or SCIOS NOVA becoming insolvent or going into liquidation where such
insolvency or liquidation is not withdrawn within 90 days. To
implement the foregoing license, promptly after setting the COMMERCIAL
PRICE as per Article 5.5, BC will take all steps necessary to disclose
all details concerning the 3,000 liter PROCESS and 150 liter PROCESS
to SCIOS NOVA in order to enable SCIOS NOVA itself to manufacture BULK
SOLUTION pursuant to this provision. BC shall not be required to make
available members of its staff for face-to-face meetings with SCIOS
NOVA for more than 100 person hours in the aggregate. SCIOS NOVA shall
reimburse BC for reasonable travel, living, other out-of-pocket
expenses, and for the work at the rates incurred by BC in providing
assistance to SCIOS NOVA under this paragraph.
9. Investment in Specific Equipment
9.1 Investment. In order to manufacture BULK SOLUTION in DEVELOPMENT PHASE
II, BC will invest in planning, purchasing and installing of specific
equipment, such activities and equipment to be listed in Annex 6 to
this Agreement as investment. Any such equipment shall be ordered by
BC and any such construction activity shall be started not later than
[*****].
BC's investment under this Article, including BC's internal and
external planning cost, specific equipment and installation thereof
shall not exceed [*****] in the aggregate without SCIOS NOVA's prior
written approval.
Subject to Article 9.3, full and unencumbered title to all such
investment by BC under Article 9.1 shall at all times be with BC.
9.2 Identification of Cost and Payment. BC agrees to notify SCIOS NOVA in
writing of the actual cost of BC's investment under Article 9.1 not
later than [*****]. BC's notification shall be accompanied by BC's
invoice and by copies of the respective third parties' invoices for
any work and delivery performed and BC's internal activity-report and
charges according to BC's accounting guidelines. [*****]
9.3 Effects of Termination on Investment. The termination of this
Agreement shall not affect SCIOS NOVA's obligation to reimburse BC's
investment as per Article 9.1 and 9.2.
Upon a termination before the first purchase of BULK SOLUTION in the
COMMERCIAL PHASE as per Article 6:
[*****]
. BC shall credit SCIOS NOVA with the amount of [*****], provided
such amount had been reimbursed by SCIOS NOVA for the [*****] as
detailed in item 1 of Annex 6 as per Article 9.2.
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
13
10. Term and Discontinuance
10.1 Term. Unless earlier terminated pursuant to the provisions of this
Article 10, this Agreement shall remain in full force and [*****]
under Article 6 or until this Agreement is superseded by the
COMPREHENSIVE AGREEMENT.
10.2 Termination after DEVELOPMENT PHASE I. Pursuant to Article 4.1, the
parties shall determine whether or not to proceed to DEVELOPMENT PHASE
II after reviewing the results of DEVELOPMENT PHASE I. If SCIOS NOVA
elects not to continue to DEVELOPMENT PHASE II and to terminate the
Agreement even though BC has proposed a REVISED TARGET PRICE that is
not higher than the TARGET PRICE and BC has otherwise succeeded in the
goals of DEVELOPMENT PHASE I, then SCIOS NOVA shall pay to BC (in
addition to any payments due under Article 3) a cancellation fee equal
to [*****] of the charge under Article 3.3 for the DEVELOPMENT PHASE I
work. In all other cases (i.e., if SCIOS NOVA terminates after BC has
proposed a REVISED TARGET PRICE under Article 5.2 that is higher than
the TARGET PRICE or after the goals of DEVELOPMENT PHASE I are not met
or if BC elects to terminate under any circumstances), then no
additional payment shall be due from SCIOS NOVA to BC.
10.3 Termination after DEVELOPMENT PHASE II. If the COMMERCIAL PRICE as
proposed by BC under Article 5.2 is higher than the REVISED TARGET
PRICE and the parties are unable to agree under Article 5.5 on a
COMMERCIAL PRICE and on the other terms specified in Article 5.5, then
either party may terminate this Agreement without additional payment.
10.4 Termination for NATRECOR Results. SCIOS NOVA may also terminate this
Agreement any time during or after DEVELOPMENT PHASE II if it believes
the clinical results for NATRECOR warrant such termination so that
SCIOS NOVA finally decides not to market directly or indirectly
NATRECOR. In the event SCIOS NOVA so terminates this Agreement after
giving notice to BC to commence DEVELOPMENT PHASE II, then SCIOS NOVA
shall pay to BC (in addition to any payments due under Articles 3) a
cancellation fee equal to [*****] of the cost that SCIOS NOVA
previously paid to BC for the DEVELOPMENT PHASE I work.
