Document:

Exhibit 10.1

 

CERTAIN INFORMATION IN THIS
EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY WITH THE COMMISSION. CONFIDENTIAL
TREATMENT HAS BEEN REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.

 

SYNTEX (U.S.A.) INC. - AMERICAN HOME PRODUCTS CORPORATION

SUBLICENSE AND SUPPLY AGREEMENT

DATED SEPTEMBER 1, 1993 RE: NICARDIPINE IV

 

TABLE OF CONTENTS

 

	
  1.

  	
   

  	
  DEFINITIONS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  2.

  	
   

  	
  GRANT OF LICENSES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  3.

  	
   

  	
  SUPPLY OF BULK PRODUCT

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  4.

  	
   

  	
  DEVELOPMENT WORK AND REGULATORY APPROVALS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  5.

  	
   

  	
  TRADEMARKS AND QUALITY CONTROL

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  6.

  	
   

  	
  PROMOTION

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  7.

  	
   

  	
  OPERATING PROCEDURES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  8.

  	
   

  	
  TECHNOLOGY AND PATENTS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  9.

  	
   

  	
  INDEMNIFICATION

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  10.

  	
   

  	
  TERM AND TERMINATION

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  11.

  	
   

  	
  CONFIDENTIALITY, NON USE AND PUBLIC
  STATEMENTS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  12.

  	
   

  	
  ACCOUNTING PROCEDURES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  13.

  	
   

  	
  GOVERNING
  LAW

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  14.

  	
   

  	
  ASSIGNMENT AND DELEGATION

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  15.

  	
   

  	
  FORCE
  MAJEURE

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  16.

  	
   

  	
  SEVERABILITY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  17.

  	
   

  	
  CAPTIONS

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  18.

  	
   

  	
  NOTICES

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  19.

  	
   

  	
  SURVIVAL

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  20.

  	
   

  	
  INDEPENDENT PARTY

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  21.

  	
   

  	
  WAIVER

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  22.

  	
   

  	
  ENTIRE AGREEMENT

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Schedule
  A

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Schedule
  B

  	
   

  

 

 

SUBLICENSE AND SUPPLY AGREEMENT

 

This AGREEMENT is made to be effective as of September 1, 1993 (the “effective
date”), by and between American Home Products Corporation (“AMPC”), a
corporation organized and existing under the laws of the State of Delaware,
acting by the through its Wyeth-Ayerst Laboratories Division (“Wyeth-Ayerst”),
having a mailing address at P.O. Box 8299, Philadelphia, Pennsylvania 19101,
and syntex (U.S.A.) Inc., a corporation organized and existing under the laws
of the State of Delaware, having a business address at 3401 Hillview Avenue,
Palo Alto, California 94304 (“Syntex”).

 

RECITALS

 

WHEREAS, Syntex, a wholly-owned subsidiary of Syntex Corporation, is
the assignee of the rights of Syntex Corporation granted by Yamanouchi
International Limited (“Yamanouchi”) pursuant to an Agreement dated December,
16, 1977 (the “License Agreement”) to make, have made, use and sell the
compound nicardipine hydrochloride (USAN), which has the full chemical name 2,
6-dimethyl-4-(3-nitrophenyl)-1, 4-dinydro-pyridine-3, 5-dicarboxylic acid 3-[2-(N-benzyl-N-methylamino]
ethyl ester 5-methyl ester hydrochloride, which is also known as YC-93 and
RS-69216-003 (the “Agreement Compound”), in certain countries;

 

WHEREAS, Syntex and American Hospital Supply Corporation (“AHSC”),
acting through its American Critical Care Division (“ACC”), entered into an
Agreement (the “Agreement”) providing for the marketing by ACC of the
intravenous form of the Agreement

 

 

Compound in
the United States;

 

WHEREAS, E.I. du Pont de Nemours & Company (“du Pont”), a Delaware
corporation, acquired certain assets relating to the critical care business of
AHSC, and received an assignment, with the consent of Syntex, whereby du Pont
succeeded to all of the rights and obligations of AHSC under the Agreement;

 

WHEREAS, Syntex and du Pont entered into an Amendment to the Agreement
to substitute “du Pont” for “ACC” throughout the Agreement and to include
Canada as part of the Territory covered by the Agreement;

 

WHEREAS, du Pont and Calgon Corporation, a Delaware corporation and a
wholly-owned subsidiary of Merck & Co., a New Jersey corporation, entered
into a partnership agreement establishing The Du Pont Merck Pharmaceutical
Company (“Du Pont Merck”), a Delaware partnership;

 

WHEREAS, du Pont assigned, with the consent of Syntex, its rights under
the Agreement (as amended) to Du Pont Merck;

 

WHEREAS, Du Pont Merck desired to be relieved of its obligation to
market the Covered Product (as defined below) in the Territory and, in
furtherance thereof, has assigned its rights under the Agreement (as amended)
to Syntex in contemplation, and with the knowledge, that such rights might be
granted to AHPC, acting through Wyeth-Ayerst;

 

WHEREAS, AHPC desires to market, and is capable of marketing

 

2

 

through
Wyeth-Ayerst, the intravenous form of the Agreement Compound in the United
States;

 

WHEREAS, Syntex desires that AHPC through Wyeth-Ayerst market the
intravenous form of the Agreement Compound in the United States and, in
furtherance thereof, is willing to sell the Agreement Compound to AHPC in bulk
form to be processed by or on behalf of AHPC into the finished intravenous
form(s) of the Agreement Compound for distribution and marketing by
Wyeth-Ayerst in the United States; and

 

WHEREAS, AHPC is willing to purchase the Agreement Compound from Syntex
in bulk form to be processed by or on behalf of AHPC into the finished
intravenous form(s) of the Agreement Compound and to have Wyeth-Ayerst
distribute and market such finished intravenous form(s) in the United States.

 

NOW, THEREFORE in consideration of the foregoing and of the mutual
promises herein contained, AHPC and Syntex do hereby agree as follows:

 

1.               Definitions

 

1.1                                 “Affiliate”
of a party shall mean any corporation or any other business entity controlling,
controlled by or under common control with such party. “Control” shall mean the
direct or indirect ownership of more than fifty percent (50%) of the voting or
income interest in such corporation or other business entity. Any reference to
Syntex or AHPC shall, unless otherwise expressly

 

3

 

indicated,
include reference to Syntex’s or AHPC’s affiliates (as the case may be), as
defined in this Section.

 

1.2                                 “Average
Net Selling Price” shall mean (a) the aggregate proceeds invoiced by
Wyeth-Ayerst for sales of Covered Product (as herein defined) to non-Affiliated
purchasers during the Quarter (as herein defined) in question, less (i) trade
and cash discounts actually allowed and taken with respect to the Covered
Product, (ii) credits or allowances actually allowed and taken for damaged,
outdated, returned or recalled Covered Product, (iii) transportation or
shipping charges invoiced to such purchasers, (iv) sales taxes imposed directly
on such sales of the Covered Product by Wyeth-Ayerst, (v) volume or formulary
or other positioning discount amounts paid or credited by AHPC to a wholesaler,
purchaser, third party payor or other contractee as a result of a contractual
arrangement specific to the Covered Product, (vi) rebates paid or credited by
AHPC to any governmental agency (or branch thereof) or to any third party
payor, administrator or contractee with respect to sales of the Covered
Product, and (vii) discounts paid or credited by AHPC that are mandated by, or
granted in response to, applicable federal or state law with respect to sales
of the Covered Product, divided by (b) the aggregate number of grams of
Agreement Compound contained in the quantities of Covered Product (according to
package content as stated on the Covered Product label) invoiced during such
Quarter.

 

4

 

1.3                                 “Bulk
Product” shall mean the Agreement Compound in unfinished form, having the
specifications set forth in Schedule A to this Agreement.

 

1.4                                 “Covered
Product” shall mean the Agreement Compound packaged (in other than oral dosage
form) for use as an intravenous solution, the specifications of which shall be
consistent with and shall conform to the requirements of the United States Food
and Drug Administration (“FDA”).

 

1.5                                 “Indications”
shall mean use of the Covered Product in the (a) short-term treatment of
hypertension when oral therapy is not feasible or not desirable (b) such other
indications for the Covered Product as may be approved by the FDA, and (c) use
of the Covered Product in such other indications supported by clinical data.

 

1.6                                 “Licensed
Patents” shall mean United States Patents Nos. 3,985,758, 4,880,823 and
5,164,405.

 

1.7                                 “Quarter”
shall mean each calendar quarter, which shall begin each January 1st, April
1st, July 1st and October 1st during the term of this Agreement, or the portion
of a calendar quarter just prior to termination or expiration hereof (as the
case may be)

 

1.8                                 “Trademark”
shall mean the product mark or marks, whether registered or not, designated by
Syntex and owned by Syntex in the Territory for the Covered Product, and shall
be the same product

 

5

 

mark or marks
used by Syntex in the Territory for its oral dosage forms of the Agreement
Compound, which currently is “CARDENE”®.

 

1.9                                 “Territory”
shall mean the United States of America and any of its territories or
possessions, including the Commonwealth of Puerto Rico.

 

2.               Grant of Licenses

 

2.1                                 The
grant of licenses are as follows:

 

(a)                                  Syntex
grants to AHPC an exclusive sublicense under the License Agreement, including
United States Patents Nos. 3,985,758 and 4,880,823, to (i) carry out the
processing (including pharmaceutical formulation) and packaging of the Bulk
Product into the Covered Product on its own or by a third party manufacturer
approved by Syntex in accordance herewith and (ii) have Wyeth-Ayerst market,
distribute, promote and sell the Covered Product in the Territory for use in
the treatment of the Indications. Syntex represents and warrants that it has
the right to grant such a sublicense under the License Agreement and the
Licensed Patents listed above in this Section 2.1(a) and that such sublicense
will not violate the rights of any party not a party hereto, including, without
limitation, Yamanouchi, AHSC, du Pont and Du Pont Merck. In the event Syntex
loses that right, this Agreement shall be terminated forthwith, but Syntex
shall attempt, in good faith, to secure from Yamanouchi AHPC’s right to
continue to manufacture, market, distribute, promote and sell the Covered
Product in the

 

6

 

Territory for
use in the treatment of the Indications upon terms and conditions comparable to
those set forth herein.

 

(b)                                 Syntex
grants to AHPC an exclusive license under United States Patent No. 5,164,405 to
(i) carry out the processing (including pharmaceutical formulation) and
packaging of the Bulk Product into the Covered Product and (ii) have
Wyeth-Ayerst market, distribute, promote and sell the Covered Product in the
Territory for use in the treatment of the Indications. Syntex represents and
warrants that it has the right to grant such a license under United States
Patent No. 5,164,405.

 

(c)                                  Subject
to Syntex’s right to detail and promote the Covered Product as set forth in
Section 6.6 below, the licenses granted to AHPC in Sections 2.1(a) and 2.1(b)
above are exclusive even as against Syntex.

 

(d)                                 Syntex
grants to Wyeth-Ayerst a license to use the Trademark only with respect to the
marketing, distribution, promotion and sale of the Covered Product in the
Territory during the term of this Agreement, subject to the terms and
conditions set forth herein.

 

2.2                                 (a)                                  AHPC,
on behalf of itself and Wyeth-Ayerst, hereby accepts the rights granted in
Section 2.1 above and agrees to endeavor in good faith to process (including
pharmaceutical formulation), package, market, distribute, promote and sell the
Covered Product in the Territory at its own expense under the

 

7

 

Trademark for
any and all of the Indications, using generally the same channels and methods,
exercising the same diligence and adhering to the same standards that
Wyeth-Ayerst employs in processing (including pharmaceutical formulation),
packaging, marketing, distributing, promoting and selling its own
pharmaceutical products in the Territory. Wyeth-Ayerst shall, in its sole
discretion, determine its prices and other terms and conditions for sales of
the Covered Product to third parties.