10.5 Termination for Breach. Either party may terminate this Agreement upon
a material breach by the other party which goes uncured for more than
30 days after receipt of written notice identifying the alleged
breach. [*****]
10.6 Termination for Third Party Patent. If a party receives a claim that a
third party patent on BNP would be infringed by BC's manufacture of
BNP for SCIOS NOVA under this Agreement, the parties shall attempt to
agree on a strategy to respond to such claim. If the parties are
unable to agree within 90 days, then notwithstanding the obligations
of the parties in Article 11.4, either party may terminate this
Agreement effective upon 60 days notice to the other party.
In the event such termination shall be based upon a claim of a third
party, alleging infringement based on the structure of BNP or the fact
that BC is manufacturing BNP, then SCIOS NOVA shall pay to BC a
cancellation fee equal to [*****] of the cost that SCIOS NOVA
previously paid to BC for the DEVELOPMENT PHASE I work.
In the event of a termination under this Article 10.6, the license to
SCIOS NOVA under
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
14
Article 8 shall be deemed to have been granted under Article 8.2 and
bear the 1% royalty set forth in Article 8.2.
10.7 Notice. Each party shall give notice to the other of any
discontinuance or breach by registered air mail letter or air courier.
10.8 Survival of Certain Obligations. Termination shall not affect any
right or obligation previously accrued. In addition, Article 4.3,
Article 7, Article 8, Article 9, Article 11, Article 12, Article 13
and Article 14 shall survive and continue to have effect following any
termination of this Agreement.
11. Intellectual Property
11.1 General. Recognizing: (a) that SCIOS NOVA has developed SCIOS NOVA
KNOWHOW and holds the SCIOS NOVA PATENT RIGHTS; (b) that SCIOS NOVA
will contribute to BC to develop the 150 liter PROCESS and the 3,000
liter PROCESS; and (c) that in the course of developing the 150 liter
PROCESS and 3,000 liter PROCESS BC may develop the BC KNOWHOW and the
BC PATENT RIGHTS, the parties agree as follows concerning intellectual
property matters.
11.2 License to BC. SCIOS NOVA hereby grants to BC a non-exclusive,
non-transferable license to use SCIOS NOVA KNOWHOW and SCIOS NOVA
PATENT RIGHTS solely for the purpose of manufacturing BNP for SCIOS
NOVA as provided in this Agreement. The license granted under this
Article 11.2 should automatically terminate upon the expiration or
termination of this Agreement.
11.3 BC Ownership, License to Scios Nova. BC shall own the BC KNOWHOW and
BC PATENT RIGHTS. Pursuant to Article 4 and Article 8 BC has granted
to SCIOS NOVA certain licenses to use or to authorize others to use
any of the of the BC KNOWHOW or BC PATENT RIGHTS solely for the
purpose of manufacturing BNP pursuant to SCIOS NOVA's exercise of its
rights in accordance with such articles.
11.4 Third Party Claims. [*****]
11.5 Non-Use. Recognizing that the transfer by SCIOS NOVA of SCIOS NOVA
KNOWHOW constitutes a disclosure of valuable proprietary information
of SCIOS NOVA and also that it may be difficult to separate SCIOS NOVA
KNOWHOW from BC KNOWHOW, BC agrees that during the term of this
Agreement BC shall not undertake a project involving the manufacture
of a BNP COMPOUND without first obtaining the written approval of
SCIOS NOVA.
11.6 Allowed Use. SCIOS NOVA acknowledges and agrees that BC shall be free
to:
. Manufacture any compound other than a BNP COMPOUND at any time
using the BC KNOWHOW and/or BC PATENT RIGHTS, if such manufacture
can be done without infringing or using any of the SCIOS NOVA
PATENT RIGHTS or SCIOS NOVA KNOWHOW falling within the scope of
Article 12;
. Manufacture a BNP COMPOUND for itself or third parties following
any termination of this Agreement to the extent such manufacture
will not infringe SCIOS NOVA PATENT RIGHTS or SCIOS NOVA KNOWHOW
being covered by Article 12.