 

2.2                                 (b)                                 In
view of the fact that the FDA has approved the marketing of the Covered Product
in the United States for the treatment of hypertension, AHPC and Syntex agree
that it would be to the benefit of both parties, and the consuming public, if
the Covered Product is launched in the Territory for that Indication as soon as
is possible. Accordingly, the parties agree that:

 

(i)                                     AHPC
and Wyeth-Ayerst shall endeavor in good faith to have One Hundred Thousand
ampoules of non-shortdated, saleable (i.e., released) Covered Product in
inventory by November 1, 1993; and

 

(ii)                                  AHPC,
Wyeth-Ayerst and Syntex shall work together and endeavor in good faith to (x)
review and submit promotional launch materials to the FDA as soon as possible
and (y) assist the FDA in its review of such materials, including meeting with the
FDA to seek and obtain FDA approval of such materials by November 1, 1993.

 

8

 

If both (i) and (ii) above
occur, then Wyeth-Ayerst shall launch the Covered Product in the Territory for
that Indication by November 1, 1993. If (i) above is not achieved, after good
faith pharmaceutical manufacturing efforts by AHPC and Wyeth-Ayerst (in
conjunction with Berk (U.K.) to do so, launch may be delayed by Wyeth-Ayerst
until December 1, 1993, but not beyond that date without the prior written
approval of Syntax, which shall not unreasonably be withheld. If the FDA
approval contemplated by (ii) above has not been obtained, after good faith
efforts to obtain such approval, then launch may be delayed until such
materials have been approved by the FDA.

 

2.3                                 Only
Wyeth-Ayerst and not any Affiliate (s) thereof, shall market, distribute,
promote (subject to Syntex’s right to detail and co-promote as set forth in Section
6.6 below) and sell the Covered Product in the Territory, unless Syntex agrees
in writing to such activities being conducted by an Affiliate of Wyeth-Ayerst,
such agreement by Syntex not to be unreasonably withheld.

 

3.               Supply of Bulk
Product

 

3.1                                 Syntex
shall supply, and AHPC shall purchase, all quantities of Bulk Product that AHPC
requires to process, package, market, distribute, promote and sell the Covered Product
in Territory, such supply and purchase to be in accordance with the following
provisions of this Agreement. AHPC shall use all Bulk

 

9

 

Product supplied by Syntex only
to manufacture Covered Product for use or sale in the Territory for the
Indications or for research purposes in support of such use or sale.

 

3.2                                 (a)                                  Syntex
agrees that all quantities of Bulk Product supplied hereunder shall meet the
specifications set forth in Schedule A attached hereto and made a part hereof,
which shall conform to or be amended to conform to all applicable governmental
requirements (whether or not contained in governmental regulatory approvals) in
the Territory. In addition, Schedule A may be amended from time to time by
written agreement of the parties. Syntex, with each quantity of Bulk Product
supplied hereunder, shall provide AHPC with a Certificate of Analysis
documenting that such Bulk Product complies with the specifications therefor as
set forth in Schedule A hereto as determined according to the methods of
analysis referenced in such specifications.

 

3.3                                 (b)                                 All
Bulk product received by AHPC shall be deemed accepted, unless AHPC shall give
written notice to Syntex within thirty (30) days after receipt of such Bulk
Product specifying the manner in which the Bulk Product does not conform to the
specifications therefor. Such notice shall be accompanied by written reports of
any testing performed by AHPC on the Bulk Product. Upon receipt of such notice,
Syntex may request AHPC to return the non-accepted Bulk Product, or samples
thereof, for further testing by Syntex. AHPC’s test results shall be conclusive

 

10

 

unless Syntex notifies AHPC
within thirty (30) days after receipt by Syntex of the non-accepted Bulk
Product, or samples thereof, that it disagrees with such test results. In the
event of such notice of Syntex, (i) AHPC, to the extent necessary or required,
shall conduct an investigation to determine if there are legally sufficient
grounds upon which to invalidate its test results that suggested
non-conformance of such Bulk Product with the specifications therefor, and (ii)
the Bulk Product, or samples thereof, shall be submitted to a mutually
acceptable independent laboratory for analysis. The results of the independent
testing laboratory shall be binding upon AHPC and Syntex for the purposes of
acceptance of, and the obligation to pay for, such Bulk Product. The costs of
the independent testing laboratory shall be paid by the party against whom the
discrepancy is resolved. In the event any Bulk Product not accepted by AHPC
does not meet the specifications therefor as determined in accordance with this
Section 3.2, Syntex will give AHPC full credit for such Bulk Product at the
price invoiced by Syntex or paid by AHPC and will replace such Bulk Product
with conforming Bulk Product to be invoiced at the original invoice price per
gram. All transportation, shipping and insurance cost, and other fees incident
to the shipping of such replacement (to the extent previously paid by AHPC with
respect to the non-conforming Bulk Product) will be paid for by Syntex. Such
replacement shall be

 

11

 

made immediately upon written
request by AHPC (so as to be able to maintain scheduled pharmaceutical
manufacturing dates) or, if no such request is made, then within sixty (60)
days after it is determined by the independent laboratory or agreed by both
parties hereto that the Bulk Product was non-conforming unless the parties
agree in writing to another delivery date.

 

3.2                                 (c)                                  Wyeth-Ayerst
and Syntex agree that Syntex shall prepare and file, with the assistance and
cooperation of Wyeth-Ayerst, the necessary documentation with the FDA to
substitute Syntex’s Quality Control Method-QC-1203 (Limulus Amebocyte Lysate
(LAL) gel clot test for bacterial endotoxins) as the NDA specification for
pyrogens in place of the USP (151) rabbit test, which is less preferable to both
parties.

 

3.2                                 (d)                                 Wyeth-Ayerst
and Syntex agree that Syntex shall prepare, with the assistance and cooperation
of Wyeth-Ayerst, and file with the FDA a U.S.P. monograph referencing the best
analytical methods for the Covered Product (selected from the USP methods
referenced in the attachment to Schedule A hereto, Syntex’s Quality Control
methods for the Bulk Product, and the LAL method referred to in Section
3.2(c)), such filing being done for the purpose of establishing new methods of
analysis (acceptable to the FDA) for the Bulk Product to be supplied by Syntex,
and purchased by AHPC or Wyeth-Ayerst, hereunder.

 

12

 

3.3                                 (a)                                  In
connection with AHPC’s first purchase of Bulk Product, AHPC shall give Syntex written
notice of the amount of such initial order prior to the execution and delivery
hereof by the parties hereto. In connection with each subsequent order, AHPC
shall provide Syntex with a written estimate during the first month of each
Quarter as to the amount that it desires for delivery during the next
succeeding Quarter. AHPC agrees to submit its firm order for the Bulk Product
at least sixty (60) days prior to the desired delivery date and Syntex agrees
to ship the Bulk Product to AHPC within sixty (60) days after receipt of AHPC’s
firm order. Syntex will fill AHPC’s firm orders up to twice the amount
specified in the Quarterly estimate applicable thereto (in five (5) kilogram
pack increments, unless otherwise agreed to in writing by the parties), and
will, in good faith, attempt to fill the balance (if any) as soon as possible,
due consideration being given to Syntex’s own needs and the needs of the other
parties to which it supplies the Bulk Product.

 

3.3                                 (b)                                 With
respect to Covered Product that is pharmaceutically formulated outside the
Territory, title to any quantities of Bulk Product sold by Syntex to AHPC for
use in such formulation shall pass to AHPC upon delivery by Syntex to AHPC at
Syntex’s European depot (currently Antwerp, Belgium) or such other Syntex
facility as may be agreed to in writing by the parties. With respect to Covered
Product that is pharmaceutically formulated

 

13

 

in the Territory, title to any
quantities of Bulk Product sold by Syntex to AHPC for use in such formulation
shall pass to AHPC upon delivery by Syntex to AHPC at any Syntex warehouse in
the United States (currently Columbus, Ohio). AHPC shall select the common
carrier and determine the method of transportation and routing for all
shipments of Bulk Product and shall pay (and be responsible for) all freight
and insurance costs therefor.

 

3.4                                 (a)                                  The
price of Bulk Product shall be, on a per gram basis for Bulk Product supplied
by Syntex hereunder, [*] percent ([*]%) of the Average Net Selling Price (as
defined in Section 1.2 above) in the Territory during the Quarter in which such
Bulk Product is shipped times the number of grams of Bulk Product so shipped by
Syntex.

 

3.4                                 (b)                                 An
initial price per gram shall be invoiced by Syntex and paid by AHPC, which
shall be equal to the actual price per gram calculated as above for the most
recently reported Quarter (due to inherent time lag in the filing of Quarterly
reports hereunder, the actual price for any given Quarter will become the
estimated or invoice price for the second quarter thereafter, subject, or
course, to the retroactive adjustment set forth in Section 3.4(c) below). The
initial price per gram for orders for commercial quantities shipped to AHPC
during the Quarter or Quarters immediately prior to commercial launch of the
Covered Product in the Territory shall be [*] percent ([*]%) of

 

14

 

Wyeth-Ayerst’s estimated initial ex-factory price of Covered Product,
set by Wyeth-Ayerst in good faith.

 

3.4                                 (c)                                  Within
sixty (60) days after the end of each Quarter, AHPC shall calculate the actual
price due Syntex hereunder and shall give Syntex written notice thereof. Such
notice shall specify all information on which the calculation is based as well
as stating the actual price due. If the initial price paid by AHPC was less
than the price actually due Syntex, AHPC shall remit to Syntex the difference
together with its notice. If the initial price was greater than the price
actually due Syntex, Syntex shall apply such difference as a credit against
future purchases of Bulk Product hereunder, and upon termination or expiration
of this Agreement, Syntex shall remit to AHPC within forty-five (45) days after
receipt to such notice any credit(s) that have not been exhausted by subsequent
purchases of Bulk product.

 

3.4                                 (d)                                 In
the event there is a verifiable rejection of all or a substantial portion of a
batch of Covered Product during the manufacture thereof and the loss associated
with such rejection is not covered by insurance, Syntex shall replace the
quantity of Bulk Product included within the rejected Covered Product for an
additional price, on a per gram basis for each gram of Bulk Product supplied
under this Section 3.4(d), of [*] percent ([*]%) of the price paid or to
be paid by AHPC with respect thereto pursuant to Sections 3.4(a) or 3.4(b) above
(i.e., [*] percent ([*]%) of

 

15

 

[*] percent ([*]%), which is equal to [*] percent ([*]%) of the Average
Net Selling Price, on a per gram basis).

 

3.4                                 (e)                                  Payment
for each purchase of Bulk Product hereunder plus any other charges due Syntex
shall be paid by AHPC forty-five (45) days after the date of Syntex’s invoice
for each such purchase and shall be paid by AHPC in United States Dollars.

 

3.4                                 (f)                                    AHPC
shall be responsible for and pay any and all customs duties, brokerage fees,
excise, sales or use taxes, and other governmentally-imposed taxes (if any)
incurred directly with respect to the shipment of Bulk Product supplied by
Syntex hereunder of Covered Product shipped by AHPC of Wyeth-Ayerst hereunder,
and shall pay or reimburse Syntex upon demand for customs duties, brokerage
fees, excise, sales or use taxes or other governmentally-imposed taxes (if any)
imposed directly by any taxing authority with respect to the sale of the
Covered Product.