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
15
The foregoing shall not be deemed to grant BC any right in the continued
use of SCIOS NOVA KNOWHOW or SCIOS NOVA PATENT RIGHTS after the term of
this Agreement.
12. Secrecy and Non-Use
12.1 General. Each party shall keep strictly secret and use solely for the
purposes described or authorized herein any CONFIDENTIAL INFORMATION
it may receive from the other party through the activities described
in this Agreement. Except as may be required by law or for SCIOS NOVA
to secure a licensee for BNP, neither party may discuss the terms of
this Agreement without the prior approval of the other party.
12.2 Exclusions. Such secrecy and non-use obligations shall not apply to
any facts which
. are or will be part of the public domain without breach of these
secrecy provisions;
. is already in the receiving parties possession at the time of
receipt; or
. will be made available to a party through a third party who has not
breached an obligation of confidentiality in so doing.
12.3 Non-exclusion. Information which is specific shall not be excluded
from a secrecy and non-use obligation when it is in general form in
the public domain or being made available to the receiving party.
12.4 Term. These secrecy and non-use obligation shall be enforced for the
term of this Agreement and 10 years thereafter.
12.5 Outside Patent Counsel. BC shall be free to disclose the SCIOS NOVA
KNOWHOW solely to BC's patent advisors, including those in BC's
affiliated company [*****], provided such advisors are subject to the
same obligations of secrecy and non-use as set out in this Article 12
and such disclosure is made and used solely for the purpose of BC
obtaining patent advice to implement the purposes of the Agreement.
13. Interpretation and Jurisdiction
13.1 No Agency. This Agreement shall not be interpreted as a contract of
association or agency and, except as specifically set forth herein,
the parties shall be under no obligation to enter into any further
agreement or to make available to each other any CONFIDENTIAL
INFORMATION.
13.2 Governing Law. This Agreement shall be governed by the laws of
Switzerland.
13.3 Dispute Resolution. Any dispute arising out of this Agreement shall be
finally settled by arbitration according to the Rules of Conciliation
and Arbitration of the International Chamber of Commerce headquartered
in Paris, France. The arbitration shall be effected by 3 arbitrators
to be appointed according to said rules and the arbitration shall be
held in Geneva, Switzerland in the English language.
14. Miscellaneous
14.1 Assignment. Neither party may assign its obligations under this
Agreement without the written consent of the other party, except that
(a) either party shall assign its rights and obligations to a third
party which merges with or otherwise acquires substantially all of its
assets; and (b) SCIOS NOVA may assign its rights and obligations to a
third party which
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
16
acquires rights to distribute NATRECOR.
14.2 Entire Agreement. This Agreement sets forth the entire Agreement of
the parties, relating to the subject matter hereof, and supersedes all
prior understandings.
14.3 Notices. Any notices under this Agreement shall be in writing and may
be transmitted personally, by telefax, mail or courier. Notices shall
be deemed to have been given upon receipt. Until changed by further
notice from one party to another, the following address shall be used
for Notices under this Agreement:
If to SCIOS NOVA:
2450 Bayshore Parkway
Scios Nova Inc.
Mountain View, CA 94043
Telefax: 01-415-962-5816
Attention: General Counsel
If to BC:
Biochemie Gesellschaft m.b.H.
A-6250 Kundl/Austria
Telefax: 0043-5338-8828
Attention: General Counsel
14.4 Waiver. Should either party fail to enforce any provision of this
Agreement or fail to exercise or waive any right with respect thereto,
such failure shall not be deemed a waiver or continuing waiver of its
rights to enforce such provision or any other provisional right.
14.5 Further Assurances. From time to time, either SCIOS NOVA or BC shall,
at the request of the other party, take or cause to be taken, such
other actions as the other party may reasonably deem necessary or
desirable in order to carry out the transactions contemplated by this
Agreement.
14.6 Force Majeure. No failure or omission by a party hereto in the
performance of any obligation of this Agreement shall be deemed a
breach of this Agreement nor creating a liability, if the same shall
arise from any cause or any causes beyond the control of the party,
including, but not limited to, the following, which, for the purposes
of this Agreement, shall be regarded as beyond the control of the
party in question: acts of God; acts or omissions of any government;
any rules, regulations or orders issued by governmental authority or
by any officer, department, agency of instrumentality thereof; fire,
storm; flood; earthquake; accident; war; rebellion; insurrection;
riot; invasion; strikes and lockout. Performance shall be excused only
for the duration of such an event and upon cessation of the cause of
non-performance the party whose performance has been delayed shall
promptly resume performance and use all reasonable efforts to make up
time lost in the delay. If the delay in performance shall extend for
more than [*****] days, then the party whose performance is not being
delayed may terminate this Agreement by notice to the other or SCIOS
NOVA may exercise its rights under Article 8.1.