 

3.5                                 (a)                                  For
each [*] grams of Bulk Product purchased by AHPC at the [*] percent ([*]%)
price set forth in Section 3.4 above through June 30, 1995, Syntex shall
provide [*] grams of Bulk Product free of any charge under Section 3.4(a) above
(AHPC shall, however, be responsible for all freight, insurance, customs
duties, brokerage fees, excise, sales or use taxes and other governmentally-imposed
taxes (if any) referred to in Section 3.3(b) and 3.4(f) above).
This material is

 

16

 

provided by Syntex to assist AHPC with estimated yield losses of [*]
percent ([*]%) during pharmaceutical formulation of the Bulk Product into the
Covered Product.

 

3.5                                 (b)                                 Syntex
will also provide such assistance to AHPC for the first six (6) months of
pharmaceutical formulation of the Bulk Product into the Covered Product by AHPC
(or Wyeth-Ayerst) in its own facilities even if such assistance extends beyond June 30,
1995, but such assistance by Syntex for all or any portion of such six (6)-month
period after June 30, 1995 will only be applicable to that Bulk Product
purchased by AHPC for pharmaceutical formulation in its (or Wyeth-Ayerst’s)
facilities, unless otherwise agreed to in writing by Syntex.

 

3.5                                 (c)                                  During
the Quarter ending June 30, 1995, and after completion of six (6) months
in-house production experience by AHPC (or Wyeth-Ayerst) (if later), AHPC (or
Wyeth-Ayerst) and Syntex shall meet to discuss what level of yield loss
assistance Syntex, in its sole discretion, considers appropriate under the
circumstances (given the formulating experience by or on behalf of AHPC to that
time) and will thereafter make available to AHPC (or Wyeth-Ayerst).

 

3.6                                 (a)                                  For
each [*] grams of Bulk Product purchased by AHPC at the [*] percent ([*]%)
price set forth in Section 3.4 above, Syntex shall provide [*] grams of
Bulk Product free of any charge under Section 3.4(a) above (AHPC

 

17

 

shall, however, be responsible for all freight, insurance, customs
duties, brokerage fees, excise, sales or use taxes and other
governmentally-imposed taxes (if any) referred to in Sections 3.3(b) and
3.4(f) above), which free material shall be in support of AHPC’s (or
Wyeth-Ayerst’s) importation, packaging, marketing, distributing, promoting
(including sampling) and selling of the Covered Product. This support shall
only apply for that period of time when the Covered Product is pharmaceutically
formulated outside the United States and a duty on the formulated Covered
Product must be paid upon importation thereof into the United States.
Thereafter, the support of Syntex under this Section 3.6 shall be limited
to [*] grams per each [*] grams of Bulk Product purchased by AHPC at the [*]
percent ([*]%) price set forth in Section 3.4 above

 

3.6                                 (b)                                 AHPC
shall provide written documentation showing duties paid by AHPC upon important
of the Covered Product into the United States for so long as the Covered
Product is pharmaceutically formulated outside the United States, duties are
paid upon the importation thereof into the United States, and support is sought
by AHPC under Section 3.6(a) above for such duties.

 

4.               Development Work and
Regulatory Approvals

 

4.1                                 Upon
execution of this Agreement and periodically thereafter, Syntex shall provide
AHPC, subject to the provisions of

 

18

 

Section 11 below, relevant information and data developed by it
with respect to the agreement Compound, the Bulk Product and/or the Covered
Product. Syntex shall continue to provide such information and data that is
relevant to additional development work to be undertaken by AHPC with respect
to the Covered Product during the term of this agreement. Syntex shall provide
written consent directly to the FDA to permit AHPC to refer to Syntex’s Notice
of Claimed Investigational Exemption for New Drug and New Drug Application (“NDA”)
for the Agreement Compound, and all information relating to the manufacture and
control of the Bulk Product, with respect to development work that is conducted
by AHPC in accordance with this agreement.

 

4.2                                 (a)                                  Syntex
shall make available to AHPC all information received from Du Pont Merck that
Du Pont Merck has developed for a subarachnoid hemorrhage indication for the
Covered Product (the “SAH Indication”). AHPC shall promptly review such
information and determine, in good faith, if in AHPC’s judgment the development
of the SAH Indication is appropriate or desirable.

 

4.2                                 (b)                                 If
the development of the SAH Indication is considered appropriate or desirable by
AHPC, then AHPC shall conduct all clinical tests and develop all technical data
reasonably necessary to seek FDA approval for the SAH Indication. The NDA for
the SAH Indication to be submitted to the FDA shall be reviewed and approved by
Syntex in writing in advance of submission

 

19

 

to the FDA. In addition, AHPC shall provide Syntex fifteen (15) working
days to review all data, including all technical and clinical data (including
summaries thereof), to be submitted by Syntex to the FDA. All such data, and
the back-up data pertaining thereto, shall be available for inspection and
review by Syntex at any reasonable time, and copies thereof shall be promptly
provided to Syntex upon Syntex’s written request therefor. AHPC shall use
reasonable efforts to complete the SAH studies (but may terminate its efforts
at any time in its sole discretion) and shall file, in Syntex’s name, NDA or a
supplemental NDA for the SAH Indication. All technical and clinical data
developed by AHPC in support of the SAH Indication shall be and remain the
property of AHPC. Syntex shall, however, own any resulting registration and
AHPC shall ensure that any such registration (including all right, title and
interest thereto) is issued in Syntex’s name.

 

4.2                                 (c)                                  At
least semi-annually, AHPC shall provide to Syntex a written report on any
development undertaken by AHPC of the SAH Indication.

 

4.2                                 (d)                                 In
addition to any reports provided to Syntex by AHPC under Section 4.2(c) above,
SAH Indication review meetings shall be held at least annually at locations to
be agreed on until the NDA or supplemental NDA for the SAH Indication is
approved. At such meetings, AHPC shall report on its progress in the
development of the SAH Indication for the Covered Product. Each party hereby

 

20

 

designates the person listed in Schedule B as its clinical
co-ordinator to receive and respond to inquiries during the regulatory phase
concerning the SAH Indication and to make arrangements for the joint review
meetings.

 

4.3                                 (a)                                  Syntex
shall have and retain ownership of the NDA for the Covered Product. Syntex
shall inform the FDA in writing that AHPC, acting through Wyeth-Ayerst, has
become Syntex’s exclusive sub-licensee of the Covered Product in the Territory
and will have the right, in conjunction with Syntex, to interact with the FDA
with respect to the NDA pertaining thereto, subject to the terms and conditions
hereof.

 

4.3                                 (b)                                 Each
party shall promptly provide to the other copies of all correspondence received
from the FDA concerning the Covered Product, and shall advise each other within
ten (10) working days of any oral communications that it receives from the
FDA concerning the Covered Product.

 

4.3                                 (c)                                  Unless
otherwise required by law, or required by the FDA in written correspondence
with Wyeth-Ayerst, or by this agreement, Wyeth-Ayerst shall provide Syntex
fifteen (15) working days to review and approve correspondence to the submitted
by Wyeth-Ayerst to the FDA with respect to the Covered Product (if the FDA
requires that the correspondence be submitted to the FDA in less than fifteen
(15) days, then Wyeth-Ayerst shall provide Syntex at least two (2) full
working days to review and approve such

 

21

 

correspondence). Wyeth-Ayerst shall not submit any such correspondence
that is objected to by Syntex in good faith, unless required by law or the FDA in
writing. Syntax agrees to make all necessary filings to the FDA with respect to
the NDA for the Agreement Compound, including Annual Reports (21 C.F.R. 314.80(c) (2))
and promotional submissions (21 C.F.R. 314.81(b) (3) (i), as are (i) prepared
by Wyeth-Ayerst, provided on a timely basis by Wyeth-Ayerst to Syntex, and
reviewed and approved by Syntex in accordance with the provisions of this
Agreement, or (ii) prepared by Syntex (e.g., periodic or increased
frequency adverse drug event reports (21 C.F.R. 314.81(b) (2) and
provided by Syntex to Wyeth-Ayerst for comment prior to any such filing.

 

4.3                                 (d)                                 Each
party shall inform the other party of any meetings scheduled with the FDA
concerning the Covered Product and shall provide the other party the
opportunity to review and approve any submissions (including promotional
materials and labeling) to be sent to, reviewed by, or any presentations to be
made to, the FDA with respect to the Covered Product and to have
representatives present at any meetings pertaining to the Covered Product;
provided, however, that Syntex, by virtue of its ownership of the NDA for the
Covered Product, shall be the primary contact with the FDA, unless the parties
agree otherwise in writing.

 

4.3                                 (e)                                  Syntex’s
approval under this Section 4.3 shall not be unreasonably withheld, but
may be withheld, in Syntex’s sole

 

22

 

discretion, if Syntex considers, in good faith, that any Wyeth-Ayerst
correspondence or presentation will have an adverse impact on the other dosage
forms of the Agreement Compound that are being marketed in, or being developed
for, the Territory by or on behalf of Syntex.

 

4.3                                 (f)                                    Syntex
agrees, subject to the review and approval procedures set forth in this
Agreement, to submit to the FDA Supplementary data supplied to Syntex by AHPC
or Wyeth-Ayerst to permit AHPC or Wyeth-Ayerst to manufacture and test the
Covered Product in its facilities, and to substitute supplementary or alternative
packaging designs or Covered Product presentations that Wyeth-Ayerst desires.
Subject to the terms and conditions of this agreement, all data developed by
AHPC or Wyeth-Ayerst in support of such submissions to the FDA shall be and
remain the property of AHPC or Wyeth-Ayerst.

 

4.4                                 All
data developed by AHPC or Wyeth-Ayerst for the United States NDA or
supplemental NDA may be used by Syntex for filing applications for government
registration in countries outside the Territory and in supporting FDA filings
for other products containing the Agreement Compound. AHPC and Wyeth-Ayerst
shall provide to Syntex without charge all data requested by Syntex for this
purpose and hereby consents to Syntex’s use of such data for the sole purposes
of obtaining foreign registrations in any and all countries outside the
Territory and formulating, packaging,

 

23

 

distributing, marketing, promoting and selling the products covered by
such registrations pursuant thereto. Syntex agrees to keep all such data
confidential in accordance with Article 11 hereof, and shall not use such
data except as provided for herein. Neither AHPC nor Wyeth-Ayerst shall be
required to develop data to be used solely for Syntex’s needs or desires
outside the Territory, unless AHPC or Wyeth-Ayerst is willing to do so upon
terms and conditions to be agreed upon in writing by the parties.

 

4.5                                 As
an inducement for Syntex to continue to furnish information and data pertaining
to the Agreement Compound and the Bulk Product, to cooperate in filing and
obtaining approval of any NDA for the SAH Indication, to provide subsequent
information (including trade secrets and other confidential information
relating to the marketing of products containing the Agreement Compound), and
to grant to AHPC the exclusive rights to the Covered Product in the Territory
(as set forth herein), including with respect to the currently approved NDA for
certain indications for the Covered Products, AHPC, on behalf of itself and Wyeth-Ayerst,
agrees that it shall not manufacture or sell in the Territory, or apply for FDA
approval to manufacture or sell in the Territory, any product containing the
Agreement Compound except the Covered Product during the term of this
agreement. This provision shall not preclude AHPC from manufacturing

 

Covered Product (a) in the Territory with Bulk Product purchased

 

24

 

from Syntex hereunder for sale by Wyeth-Ayerst in accordance with this
agreement or (b) for Syntex for countries outside the Territory pursuant
to separate written agreements between the parties.

 

5.               Trademarks and
Quality Control

 

5.1                                 The
use of the Trademark by Wyeth-Ayerst shall be governed by the following
provisions:

 

(a)                                  Syntex
shall have equitable and legal ownership of the entire right, title and
interest in and to the Trademark.

 

(b)                                 Syntex
shall file and maintain registration of the Trademark in the Territory, and
neither AHPC, Wyeth-Ayerst nor any of their respective Affiliates shall obtain
any right, title of interest in the Trademark, except the right to use the
Trademark on the Covered Product pursuant to this Agreement.

 

(c)                                  If
AHPC or Wyeth-Ayerst becomes aware that a third party is infringing any of
Syntex’s rights with respect to the use of the Trademark on the Covered
Product, AHPC or Wyeth-Ayerst shall give notice to Syntex of such infringement.
Syntex may, at its sole discretion, bring legal action to restrain such
infringement and for damages, and AHPC and Wyeth-Ayerst agree to cooperate at
their own expense in any such action involving the Covered Product. If within
six (6) months after receipt of such notice, Syntex does not effect a
cessation of such infringement or institute a legal action for infringement,
then AHPC or Wyeth-Ayerst shall have the right,

 

25

 

at their own expense, to bring suit against any such infringing party.
If such a suit by AHPC or Wyeth-Ayerst is successful, AHPC or 

Wyeth-Ayerst shall be entitled to any monetary recovery obtained. If
AHPC or Wyeth-Ayerst elects to bring such action, it agrees to fully indemnify
Syntex for any costs, expenses or losses incurred by Syntex as a result of any
such action. Syntex reserves the right to intervene in any such action at its
own expense. AHPC or Wyeth-Ayerst shall only have the right to bring a
trademark infringement or related action in the Territory against a third party
who uses the precise Trademark on the precise Covered Product, and nothing
herein shall grant AHPC or Wyeth-Ayerst the right to otherwise enforce the
Trademark. AHPC or Wyeth-Ayerst shall not settle any such suit without the
prior written approval of Syntex.

 

(d)                                 Each
Covered Product processed and distributed by Wyeth-Ayerst shall bear a Trademark
and a label approved by Syntex featuring the Wyeth-Ayerst name and the Syntex
name in a manner acceptable to the FDA and to both parties. Neither party, by
virtue of this agreement, obtains any rights whatsoever in the trade name of
the other party. Wyeth-Ayerst shall use the same format/font and style for the
Trademark and Syntex’s name on such labeling (and on all other promotional
material) as Syntex then-currently uses with respect to the oral dosage form of
the Agreement Compound in the Territory.

 

26

 

(e)                                  Syntex
may, for the purpose of avoiding trademark infringement, change the Trademark,
and Wyeth-Ayerst will, when requested by Syntex to do so, case further sue of
the earlier designated Trademark and use only the newly designated Trademark.
This provision may be invoked by Syntex only if Syntex is itself ceasing the
further use of the Trademark on the oral dosage form of the Agreement Compound
(which is currently contemplated to be unlikely in view of the marketing by
Syntex of such oral dosage form under the Trademark in the Territory since
March, 1989). In the case of any such redesignation, Syntex shall reimburse
Wyeth-Ayerst for any new packaging and package inserts required by Syntex’s
request to convert to the newly designated Trademark, but shall not otherwise
be liable to Wyeth-Ayerst (and, in this regard, shall not be obligated to
reimburse Wyeth-Ayerst for the printing of any new promotional materials that
are required).

 

5.2                                 The
parties recognize that Syntex has a proper concern in maintaining and
controlling the quality of products containing the Agreement Compound (e.g.,
the Covered Product) marketed under a Trademark owned by Syntex, which products
are publicly associated with Syntex research and are or will be marketed by
Syntex and its Affiliates, sublicensees and distributors both inside and
outside the Territory. The parties accordingly agree as follows:

 

(a)                                  AHPC and Wyeth-Ayerst
warrant that the Covered Product will meet the quality standards specified by
Syntex in this

 

27

 

Agreement and as required by the FDA.

 

(b)                                 To
ensure that the quality standards for the Covered Product are met, AHPC shall
purchase from Syntex all quantities of the Bulk Product to be used in the
manufacture of Covered Product by or on behalf of AHPC. If for any reason
Syntex is unable to deliver Bulk Product of its own manufacture within sixty
(60) days after receipt of any order placed by AHPC, Syntex shall arrange for
delivery of Bulk Product from another source; provided, however, that such
source has been approved by the FDA as a supplier of Bulk Product.

 

(c)                                  AHPC
shall not include any Agreement Compound as an ingredient or component part of
a composition containing one or more other active medicinal, therapeutic or
prophylactic agents without the prior written approval of Syntex.

 

(d)                                 All
dosage forms of the Agreement Compound suitable for intravenous administration
to be manufactured by AHPC or marketed by Wyeth-Ayerst must have the prior
written approval of Syntex, and each Covered Product shall be distributed only
in dosage forms suitable for intravenous administration as approved in writing
by Syntex and the FDA. If Syntex does not indicate approval or disapproval within
sixty (60) days after receipt of a complete package of information from AHPC
(or Wyeth-Ayerst) for the development and distribution of a new dosage from of
the Agreement Compound suitable for intravenous administration, such package
will

 

28

 

be deemed approved.

 

(e)                                  AHPC
may employ a third party manufacturer for any portion of the pharmaceutical
manufacturing, processing or packaging process of the Covered Product, but only
with the prior written approval of Syntex, which shall not be unreasonably
withheld, and the FDA.

 

5.3                                 Subject
to Section 5.2(e) above, AHPC shall perform such pharmaceutical manufacturing,
processing and packaging necessary to convert the Bulk Product purchased from
Syntex into finished pharmaceutical dosage form packaged for resale to the
ultimate consumer. AHPC shall have full responsibility for maintaining, at its
own expense, suitable manufacturing procedures and quality controls, which
shall comply with all federal and local laws and regulations, with Good
Manufacturing Practices (GMPs) for the manufacture of pharmaceutical products
in the Territory, and with Syntex quality standards set forth in the NDA for
the Covered Product. In addition to, and without in any way limiting the
foregoing, the following procedures shall be observed:

 

(a)                                  Syntex
shall provide to AHPC such documents as it has developed pertaining to
pharmaceutical manufacture, package and control procedures for the Covered
Product. Based on such information and on its own procedures pertaining to the
manufacture of sterile intravenous products, AHPC shall develop manufacturing,
packaging and control procedures for the Covered Product, which it

 

29

 

shall submit to Syntex for
Syntex’s prior review and written approval. If Syntex does not indicate
disapproval within sixty (60) days after receipt from AHPC of AHPC’s
pharmaceutical manufacturing, packaging and control procedures for the Covered
Product, such procedures as are received by Syntex shall be deemed approved.

 

(b)                                 AHPC
warrants that it shall strictly follow such procedures as required to comply
with GMPs; however, minor infractions by themselves will not be the basis for
termination of this Agreement.

 

(c)                                  AHPC
shall promptly forward to Syntex a reasonable number of samples and copies of
analytical reports with respect to the first three (3) commercial batches of
the Covered Product that are produced by AHPC (or by subsequent manufacturer
approved by Syntex pursuant to this Agreement), and such additional reports as
may be reasonably requested by Syntex from time to time. None of these
commercial batches shall be distributed by or on behalf of Wyeth-Ayerst prior
to receipt of Syntex’s written approval thereof.

 

(d)                                 AHPC
shall, whenever requested by Syntex, send a reasonable number of random samples
(and copies of the corresponding batch sheets) to Syntex to be re-checked for
quality control purposes by Syntex. The cost of such random samples shall be
borne by AHPC, and the cost of all re-checking shall be borne by Syntex. Syntex
shall promptly send a copy of the results of such

 

30

 

re-checking to AHPC.

 

(e)                                  Syntex
shall have the right, upon reasonable notice to AHPC and during regular
business hours, to visit and inspect AHPC’s (or Wyeth-Ayerst’s premises or the
premises of any third party manufacturer employed by AHPC) where the Bulk
Product is stored and the Covered Product is pharmaceutically manufactured from
such Bulk Product, processed, packaged and/or stored.

 

6.               Promotion

 

6.1                                 Wyeth-Ayerst
shall meet with, present and submit to Syntex a marketing plan for the Covered
Product as soon as possible, and in any event not later than thirty (30) days
after the effective date hereof. Such plan shall cover in detail the period
beginning with the effective date hereof and ending at the end of the
then-current calendar year. The marketing plan for calendar year 1994 (the “Initial
Plan Year”) shall also contain estimates for the three (3) -year period
starting with that Initial Plan Year. Each calendar year during the term
hereof, after the Initial Plan Year, shall be referred to as a “Plan Year”. The
marketing plan shall include at least the following:

 

(a)                                  market
analysis, including review of competitive products, presentations, dosages and
dosage forms, and if possible, sales volume;

 

(b)                                 estimated
sales (in number of units) of the Covered Product by dosage form for the
Initial Plan Year and the three

 

31

 

(3) -year period starting with
the Initial Plan Year (only the estimates for the Initial Plan Year or for any
subsequent Plan Years shall be used to measure performance pursuant to Section
10.5 below);

 

(c)                                  proposed
labeling (including label, package and carton, package insert, introductory
folder and advertising), recognizing that such materials may be subject to FDA
modification and approval (modifications or revisions to the labeling approved
by Wyeth-Ayerst and Syntex shall be permitted without resubmission of the
marketing plan);

 

(d)                                 selected
strategic option;

 

(e)                                  proposed
literature and mailing plan;

 

(f)                                    media
advertising plan;

 

(g)                                 amount,
percent of and bonus weighting for, detail effort by the sales force to be
dedicated on an annual basis to the Covered Product;

 

(h)                                 sampling
(package sizes and number to be distributed); and

 

(i)                                     other
marketing activities.

 

5.2                                 Syntex
shall, not later than thirty (30) days after receipt of the marketing plan,
send Wyeth-Ayerst a notification containing its approval, disapproval or any
suggested modifications. If Syntex does not notify Wyeth-Ayerst of its
disapproval of the marketing plan within such period of time, it

 

32

 

will be deemed approved. If
Syntex does not approve the plan, or if any of its suggested modifications are
not acceptable to Wyeth-Ayerst, representatives of the parties shall meet and
confer, and a mutually acceptable plan shall be developed within the next thirty
(30) days. Wyeth-Ayerst will endeavor in good faith to achieve a consistent
brand image for the Covered Product with the oral dosage forms of the Agreement
Compound. The parties recognize that situations may exist in which promotional
strategies for the Covered Product may necessarily be different than for the
oral dosage forms of the Agreement Compound. Use of such different promotional
strategies shall not be reason for Syntex to refuse approval of Wyeth-Ayerst’s
promotional plan, unless Syntex believes, in good faith, that Wyeth-Ayerst’s
strategy would be damaging to the image or medical acceptance of the oral
dosage forms of the Agreement Compound or inconsistent, in significant respect,
with Syntex’s promotional strategy for the oral dosage forms of the Agreement
Compound.

 

6.3                                 For
each succeeding Plan Year (or portion thereof) during the term of this
Agreement, Wyeth-Ayerst shall prepare and submit to Syntex a marketing plan
containing the information specified in Section 6.1 above for the ensuing
twelve (12)-month and any three (3)-year or lesser periods remaining during the
term of this Agreement. The plan shall be submitted to Syntex ninety (90) days
prior to the beginning of Plan Year or period to which it pertains,

 

33

 

and any objections by Syntex
shall be handled as set forth in Section 6.2 above.