14.7 Currency. The parties have selected the German Deutsche Mark
(abbreviated DM) as the currency for all payments under this Agreement
and all payment amounts expressed herein are intended to be references
to the Deutsche Mark.
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
17
IN WITNESS WHEREOF, the parties have executed this Agreement as of the
day and year first above written.
SCIOS NOVA INC., a Delaware BIOCHEMIE
Corporation Gesellschart m.b.H.
By: ____________________________ By: ______________________________
Its: ____________________________ Its: _____________________________
List of Annexes:
Annex 1 BNP SPECIFICATIONS
Annex 2 SPECIFICATIONS FOR BULK SOLUTION
Annex 3 Details 10 liter PROCESS per Article 1.19
Annex 4 Samples and tests to be provided from DEVELOPMENT PHASE I and
Development Phase II
Annex 5 Description of BC's DEVELOPMENT PHASE I effort and charges
Annex 6 Investment in Equipment
Annex 7 Chromatography Filling Materials
18
Annex 1
SPECIFICATIONS FOR HUMAN BRAIN NATRIURETIC
PEPTIDE (1-32)
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
19
Annex 2
SPECIFICATIONS FOR BULK SOLUTION
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
20
Annex 3
SCIOS NOVA DELIVERABLES (Details of 10 liter PROCESS as per Article 1.19)
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
21
Annex 4
SAMPLES AND TESTS TO BE PROVIDED FROM DEVELOPMENT
PHASE I AND DEVELOPMENT PHASE II
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
22
Annex 5
DESCRIPTION OF BC'S DEVELOPMENT PHASE I EFFORT AND CHARGES
All rates are given in DM/hour
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
23
Annex 6
INVESTMENT IN EQUIPMENT
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
24
Annex 7
CHROMATOGRAPHY FILLING MATERIALS
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
25
FIRST ADDENDUM
to the BNP Agreement (1995)
entered into as of November 17, 1995
entered into as of April 30, 1996 by and between
SCIOS INC.
2450 Bayshore Parkway
Mountain View, CA 94043/USA
and
BIOCHEMIE Gesellschaft mbH
A-6250 Kundl/Austria
WHEREAS, BIOCHEMIE Gesellschaft mbH (hereinafter "BC") and Scios Nova Inc.
entered into the BNP AGREEMENT (1995) as of November 17, 1995 (the "Agreement").
WHEREAS, Scios Nova Inc. subsequently changed its name to Scios Inc.
(hereinafter "Scios").
WHEREAS, BC and Scios wish to amend the Agreement to document their agreements
on the following matters: (1) their agreement on four items as specified in
article 4.1 of the Agreement; (2) their agreement that Development Phase H shall
be conducted by BC; and (3) their agreement according to article 2.5 of the
Agreement that BC shall perform lyophilization of the BULK SOLUTION and ship BNP
in solid form to Scios.
The parties hereto agree as follows:
1. Definitions
Capitalized terms used herein shall have the meaning given to them in the
Agreement unless otherwise defined herein. All references To "Scios Nova" in the
Agreement shall be deemed to be references to Scios.
2. Analysis and discussion as per article 4.1
a. BNP SPECIFICATIONS
The BNP SPECIFICATIONS remain unchanged and shall be as set
forth in Annex 1 to the Agreement.
b. SPECIFICATIONS FOR BULK SOLUTION
The SPECIFICATIONS FOR BULK SOLUTION remain unchanged and
shall be as set forth in Annex 2 to the Agreement. Based on
the changes below to incorporate lyophilization into the
manufacturing process to be performed by BC in DEVELOPMENT
PHASE II and thereafter, the SPECIFICATIONS FOR BULK SOLUTION
now have application primarily to the DEVELOPMENT PHASE I
work.
c. SOP FOR 3000 liter PROCESS
The standard operating procedure to be used for the 3000 liter
PROCESS in DEVELOPMENT PHASE II and thereafter has been agreed
on in a separate document which will be signed by both
parties.
d. REVISED TARGET PRICE
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
26
3. Agreement on DEVELOPMENT PHASE II (3000 liter PROCESS)
The parties agree that DEVELOPMENT PHASE II shall be conducted by BC
according to the terms of article 5 of the Agreement.