 

6.4                                 (a)                                  Wyeth-Ayerst
shall submit for prior medical, regulatory and marketing (review only) review
and approval by Syntex all advertising materials that it prepares or has prepared
concerning the Covered Product prior to publication thereof. For purposes of
this provision, advertising/promotional material includes, without limitation,
copy and art work for magazine and journal publications, sales aids, television
and radio advertising, leaflets, brochures, medical services related materials,
press releases, and any other printed, audio or visual materials pertaining to
the Covered Product. Syntex may request modifications to such materials to
ensure medical and regulatory consistency with its advertising of other
products containing the Agreement Compound and with the approved marketing
plans. Wyeth-Ayerst shall not publish, broadcast, announce, exhibit or
distribute any advertising materials for the Covered Product that have not been
approved in writing by Syntex. Such approval shall not be unreasonably
withheld, and Syntex shall advise of approval or disapproval within fifteen
(15) working days after receipt thereof. If Syntex does not indicate
disapproval within fifteen (15) working days after receipt from Wyeth-Ayerst of
such materials, such materials as are received by Syntex shall be deemed
approved.

 

34

 

6.4                                 (b)                                 Wyeth-Ayerst
and Syntex shall endeavor in good faith to establish procedures whereby Syntex
is involved in the review and approval of the advertising materials referred to
in Section 6.4(a) above as such materials are being prepared by Wyeth-Ayerst,
so as to minimize the potential for “last minute” disapproval thereof by Syntex
under Section 6.4(a) above.

 

6.4                                 (c)                                  Wyeth-Ayerst
shall have the right, with respect to such advertising and promotional
materials, to communicate directly with the FDA’s Division of Drug Advertising,
Marketing and Communications, subject to Syntex’s right of review, approval and
participation as set forth in this Agreement.

 

6.5                                 If
Wyeth-Ayerst and Syntex disagree on specific aspects of the marketing plan or
the advertising/promotional material to be used in marketing and promoting the
Covered Product in the Territory, the parties agree to promptly meet and
attempt to resolve such differences of opinion. If after good faith attempt to
resolve such differences the parties still cannot agree, the position to be
followed shall be decided by Syntex as holder of the regulatory approval for
the marketing of the Covered Product in the Territory.

 

6.6                                 (a)                                  Syntex
may engage in its own detailing and promotional activities for the Covered
Product during the term of this Agreement, and it shall inform Wyeth-Ayerst of
all such activities that it undertakes. Wyeth-Ayerst shall provide to

 

35

 

Syntex reasonable quantities of
advertising/promotional materials prepared by Wyeth-Ayerst to be used for
informational and promotional purposes by Syntex professional medical
representatives. The cost of the advertising/promotional materials provided by
Wyeth-Ayerst to Syntex shall be reimbursed by Syntex at Wyeth-Ayerst’s cost
within thirty (30) days after receipt of Wyeth-Ayerst’s invoice therefor.

 

6.6                                 (b)                                 Syntex
shall submit to Wyeth-Ayerst for review all advertising/promotional materials
that it may develop for the Covered Product prior to publication, and
Wyeth-Ayerst shall confer with Syntex if it objects to any such materials.
Syntex shall also provide to Wyeth-Ayerst, for its information, copies of all
published advertising for other products containing the Agreement Compound. To
permit appropriate coordination of activities, Syntex shall keep Wyeth-Ayerst
advised of its marketing plans with respect to the Agreement Compound on an
annual basis and shall endeavor in good faith to provide such plans prior to
Wyeth-Ayerst’s submission of its marketing plans for each plan Year.

 

6.6                                 (c)                                  Wyeth-Ayerst
shall, upon written request from Syntex, provide Syntex with a reasonable
number of samples of the Covered Product for (a) sampling by Syntex and (b)
conducting by Syntex of any Phase IV studies. The cost of the samples provided
by Wyeth-Ayerst to Syntex shall be reimbursed by Syntex at Wyeth-Ayerst’s cost
(exclusive of any Bulk Product cost).

 

36

 

6.7                                 If
either party distributes samples of the Covered Product to its sales force,
such party shall maintain records concerning such sample distribution as
required by the Prescription Drug Marketing Act of 1987 (the “Act”) and
relevant state laws. Each party shall take such steps as are necessary to
ensure that its sales force representatives comply with all requirements of the
Act, including but not limited to obtaining requests and receipts signed by
licensed prescribers for all samples delivered. Each party shall have access,
upon reasonable notice to the other party, to such records of the other party
so as to be able to meet its obligations under the Act. Wyeth-Ayerst and Syntex
each indemnify and hold the other party harmless from any liability that the
other party may incur, whether civil, criminal or otherwise, by reason of a
violation of the Act by Wyeth-Ayerst or Syntex (as the case may be) or by any
member of their respective sales forces.

 

6.8                                 Subject
to the applicable review and approval provisions set forth in this Agreement,
Wyeth-Ayerst shall prepare on a timely-basis and provide to Syntex for filing
with the FDA a form FDA-2253, or its replacement, for the purpose of submitting
copies of advertising and promotional labeling to the FDA at the time of
initial dissemination of such labeling and at the time of initial publication
of any such advertising material. Such form and advertising and promotional
labeling shall be provided to Syntex in accordance with 21 C.F.R. 314.81(b) (3)
(i).

 

37

 

7.                                       Operating
Procedures

 

7.1                                 Wyeth-Ayerst
and Syntex shall exchange information concerning technical and scientific data
and therapeutic claims to be used in advertising materials, sales literature,
professional journals and the like with respect to the Covered Product and the
Agreement Compound and shall confer concerning any inconsistencies or
objections noted by either party.

 

7.2                                 Wyeth-Ayerst
shall as promptly as practicable submit written reports to Syntex as follows:

 

(a)                                  semi-annual
clinical and other Covered Product development progress reports;

 

(b)                                 semi-annual
reports showing the status of any application for FDA approval to market the
Covered Product for the SAH Indication and any further indication to be
developed for the Covered Product as may be agreed upon in writing by the
parties hereto;

 

(c)                                  Quarterly
reports showing cumulative sales of each ampoule size and concentration of the
Covered Product (in terms of units and dollars) for the Quarter; and

 

(d)                                 Quarterly
reports showing the amount of inventory on hand of the Bulk Product and the
Covered Product, including work in progress.

 

7.3                                 The
Quarterly reports referred to in Sections 7.2 above shall be submitted by
Wyeth-Ayerst to Syntex along with the notice

 

38

 

given by Wyeth-Ayerst to Syntex
pursuant to Section 3.4(c).

 

7.4                                 During
the clinical testing (if any) of the Covered Product for the SAH Indication,
Wyeth-Ayerst shall, in accordance with federal regulations, report to the FDA
any information that it receives concerning an adverse drug event associated
therewith. At the same time that it submits such report to the FDA,
Wyeth-Ayerst shall notify Syntex by facsimile letter or message (Manager,
Central Drug Experience Reporting Group; facsimile number 415-852-3013) that it
is submitting a report and shall transmit a copy of the report to Syntex
(Attention: Manager, Central Drug Experience Reporting Group, Corporate
Regulatory Affairs, Syntex (U.S.A.) Inc., 3401 Hillview Avenue, Palo Alto,
California 94304) by express delivery service.

 

7.5                                 (a)                                  Wyeth-Ayerst
shall promptly (i.e., within seven (7) business days) report to Syntex in
accordance with FDA regulations any information that Wyeth-Ayerst receives
concerning an adverse drug event associated with the Covered Product that is
serious, as defined in the applicable federal regulations, including, without
limitation, 21 C.F.R. 314.80, or such other definition of serious as the
parties may agree upon to take into consideration, and satisfy, international
reporting requirements (“Serious”), which report shall include a completed Form
1639 (or any successor form) prepared by Wyeth-Ayerst for subsequent filing by
Syntex with the FDA in accordance with the applicable regulations.

 

39

 

7.5                                 (b)                                 Syntex
shall attempt to immediately refer any telephone call received by Syntex
regarding an adverse drug event associated with use in the Territory of the
Covered Product that is Serious, to Wyeth-Ayerst for direct handling. However,
if that can not be done, Syntex shall promptly (i.e., within two (2) business
days) refer (by telephone call or facsimile transmission) to Wyeth-Ayerst any
information that Syntex receives concerning such adverse drug event.
Wyeth-Ayerst shall follow-up with the person or persons making the initial
adverse drug event report to Syntex and shall report back to Syntex within five
(5) business days after the date of Syntex’s telephone call or facsimile
transmission, which report back to Syntex shall include a completed Form 1639
(or any successor form) prepared by Wyeth-Ayerst for subsequent filing by
Syntex with the FDA in accordance with the applicable regulations.

 

7.5                                 (c)                                  Syntex
shall also inform Wyeth-Ayerst of any Serious adverse drug event associated
with the use outside the Territory of a Covered Product that was manufactured with
Bulk Product supplied by Syntex. This information shall be reported to
Wyeth-Ayerst by Syntex sending a copy of any report or form filed with the FDA
with respect to such use or promptly by Syntex if not reportable to the FDA (i.e.,
is Serious labelled, foreign origin).

 

7.5                                 (d)                                 Information
concerning adverse drug events that are non-serious that Wyeth-Ayerst receives
for the Covered Product shall be provided to Syntex in sufficient time for
reporting to the

 

40

 

FDA by Syntex in accordance
with the FDA’s required reporting schedule. Syntex shall also keep Wyeth-Ayerst
advised of any information that Syntex receives concerning a non-Serious
adverse drug event associated with the use (either inside or outside the
Territory) of a Covered Product that was manufactured with Bulk Product
supplied by Syntex.

 

7.5                                 (e)                                  In
addition, each party shall transmit to the other, in accordance with the above,
any report requested by or submitted to the FDA concerning safety of the
Agreement Compound and/or the Covered Product.

 

7.5                                 (f)                                    Syntex
shall, utilizing the information contained in Wyeth-Ayerst’s reports to Syntex
and other adverse event information available to it, prepare those formal
(i.e., periodic and increased frequency) reports required to be provided to the
FDA in accordance with 21 C.F.R. 314.80 and shall transmit such reports on a
timely-basis to Wyeth-Ayerst for Wyeth-Ayerst’s comments. Wyeth-Ayerst shall
return such draft reports to Syntex along with its comments in time for Syntex
to file such reports with the FDA in accordance with the applicable reporting
schedule(s). Syntex shall submit such reports to the FDA and shall also send to
Wyeth-Ayerst (Attention: Wyeth-Ayerst Laboratories, Executive Director, Worldwide
Safety Surveillance Division (555-3), 555 E. Lancaster Avenue, St. Davids,
Pennsylvania 19087 by express delivery service a copy of any such report
eventually submitted to

 

41

 

the FDA.

 

7.6                                 If
either party receives any information concerning an adverse drug event caused
by a form of the Agreement Compound other than the Covered Product, then such
party shall promptly report such information in writing to the other party but
if the adverse drug event is Serious and unexpected (as defined by the
applicable federal regulations), such report shall be given by (a) Wyeth-Ayerst
to Syntex within two (2) working days (by telephone call or facsimile
transmission) after it is received by Wyeth-Ayerst and (b) concurrently by
Syntex with the submission of its report thereon to the FDA.

 

7.7                                 Although
Sections 7.5 and 7.6 refer solely to the FDA, the parties agree to cooperate
with each other in good faith to timely satisfy any adverse drug event
reporting obligations outside the Territory concerning the Agreement Compound
and the Covered Product.