4. Agreement on lyophilization
a. New Definitions
Article 1 is hereby amended by adding the following definitions to the
Agreement:
"1.22 BULK LYOPHILIZED BNP means lyophilized BNP that meets the
SPECIFICATIONS FOR BULK LYOPHILIZED BNP."
"1.23 SPECIFICATIONS FOR BULK LYOPHILIZED BNP shall mean the specifications
set forth in Annex 8 which shall be used beginning in Development Phase II.
Annex 8 may be updated by mutual agreement of the parties at the end of
DEVELOPMENT PHASE II. Such a revision shall take into account the then
current requirements of the characteristics for proteins manufactured by
recombinant means.
b. Lyophilization
The parties agree that BC shall perform during DEVELOPMENT PHASE II and the
commercial phase as per article 6 of the Agreement the lyophilization of
the BULK SOLUTION to obtain BULK LYOPHILIZED BNP that meets the
SPECIFICATIONS FOR BULK LYOPHILIZED BNP. The 3000 liter PROCESS shall
include the process for lyophilization to be developed by BC.
c. Amendment of article 5.3
To allow time for the lyophilization work to be performed by BC, Article
5.3 of the Agreement is hereby amended to read as follows:
"5.3 Assessment of DEVELOPMENT PHASE II and Payment. SCIOS shall promptly
assay the BULK LYOPHILIZED BNP produced in DEVELOPMENT PHASE II for
conformity with the SPECIFICATIONS FOR BULK LYOPHILIZED BNP and
provide the results of its analysis to BC. If three batch runs produce
BULK LYOPHILIZED BNP that satisfies the SPECIFICATIONS FOR BULK
LYOPHILIZED BNP and have a yield of at least 125 grams BNP each, then
SCIOS shall make one of the following payments to BC based on when
SCIOS received the final shipment of the three batches from
DEVELOPMENT PHASE II:
[*****]
d. Amendment of article 5.7 of the Agreement
Article 5.7 of the Agreement is hereby amended to read in its' entirety as
follows:
"5.7 Payment for Regulatory Documents. Upon the complete delivery to SCIOS
of all documentation described in Article 5.6 necessary for filings
with, and meeting the standards of the United States FDA for an ELA,
and PLA/NDA for NATRECOR, SCIOS shall pay to BC, [*****]"
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
27
e. References to BULK SOLUTION
The following references to BULK SOLUTION in the Agreement shall hereafter
be deemed to be references to BULK LYOPHILIZED BNP: Whereas clauses 3, 5, &
6, articles 1.2, 1.3, 1.8, 1.15, 1.16, 1.21, 5.2, 5.5, 5.6, 6.3, 6.4, 6.5,
6.7, 6.8, 6.9 (all paragraphs), 7.1, 8.1, 8.2, 9.1, and 9.3.
f. References to SPECIFICATIONS FOR BULK LYOPHILIZED BNP
The following references to SPECIFICATIONS FOR BULK SOLUTION in the
Agreement shall hereafter be deemed to be references to SPECIFICATIONS FOR
BULK LYOPHILIZED BNP: articles 5.4, 5.5, 5.6, 6.1 and 6.5.
28
IN WITNESS WHEREOF, the parties have executed this Addendum, which shall
form an integral part of the Agreement and shall come into force as of
April 30, 1996.
SCIOS INC., a Delaware BIOCHEMIE Gesellschaft m.b.H.
corporation
By:_____________________________ By:_____________________________________
Name: Armin H. Ramel Name: Dr.W.Ki11iches Dr.F.Nachtmann
---------------------------------
Its: Vice President of Its: General Counsel Director
Product Development New Business
Development
Attachment: Annex 8 - SPECIFICATIONS FOR BULK LYOPHILIZED BNP
29
Annex 8
SPECIFICTIONS FOR BULK LYOPHILIZED BNP
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
30
SECOND ADDENDUM
to the BNP Agreement (1995)
entered into as of November 17, 1995 and
amended as of April 30, 1996
entered into as of September 30, 1997 by and between
Scios Inc.
2450 Bayshore Parkway
Mountain View, CA 94043/USA
(hereinafter referred to as "SCIOS")
and
BIOCHEMIE GmbH
Biochemiestra(beta)e 10, A-6250 Kundl
(hereinafter referred to as "BC")
WHEREAS, BC and SCIOS entered into the BNP AGREEMENT (1995) (hereinafter
referred to as "AGREEMENT") as of November 17, 1995 and entered into a
first addendum to the AGREEMENT as of April 30, 1996 (hereinafter
referred to as "FIRST ADDENDUM");
WHEREAS, BC and SCIOS wish to amend the AGREEMENT and FIRST ADDENDUM, to
document their agreements on the following matters:
A. COMMERCIAL PRICE of BNP in BULK SOLUTION and in BULK LYOPHILIZED BNP
B. Payment of additional specific equipment
C. Updated specifications
the parties hereto agree as follows:
1. Definitions
Capitalized terms used herein shall have the meaning given to them
in the AGREEMENT or FIRST ADDENDUM unless otherwise defined herein.
2. Setting commercial price as per article 5.5
2.1 BULK LYOPHILIZED BNP
2.1.1. The COMMERCIAL PRICE per gram of BNP delivered to SCIOS as BNP BULK
LYOPHILIZED shall be [*****],--.
Even though BC has manufactured BULK LYOPHILIZED BNP, the parties have
agreed that, subject to SCIOS obtaining all necessary approvals, future
deliveries will be as BULK SOLUTION.
2.2 BULK SOLUTION
2.2.1 [*****]
2.2.2 [*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
31
2.2.3 [*****]
2.3 The COMMERCIAL PRICE shall be understood CIP SCIOS' facility in
Mountain View, California, USA, payment within 45 days after receipt
of delivery.
2.4 [*****]
3. Additional Specific equipment
3.1 SCIOS requests BC to purchase and install the specific equipment at a
price not to exceed [*****],-- and invoice the total cost related to
such investment as listed in Annex 9 to SCIOS by [*****]. BC's invoice
shall be paid by SCIOS within 30 days after date of invoice but not
earlier than completion of installation.
3.2 Full and unencumbered title to such investment by BC shall at all
times be with BC and such investment shall not be reimbursed by BC to
SCIOS for any reason whatsoever.
4. SPECIFICATIONS for BULK SOLUTION and BULK LYOPHILIZED BNP
4.1 The specifications for BULK SOLUTION and for BULK LYOPHILIZED BNP
shall be amended as per the annex to this SECOND ADDENDUM.
5. Continuation of validity
5.1 The terms of the AGREEMENT, the FIRST ADDENDUM and the SECOND
ADDENDUM shall apply to the purchase of BULK SOLUTION as well as
to BULK LYOPHILIZED BNP.
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
32
IN WITNESS WHEREOF, the parties have executed this Addendum, which shall
form an integral part of the AGREEMENT and shall come into force as of
September 30, 1997.
Scios Inc. BIOCHEMIE GmbH
By: __________________________ By: ____________________________
Name: John H. Newman Name: Dr. W. Killiches Dr. F. Nachtmann
Function: Vice President of Function: General Head Bioproducts
Legal Affairs Counsel
Annex 2: Specifications for BULK SOLUTION
Annex 8: Specifications for BULK LYOPHILIZED BNP
Annex 9: Specific equipment
33
Annex 2
to the BNP Agreement between SCIOS Inc. and BIOCHEMIE GmbH
entered into as of November 17, 1995 as amended by the
SECOND ADDENDUM of September 30, 1997
Specifications for BULK SOLUTION
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
34
Annex 8
to the BNP Agreement between SCIOS Inc. and BIOCHEMIE GmbH
entered into as of November 17, 1995 as amended by the
SECOND ADDENDUM of September 30, 1997
Specifications for BULK LYOPHILIZED BNP
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
35
Annex 9
to the BNP Agreement between SCIOS Inc. and BIOCHEMIE GmbH
entered into as of November 17, 1995 as amended by the
SECOND ADDENDUM of September 30, 1997
Specific Equipment
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
36
THIRD ADDENDUM
to the BNP Agreement (1995)
entered into as of November 17, 1995 and
amended as of April 30, 1996 and as of September 30, 1997
entered into as of September 1, 1998 by and between
Scios Inc.