 

7.8                                 Each
party shall keep all supporting documentation regarding adverse drug events
concerning the Agreement Compound and the Covered Product as are required by
the FDA and regulatory agencies outside the Territory for the maximum period
for which such documentation is required to be kept.

 

7.9                                 If
either party learns of any hazard concerning the Covered Product that may be of
a severity that requires action in order to protect the public interest, it
shall immediately notify

 

42

 

the other party, and the
parties shall promptly consult concerning such hazard. If after consultation
the parties agree that distribution of the Covered Product should be
discontinued and/or that Covered Product previously distributed should be
recalled, one of the parties shall be designated to notify the FDA to determine
the nature and extent of the recall.

 

7.10                           In
the event of a recall pursuant to Section 7.9 above or otherwise, Wyeth-Ayerst
shall provide services to recover Covered Product distributed by it, but the
costs of such recall, including the value of lost Covered Product and Bulk
Product, shall be borne by the party responsible, as provided in Article 9
below.

 

8.                                       Technology
and Patents

 

8.1                                 AHPC
and Wyeth-Ayerst shall promptly advise Syntex of any developments and/or
improvements made by AHPC or Wyeth-Ayerst with regard to the Agreement Compound
and/or the Covered Product (the “Sublicensee Technology”), particularly with
regard to any developments and/or improvements made by AHPC or Wyeth-Ayerst
with respect to pharmaceutical compositions and/or formulations of the
Agreement Compound, including, without limitation, compositions and/or formulations
in other that oral dosage form for use with regard to an intravenous solution
of the Agreement Compound.

 

8.2                                 (a)                                  AHPC
and Wyeth-Ayerst agree to grant, and do hereby grant, to Syntex and exclusive,
but for AHPC and Wyeth-Ayerst, royalty-free, fully paid-up license in the
Territory under the

 

43

 

Sublicensee Technology
developed by AHPC or Wyeth-Ayerst during the term hereof, and any patent
applications and patents pertaining thereto.

 

8.2                                 (b)                                 AHPC
and Wyeth-Ayerst agree to grant, and do hereby grant, to Syntex an exclusive,
but for AHPC and Wyeth-Ayerst, royalty-free, fully paid-up license in all
countries outside the Territory under the Sublicensee Technology, developed by
AHPC or Wyeth-Ayerst during the term hereof, and any patent applications and
patents pertaining thereto.

 

8.3                                 If
AHPC or Wyeth-Ayerst develop a significant new patentable use of the Agreement
Compound outside the scope of the Licensed Patents, and the foreign
counterparts thereof, AHPC and Wyeth-Ayerst hereby grant to Syntex a right of
first refusal to obtain an exclusive, but for AHPC and Wyeth-Ayerst, license
under such development and any patents pertaining thereto upon reasonable terms
and conditions to be determined by good faith negotiations between the parties.
Such right shall be exercised by Syntex, in writing, within sixty (60) days
after receipt by Syntex from AHPC or Wyeth-Ayerst of a package of information
(including any patent application(s) or patent(s) pertaining thereto)
describing any such development in sufficient detail to enable Syntex to make
an informed decision as to whether or not it wishes to obtain rights thereto as
set forth herein.

 

8.4                                 If
AHPC or Wyeth-Ayerst elect not to file for patent

 

44

 

protection within thirty (30)
days after being requested to do so by Syntex, or does not file a priority
patent application within ninety (90) days after Syntex’s request, Syntex may
do so. AHPC and Wyeth-Ayerst agree to make, execute and deliver, without
compensation from Syntex, any and all instruments and documents necessary to obtain
patents on the Sublicensee Technology in any and all countries throughout the
world.

 

8.5                                 (a)                                  In
the event that either party learns of or suspects a third party infringement of
the Licensed Patents in the Territory pertaining to the Covered Product by
manufacture, use or sale of a product conforming to the definition of Covered
Product herein, it shall promptly inform the other in writing.

 

8.5                                 (b)                                 If
AHPC or Wyeth-Ayerst becomes aware that a third party is infringing Syntex’s
U.S. Patent No. 5,164,405, AHPC or Wyeth-Ayerst shall give written notice to
Syntex of such infringement. Syntex may, at its sole discretion, bring legal
action to restrain such infringement and for damages, and AHPC and Wyeth-Ayerst
agree to cooperate at their own expense in any such action. If within six (6)
months after receipt of such notice, Syntex does not effect a cessation of such
infringement or institute a legal action for infringement, then AHPC or
Wyeth-Ayerst shall have the right, at their own expense, to bring suit against
any such infringing party. If such a suit by AHPC or Wyeth-Ayerst is
successful, AHPC or Wyeth-Ayerst shall be entitled

 

45

 

to any monetary recovery
obtained. If AHPC or Wyeth-Ayerst elects to bring such an action, it agrees to
fully indemnify Syntex for any costs, expenses or losses incurred by Syntex as
a result of any such action. Syntex reserves the right to intervene in any such
action at its own expense. AHPC any Wyeth-Ayerst shall not settle any such suit
without the prior written approval of Syntex. AHPC and Wyeth-Ayerst shall only
have the right to enforce the aforesaid Syntex patent under the conditions set
forth above, and nothing herein shall grant AHPC or Wyeth-Ayerst the right to
otherwise enforce such Syntex patent.

 

8.5                                 (c)                                  If
AHPC or Wyeth-Ayerst becomes aware that a third party is infringing Yamanouchi’s
U.S. Patent No. 4,880,823, AHPC or Wyeth-Ayerst shall give written notice to
Syntex of such infringement. Either Syntex or Yamanouchi may, at their
individual discretion, bring legal action to restrain such infringement and for
damages, and AHPC and Wyeth-Ayerst agree to cooperate at their own expense in
any such action. If neither Yamanouchi nor Syntex bring legal action to
restrain such infringement within six (6) months after the date of such notice,
Syntex will attempt, in good faith, to obtain from Yamanouchi the right for AHPC
or Wyeth-Ayerst, at their own expense, to bring suit against any such
infringing party, upon terms and conditions to be agreed upon at that time by
Yamanouchi, Syntex, and AHPC or Wyeth-Ayerst.

 

8.6                                 (a)                                  In
the event that a third party claims that AHPC’s

 

46

 

or Wyeth-Ayerst’s manufacture,
use or sale of the Agreement Compound and/or the Covered Product in the
Territory infringes the patent of such third party, AHPC or Wyeth-Ayerst shall
promptly notify Syntex of such claim.

 

8.6                                 (b)                                 If
the claim of patent infringement pertains to the Agreement Compound per se or
any formulation of the Covered Product developed by Syntex, Syntex shall be
responsible for the handling, prosecution and/or settlement of any such claim,
and the decisions of the counsel for Syntex shall be controlling (although AHPC
and Wyeth-Ayerst may, at their own expense, retain their own counsel; counsel
for Syntex shall, however, give due consideration to the advice and
recommendations of the counsel for AHPC and Wyeth-Ayerst). If AHPC or
Wyeth-Ayerst becomes obligated to pay royalties to any non-Affiliated third
party in order to make, have made, use or sell Covered Product in the
Territory, by reason of a patent of such third party, such royalties shall be
creditable against the price for Bulk Product otherwise payable to Syntex
hereunder, provided that (a) the obligation to pay such royalties arises out of
use of the formulation developed by Syntex for the Covered Product and not out
of any modification to the Covered Product made by AHPC or Wyeth-Ayerst, (b)
Syntex has the right to participate in the negotiations with such third party
and to approve of the royalties to be paid to such third party, and (c) such
credit shall not reduce the price otherwise payable to Syntex

 

47

 

by more than ([*]%) of the
price set forth in Section 3.4(a) above (that is, [*] ([*]%) of [*] percent ([*]%),
which is equal to a maximum reduction of [*] percent ([*]%) of the Average Net
Selling Price).

 

8.6                                 (c)                                  If
the claim of patent infringement pertains to any formulation of the Covered
Product developed by AHPC or Wyeth-Ayerst or initially developed by Syntex and
modified by AHPC or Wyeth-Ayerst where such modification is the basis for the
claim of infringement, AHPC and Wyeth-Ayerst shall be responsible for the
handling, prosecution and/or settlement of any such claim, and the decisions of
the counsel for AHPC or Wyeth-Ayerst shall be controlling (although Syntex may,
at its own expense, retain its own counsel; counsel for AHPC or Wyeth-Ayerst
shall, however, give due consideration to the advice and recommendations of the
counsel for Syntex).

 

8.7                                 Syntex
represents that, to the best of its current knowledge, there are no third party
patents (other than Yamanouchi’s U.S. Patents Nos. 3,985,758 and 4,880,823
referred to in Section 2.1(a) above) that would be infringed by the making,
using and selling the Covered Product in the Territory.

 

9.                                       Indemnification

 

9.1                                 Subject
to Section 9.2 below, Syntex shall be responsible for, and shall defend,
indemnify and hold AHPC and Wyeth-Ayerst harmless from and against, any and all
loss, claims, suits,

 

48

 

proceedings, expenses (including
reasonable attorneys’ fees and other litigation costs, regardless of outcome),
recoveries and damages, including costs and expenses of a total or partial
product recall, arising out of, based on, or caused by any claim of third
parties relating to the manufacture or formulation of Bulk Product furnished by
Syntex and used for the manufacture of Covered Products sold in the Territory;
provided, however, that Syntex shall incur no obligation to defend, indemnify
or hold AHPC and Wyeth-Ayerst harmless from any liability, loss or expense
resulting from AHPC’s or Wyeth-Ayerst’s clinical testing, storage (including
storage of the Bulk Product), manufacture, processing, packaging, registration
for the SAH Indication, distribution, promotion, use or sale of the Covered
Product or from the negligence or other wrongdoing of AHPC, Wyeth-Ayerst or any
third party manufacturer, distributor, purchaser or user of the Covered
Product.

 

9.2                                 AHPC
and Wyeth-Ayerst shall defend, indemnify and hold Syntex harmless from and against
any and all loss, claims, suits, proceedings, expenses (including reasonable
attorneys’ fees and other litigation costs, regardless of outcome), recoveries
and damages, including costs and expenses of a total or partial recall, arising
out of, based on, or caused by any claim relating to the clinical testing,
storage (including storage of the Bulk Product), manufacture, processing,
packaging, registration for the SAH Indication, distribution, promotion, use or
sale of the Covered

 

49

 

product in the Territory,
except any such claim for which Syntex is responsible under Section 9.1 above.

 

9.3                                 Subject
to Sections 9.1 and 9.2 above, each party warrants that, in the performance of
their respective obligations hereunder, such party and their representatives
shall, at all times, comply with all applicable laws, rules and regulations
promulgated by any governmental authority having jurisdiction over the
activities contemplated hereby, including, without limitation, the
applicability of such laws, rules and regulations to the Agreement Compound NDA
for the Indications, the manufacture of the Covered Product, and the marketing,
distribution and sale of the Covered Product in the Territory.

 

10.                                 Term
and Termination

 

10.1                           The
initial term of this Agreement shall begin as of the effective date hereof and
shall extend for the life of the last to expire of the Licensed Patents and any
extension(s) thereof.

 

10.2                           The
Agreement shall be automatically renewed for successive renewal terms of four
(4) years each, unless either party notifies the other at least one (1) year
prior to the renewal date of its intention not to renew, in which event this
Agreement shall terminate upon expiration of the initial or renewal term (as the
case may be) without further notice.

 

10.3                           Either
party shall have the right to terminate this Agreement if the other party
commits a material breach of a

 

50

 

material obligation under this
Agreement and continues in default for more than ninety (90) days after
receiving written notice of such default from the non-defaulting party. Such
termination shall be effective upon further written notice to the defaulting
party after its failure to cure the default.

 

10.4                           Either
party shall also have the right to terminate this Agreement in the event the
other party is declared insolvent or bankrupt by a court of competent
jurisdiction, or a voluntary petition of bankruptcy is filed in any court of
competent jurisdiction by the other party, or the other party shall make or
execute an assignment for the benefit of the creditors, in which case
termination shall be effective upon written notice to that effect.

 

10.5                           In
order to ensure that Wyeth-Ayerst endeavors in good faith to market the Covered
Product in the Territory as required by Section 2.2 above, Syntex may also
terminate this Agreement after the end of any Plan Year, except the Initial
Plan Year and the next succeeding Plan Year, in which Wyeth-Ayerst’s unit sales
of Covered Product fall short of its estimates to be submitted under Sections
6.1 and 6.3, and approved by Syntex under Section 6.2, by more than [*] percent
([*]%), or in which Wyeth-Ayerst’s unit sales of Covered Product are less than
[*] percent ([*]%) of its unit sales for the prior Plan Year, or less than [*]
percent ([*]%) of its highest unit sales for any Plan Year. Since it is not

 

51

 

the parties’ intention to
terminate for depressed sales due to competitive market pressures, this Section
10.5 shall not be applicable to any Plan Year during which a non-Affiliated
third party enters the market in the Territory with a new product not
previously used or sold by anyone in the intravenous market for indications
that are the same as the approved Indications. If Syntex elects to terminate
pursuant to this Section 10.5, it must give notice of such election to
Wyeth-Ayerst within ninety (90) days after receipt of

Wyeth-Ayerst’s last Quarterly report for such Plan Year pursuant to Section
7.2(c) above. Prior to giving such notice or upon giving such notice, Syntex
agrees, at the request of Wyeth-Ayerst, to meet with Wyeth-Ayerst and discuss
whether this Agreement should be terminated as proposed or desired by Syntex.
If Syntex elects, in its sole discretion after any such meeting, to continue
with its desire to terminate this Agreement, termination under this provision
shall be effective six (6) months after the date of any such notice by Syntex
or three (3) years after initial launch of the Covered Product by Wyeth-Ayerst,
whichever is later.

 

10.6                           (a)                                  Upon
the termination or expiration of this Agreement, Syntex shall have the
obligation to purchase all of AHPC’s or Wyeth-Ayerst’s existing (at time of
termination) finished inventory of Covered Product, except any such Covered
Product that (a) does not meet the then-current specifications therefor, or (b)
has less than eighteen (18) months of shelf-life remaining if the

 

52

 

Covered Product has not been
launched in the Territory by Wyeth-Ayerst, or (c) has less than twelve
(12)-months of shelf-life remaining if the Covered Products has previously been
launched in the Territory by Wyeth-Ayerst, for AHPC’s or Wyeth-Ayerst’s
acquisition cost from Syntex of the Bulk Product plus (i) shipping costs
(including customs duties, brokerage fees, excise, sales or use taxes and other
governmentally-imposed taxes (if any) paid by AHPC or Wyeth-Ayerst with respect
to the shipment of such Bulk Product from Syntex’s delivery site of AHPC’s or
Wyeth-Ayerst’s storage or pharmaceutical manufacturing facility (as the case
may be), (ii) AHPC’s or Wyeth-Ayerst’s direct cost of production of the Covered
Product (not to exceed [*] percent ([*]%) of Average Net Selling Price),
excluding production yield losses if Syntex is providing free goods in support
thereof under Section 3.5(a) above, (ii) shipping costs (including customs
duties, brokerage fees, excise, sales or use taxes or other governmentally-imposed
taxes (if any) paid by AHPC or Wyeth-Ayerst with respect to the shipment of the
Covered Product from AHPC’s or Wyeth-Ayerst’s pharmaceutical manufacturing
facility (if outside the Territory) to the Territory, but excluding customs
duties, brokerage fees, excise, sales or use taxes and other
governmentally-imposed taxes (if any) under subsections (i) and (iii) above if Syntex
is providing free goods in support thereof under Section 3.5(b) above. For the
purposes of this Section 10.6 (a) “direct cost” shall mean direct labor, direct

 

53

 

materials other than Bulk
Product, and direct labor applicable to the production of the Covered Product.

 

10.6                           (b)                                 Syntex
shall also be obliged to purchase all of AHPC’s or Wyeth-Ayerst’s inventory of
Bulk Product for AHPC’s or Wyeth-Ayerst’s acquisition cost thereof from Syntex
plus (a) shipping costs paid by AHPC or Wyeth-Ayerst with respect to the
shipment of such Bulk Product from Syntex’s delivery site to AHPC’s or
Wyeth-Ayerst’s storage or pharmaceutical manufacturing facility (as the case
may be), and customs duties, brokerage fees, excise, sales or use taxes and
other

governmentally-imposed taxes (if any) paid with respect to shipment of the Bulk
Product into the Territory, but excluding customs duties, brokerage fees,
excise, sales or use taxes and other governmentally-imposed taxes (if any) if Syntex
is providing free goods in support thereof under Section 3.5(b) above.

 

10.6                           (c)                                  Syntex
shall pay for such goods as meet the applicable specifications therefor within
sixty (60) days after the receipt thereof by Syntex at Syntex’s designated
receiving facility.

 

10.6                           (d)                                 Wyeth-Ayerst
shall be permitted to continue to sell the Covered Product until the date of
termination or expiration hereof (as the case may be). As to Covered Product
that is not purchased by Syntex, Wyeth-Ayerst shall have the right to dispose
thereof by any lawful means, whether by sale, donation, destruction

 

54

 

or otherwise, but shall not
significantly undermine Syntex’s ability to profitably market the Covered
Product in the Territory after such termination or expiration.

 

11.                                 Confidentiality,
Non-Use and Public Statements

 

11.1                           (a)                                  Both
AHPC and Syntex recognize that information disclosed by Syntex to AHPC or
Wyeth-Ayerst pursuant to the Confidentiality Agreement effective February 18,
1993, between the parties, as well as technical, business and financial
information of either party exchanged pursuant to this Agreement, are of
proprietary value and are to be considered confidential (“Confidential
Information”). Each party agrees not be disclose or transfer the other party’s Confidential
Information to others (except to its employees who reasonably require the same
for the purposes hereof and who are bound to it by a like obligation as to
confidentiality) without the express written permission of the disclosing
party, except that neither party shall be prevented from using or disclosing
that portion of the Confidential Information received from the other that (i)
the receiving party can demonstrate by written records to be known to the
receiving party before the date of disclosure (from a source other than the
disclosing party); or (ii) is now, or becomes in the future, publicly available
other than by breach of this Agreement by either party; or (iii) is lawfully
disclosed to the receiving party on a non-confidential basis by a third party
who is not obligated to

 

55

 

retain such Confidential
Information in confidence. Information that AHPC or Wyeth-Ayerst receives from
Du Pont Merck or Berk (U.K.) shall be deemed received from Syntex hereunder and
subject to the terms and conditions hereof as if received directly from Syntex.

 

11.1                           (b)                                 Each
party’s obligation of confidentiality set forth herein shall continue for a
period ending five (5) years after termination or expiration (as the case may
be) of this Agreement; except that either party’s obligation with respect to
information designated in writing by the other as highly proprietary shall
continue indefinitely. Neither party shall, however, submit or disclose
information that it considers highly proprietary to the other unless and until
the disclosing party obtains the receiving party’s written approval to receive
such information on the “highly proprietary” basis.

 

11.2                           All
information developed by AHPC or Wyeth-Ayerst in the performance of services
hereunder by the use of Syntex Confidential Information shall be considered
Syntex Confidential Information and shall be treated as such by Wyeth-Ayerst
pursuant to the provisions of Section 11.1 above. APHC and Wyeth-Ayerst shall
not use any Syntex Confidential Information except for the purpose of carrying
out its obligations under this Agreement.

 

11.3                           Except
as required to comply with federal and state securities laws or other laws, or
any order of a court or

 

56

 

government agency, neither
party shall publicly release information concerning this Agreement or the
subject matter hereof without first sending the other party, by facsimile or
express mail, a copy of the information to be disclosed, and allowing the other
party a period of five (5) business days from the date of receipt by the other
party to comment on the information. If the other party objects to the
information to be disclosed, then prior to the expiration of the five (5) day
period, the other party shall so notify the disclosing party, who shall then
delay public disclosure of the information and make reasonable efforts to
accommodate any requests for revisions made by the other party. If no
notification is received during the five (5) day period, the party proposing
disclosure shall be free to disclose the information. In the event the parties
disagree regarding disclosure of certain information pursuant to the review and
approval procedure required by this Section 11.3, the parties agree to confer
in good faith in an attempt to reach a mutually-satisfactory resolution with
respect to the information that is the subject matter of the disagreement. The
parties designate the following individuals to receive and approve releases
under this provision: Syntex - Vice President, Public Affairs; Wyeth-Ayerst -
Director of Public Affairs.

 

12.                                 Accounting
Procedures

 

12.1                           AHPC
and Wyeth-Ayerst shall keep complete and accurate records in connection with
the payments provided for under this

 

57

 

Agreement. Syntex shall have
the right to nominate an independent firm of certified public accountants
acceptable to AHPC and Wyeth-Ayerst who, after giving reasonable notice, shall
have access to the books and records of AHPC and Wyeth-Ayerst during regular
business hours for the purpose of verifying any amounts payable under this
Agreement. Such firm of certified public accountants shall not disclose to
Syntex any information other than information relating to the accuracy of, or
of the necessity for, any payment made or required to be made hereunder. The
fees and expenses of the firm of certified public accountants performing such
verification shall be borne by AHPC if such verification shows an underpayment
by AHPC to Syntex of [*] percent ([*]%) or more; in any other event, the fees
and expenses of the firm of certified public accountants performing such
verification shall be borne by Syntex.

 

13.                                 Governing
Law

 

13.1                           This
Agreement shall be governed by and interpreted in accordance with the laws of
the State of California (regardless of its, or any other jurisdiction’s, choice
of law principles).

 

14.                                 Assignment
and Delegation

 

14.1                           Syntex
shall have the right to:

 

(a)                                  assign
this Agreement or transfer any part of its interest under this Agreement to any
Affiliate, or

 

(b)                                 designate
and cause any Affiliate to perform all or part of its activities hereunder, or
to have the benefit of

 

58

 

all or part of its rights hereunder.

 

14.2                           AHPC
shall have the rights, with Syntex’s prior written approval, which shall not
unreasonably withheld, to:

 

(a)                                  assign
this Agreement or transfer any part of its interest under this Agreement to any
Affiliate, or

 

(b)                                 designate
and cause any Affiliate to perform all or part of its activities hereunder, or
to have the benefit of all or part of its rights hereunder,

 

provided that AHPC
demonstrates, to Syntex’s reasonable satisfaction, that such Affiliate has at
least the interest in, and at least the capability with respect to, that
interest or activity(ies) with respect to the Covered Product that are being
assigned or delegated to such Affiliate as Wyeth-Ayerst had at the time this
Agreement was entered into.

 

14.3                           In
addition to Section 14.2 above, AHPC shall have the right, without Syntex’s
prior written consent, to assign this Agreement, or transfer any part of its
interest under this Agreement, in connection with a reorganization of AHPC to
any Affiliate operating as a Wyeth-Ayerst activity with Wyeth-Ayerst employees,
provided that such Affiliate has at least the interest in, and at least the
capability with respect to, that interest or activity(ies) with respect to the
Covered Product that are being assigned or delegated to such Affiliate as
Wyeth-Ayerst had at the time this Agreement was entered into.