2450 Bayshore Parkway
Mountain View, CA 94043/USA
(hereinafter referred to as "SCIOS")
and
BIOCHEMIE GmbH
Biochemiestra(beta)e 10, A6250 Kundl/Austria
(hereinafter referred to as "BC")
WHEREAS, BC and SCIOS entered into the BNP AGREEMENT (1995) (hereinafter
referred to as "AGREEMENT") as of November 17, 1995 and entered into a FIRST
ADDENDUM to the AGREEMENT as of April 30, 1996 (hereinafter referred to as
"FIRST ADDENDUM") and SECOND ADDENDUM to the AGREEMENT as of September 30, 1997
(hereinafter referred to as "SECOND ADDENDUM");
WHEREAS, BC and SCIOS wish to amend the AGREEMENT and prior ADDENDUMS to
document their agreements on the following matters:
(a) Revision of COMMERCIAL PRICE of BNP in BULK LYOPHILIZED BNP;
(b) Updated specifications; and
(c) Prolongation of the AGREEMENT;
the parties hereto agree as follows:
1. Definitions
Capitalized terms used herein shall have the meaning given to them in the
AGREEMENT or prior ADDENDUMS unless otherwise defined herein.
2. Revision of the COMMERCIAL PRICE for BULK LYOPHILIZED BNP
The COMMERCIAL PRICE in DM per gram of BNP delivered to SCIOS as BNP
BULK LYOPHILIZED shall be as follows:
[*****]
Even though BC has manufactured BULK LYOPHILIZED BNP, the parties have
agreed that subject to SCIOS obtaining all necessary approvals, future
deliveries will be as BULK SOLUTION once the production process for
BULK SOLUTION has been validated. In order to accomplish the
changeover to BULK SOLUTION, the parties anticipate that certain
additional development work will be performed on a contract or project
basis as to which the parties shall separately specify the scope and
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
37
cost for each project in a separate letter agreement to be agreed
regarding work that does not produce validated BNP that may be used
for commercial purposes.
3. SPECIFICATIONS for BULK SOLUTION and BULK LYOPHILIZED BNP
3.1 The specifications for BULK SOLUTION shall be amended to now read as
per Annex 2 to this THIRD ADDENDUM and the specifications for BULK
LYOPHILIZED BNP shall be amended to read as per Annex 8 to this THIRD
ADDENDUM.
4. PROLONGATION of the AGREEMENT
4.1 Article 10.1 of the AGREEMENT shall read as follows:
10.1 Term. Unless earlier terminated pursuant to the provisions
of this Article 10, this AGREEMENT shall remain in full force and
effect for [*****] by BC to SCIOS under Article 6 or until this
AGREEMENT is superseded by the COMPREHENSIVE AGREEMENT.
4.2 The references made in the AGREEMENT and relating to the [*****] term shall
be adapted to relate to an [*****] term. The parties intend that this
modification of the term of the AGREEMENT shall also [*****] the period of
time set forth in Sections 6.9(c) and (e) during which SCIOS shall purchase
from BC at least 25 kg of BNP in BULK SOLUTION of BULK LYOPHILIZED form
from [*****].
5. Continuation of validity
5.1 The terms of the AGREEMENT, the FIRST ADDENDUM and SECOND ADDENDUM, and
this THIRD ADDENDUM shall apply to the purchase of BULK SOLUTION as well as
to BULK LYOPHILIZED BNP.
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
38
IN WITNESS WHEREOF, the parties have executed this Addendum, which shall form an
integral part of the AGREEMENT and shall come into force as of July 1, 1998.
Scios Inc. BIOCHEMIE GmbH
By: ___________________________ By: ___________________________________
Name: Elliott Grossbard, M.D. Name: Dr. F. Nachtmann
Function: Senior Vice President, Function: Head Bioproducts
Development
By: ___________________________________
Name: Dr. E. Dolejei
Function: Legal Counsel
Annex 2: Specifications for BULK SOLUTION
Annex 8: Specifications for BULK LYOPHILIZED BNP
39
Annex 2
to the BNP Agreement between SCIOS Inc. and BIOCHEMIE GmbH
entered into as of November 17, 1995 as amended by the
THIRD ADDENDUM of September 1, 1998
Specifications for BULK SOLUTION
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
40
Annex 8
to the BNP Agreement between SCIOS Inc. and BIOCHEMIE GmbH
entered into as of November 17, 1995 as amended by the
THIRD ADDENDUM of September 1, 1998
Specifications for BULK LYOPHILIZED BNP
[*****]
***** Confidential portions of the material have been omitted and filed
separately with the Securities and Exchange Commission
41