 

59

 

14.4                           In
the event of any assignment, transfer or designation permitted under Sections
14.1, 14.2 or 14.3 above, the respective Affiliate shall assume and be bound by
the provisions of this Agreement and its performance under this Agreement shall
be guaranteed by the transferring party.

 

14.5                           This
Agreement shall be binding upon and inure to the benefit of the successors or
permitted or approved assigns of Syntex or AHPC, respectively, provided that
any such successor or assign shall have acquired all or substantially all of
the stock or assets of its predecessor by reorganization, incorporation,
merger, consolidation, purchase or otherwise. Otherwise this Agreement shall be
assignable, and the rights and obligations of the parties may be transferred or
delegated (except to the limited extent provided in this Article 14) only with
the consent in writing of the other party hereto.

 

14.6                           Syntex
shall promptly notify AHPC of any such assignment, transfer or designation
permitted under Section 14.1 above and the effective date thereof.

 

15.                                 Force
Majeure

 

15.1                           Neither
party hereto shall be liable in damages for, nor shall this Agreement be
terminable or cancelable by reason of, any delay or default in such party’s
performance hereunder if such default or delay is caused by events beyond such
party’s reasonable control (“force majeure”) including, but not limited to,
acts of

 

60

 

God; regulation or law or other
action of any government or agency thereof; war or insurrection; civil
commotion; destruction of production facilities or materials by earthquake,
fire, flood or storm; labor disturbances; epidemic; or failure or suppliers,
public utilities or common carriers.

 

15.2                           In
the event the performance of either party’s obligations to the other party is
affected by force majeure as provided for in Section 15.1 above, the party so
affected shall treat its obligations under this Agreement no less favorably
than such party treats any of its own operations or any third party.

 

15.3                           Each
party shall endeavor to resume its performance hereunder as soon as reasonably
possible if such performance is delayed or interrupted by reason of force
majeure.

 

16.                                 Severability

 

16.1                           Should
any part of this Agreement be held unenforceable or in conflict with the
applicable laws or regulations of any jurisdiction, the invalid or
unenforceable part or provision shall be replaced with a provision that
accomplishes, to the extent possible, the original business purpose of such
part or provision in a valid and enforceable manner, and the remainder of this
Agreement shall remain binding upon the parties hereto.

 

17.                                 Captions

 

17.1                           The
captions of this Agreement are solely for the convenience of reference and
shall not affect its interpretation.

 

61

 

18.                                 Notices

 

18.1                           Unless
otherwise provided herein, any notices, payment, report or other correspondence
(hereinafter collectively the “Correspondence”) required or permitted to be
given hereunder shall be sent by certified or registered mail, postage prepaid,
or delivered by hand to the party to whom such Correspondence is required or
permitted to be given hereunder. If mailed, any such Correspondence shall be
deemed to have been given when mailed, as evidenced by the postmark at the
point of mailing. If delivered by hand, any such Correspondence shall be deemed
to have been given when received by the party to whom such Correspondence is
given, as evidenced by written and dated receipt of the receiving party.

 

18.2                           All
Correspondence to Syntex shall be addressed as follows:

 

Syntex
Laboratories, Inc.

3401 Hillview
Avenue

Palo Alto,
California 94304

Attention:
President

 

With a copy
to:

 

Syntex (U.S.A.)
Inc.

3401 Hillview
Avenue

Palo Alto,
California 94304

Attention:
Associate General Counsel and 

Director,
Commercial Contracts

and General
Law Department

 

62

 

18.3                           All
Correspondence to AHPC shall be addressed as follows:

 

Wyeth-Ayerst
Laboratories

P.O. Box 8299

Philadelphia,
Pennsylvania 19101

Attention:
Senior Vice President

Business Development

 

With a copy
to:

 

Wyeth-Ayerst
Laboratories

P.O. Box 8299

Philadelphia,
Pennsylvania 19101

Attention: Assistant General Counsel &

Director, Legal Division

 

18.4                           Either
party may change the address to which any Correspondence to it is to be
addressed by notification to the other party as provided herein.

 

19.                                 Survival

 

19.1                           Sections
5.2 (a), 5.3 (d), 6.7, 7.7, 7.8, 8.2(a), 8.2(b), 9.1, 9.2, 9.3, 11.1, 11.2,
13.1, 13.2, 13.3 and 14.4 shall survive expiration or termination (as the case
may be) of this Agreement.

 

19.2                           The
provisions of this Agreement that do not survive expiration or termination (as
the case may be) of this Agreement shall, nonetheless, be controlling on, and
shall be used in construing and interpreting the rights and obligations of the
parties hereto with respect to any dispute, controversy or claim

 

63

 

that may arise under, out of,
in connection with, or relating to any act (or failure to act) that occurred
during the term of this Agreement (including the initial term and any renewal
thereof).

 

20.                                 Independent
Party

 

20.1                           AHPC
shall act solely as an independent party and nothing in this Agreement shall be
construed to give either party the power or authority to act for, bind or
commit the other party hereto in any way whatsoever. Accordingly, neither party
shall use or refer to the name or business logo (if any) of the other party or
its Affiliates or this Agreement without the prior written consent of the other
party.

 

21.                                 Waiver

 

21.1                           The
failure on the part of AHPC or Syntex to exercise or enforce any rights
conferred upon it hereunder shall not be deemed to be a waiver of any such
rights nor operate to bar the exercise or enforcement thereof at any time or
times thereafter, unless specifically set forth in writing and executed and
delivered by a duly authorized representative of each of the parties hereto.

 

22.                                 Entire
Agreement

 

22.1                           This
Agreement and the Schedules hereto constitutes the entire understanding as of
the effective date hereof between the parties with respect to the subject
matter hereof and supersedes all prior agreements, negotiations, understandings,
representations, statements and writings relating thereto. No

 

64

 

modification, alteration,
waiver or change in any of the terms of this Agreement shall be valid or
binding upon the parties hereto unless made in writing and duly executed and
delivered by each of the parties.

 

IN WITNESS
WHEREOF, this Agreement has been executed and delivered by each party with the
intent that it be binding upon the parties hereto in accordance with the terms
and conditions hereof.

 

 

	
  SYNTEX
  (U.S.A.) INC.

  	
  AMERICAN HOME PRODUCTS

  CORPORATION

  
	
   

  	
   

  
	
   

  	
   

  
	
  By

  	
  /s/ Richard Powers

  	
   

  	
  By

  	
  /s/ Fred Hassan

  
	
   

  	
   

  
	
  Print Name

  	
  Richard Powers

  	
   

  	
  Print Name

  	
  FRED HASSAN

  
	
   

  	
   

  
	
  Title

  	
  Vice President

  	
   

  	
  Title

  	
  SVP

  
	
   

  	
   

  
	
  Date

  	
  September 14, 1993

  	
   

  	
  Date

  	
  9/30/93

  
											

 

 

Schedule A

 

Specifications for the Bulk Product

 

65

 

Schedule B

 

Clinical Coordinators and Marketing Coordinators

 

66

 

Five Giralda Farms

Madison, NJ 07940

 

 

October 30, 2003

 

ESP Pharma, Inc.

2035 Lincoln Highway, Suite
2150

Edison, New Jersey 08817

 

Re:                               Cardene
IV Sublicense and Supply Agreement

Acebutolol License Agreement

 

Gentlemen:

 

Reference is made to the
agreements listed in I and II below (together referred to as the “Agreements”):

 

I.                                         Sublicense
and Supply Agreement, dated September 1, 1993 as amended January 8, 2001,
between Wyeth (formerly American Home Products Corporation) acting through its
Wyeth Pharmaceuticals Division (formerly Wyeth-Ayerst Laboratories Division)
and Syntex (U.S.A) Inc.; and

 

II.                                     Acebutolol
License Agreement, dated November 9, 1977, by and between Aventis S.A. (as
successor to Rhone-Poulenc Rorer S.A. and Rhone-Poulenc Sante, together “Aventis”)
and Wyeth (as successor to American Home Products Corporation).

 

Since ESP has repaid all
amounts owed to Wyeth under the Senior Secured Promissory Note, dated May 22,
2002, in the principal amount of $9.5 million and all pertinent conditions have
been met and all necessary consents have been obtained, Wyeth hereby assigns
and ESP accepts assignment of each of the Agreements. It is agreed and
understood that ESP shall have the responsibility to comply with all of the
terms and conditions of each of the Agreements and Wyeth shall have no further
responsibility under either of the Agreements as of the date of this letter.

 

 

	
   

  	
  Wyeth
  Pharmaceuticals

  
	
   

  	
  Wyeth
  Consumer Healthcare

  
	
   

  	
  Fort Dodge
  Animal Health

  

 

 

By signing below, you confirm
your agreement with the above terms.

 

Sincerely,

 

 

	
  /s/ Jeffrey
  S. Sherman

  	
   

  
	
  Jeffrey S.
  Sherman

  
	
  Vice
  President and Associate General Counsel

  
	
   

  
	
   

  
	
  Agreed and
  Accepted

  
	
  ESP Pharma,
  Inc.

  
	
   

  
	
   

  
	
  By: 

  	
  Anthony A. Rascio

  	
   

  
	
  Name:
  ANTHONY A. RASCIO

  
	
  Title:
  SENIOR VICE PRESIDENT

  
				

 

2Exhibit 10.2

 

CERTAIN INFORMATION IN THIS
EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY WITH THE COMMISSION. CONFIDENTIAL
TREATMENT HAS BEEN REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.

 

	
   

  	
  

  
	
   

  	
  Pharmaceuticals

  

 

David R. Austin

Sr. Vice President and CFO

 

September 5, 2003

 

Howard Weisman

President

ESP Pharma

2035 Lincoln Highway, Suite
2150

Edison, NJ 08817

 

Re:                               Sublicense
and Supply Agreement

 

Dear Howard:

 

This letter, when signed for
ESP and returned to me, will amend the Sublicense and Supply Agreement of
September 1, 1993, (that is under agreement for assignment by American Home
Products Corporation, now Wyeth, to ESP) (the Agreement) on the first day of a
calendar quarter following the assignment of the Agreement to ESP and the
fulfillment of all the conditions for license assignment enumerated in the
letter agreement of April 18, 2002, among Wyeth, ESP and Roche (formerly Syntex
(U.S.A.) LLC), provided that there be no disputes about payments due Roche and
also provided that the Quality Agreement and side letter regarding quality,
both dated June 2003, are signed by all applicable parties (“Amendment Date”).
The licensor in this agreement is now Roche Palo Alto LLC, formerly Syntex
(U.S.A.) Inc.

 

The parties hereby agree to the
following amendments:

 

1.                                       Section
1.2 shall be amended by deleting from that section all of subsection (b),
beginning with “divided by” and continuing through the end of that section. And
the defined term “Average Net Selling Price” shall be replaced throughout the
Agreement with the term “Net Sales.”

 

2.                                       Section
3.4(a) shall be replaced in its entirety by the following:

3.4(a) The initial price of Bulk Product shipped to ESP, or its designated
manufacturer, shall be [*] dollars ($[*]) per kilogram through December 31,
2004.

 

	
  Roche Palo
  Alto LLC 

  	
  5491 Hillview
  Ave.

  	
  Tel.
  850-852-1140

  
	
   

  	
  Palo Alto,

  	
  Fax
  850-254-7645

  
	
   

  	
  California
  94304-1497

  	
  David.Austin@roche.com

  

 

 

Annually
thereafter, beginning on January 1, 2005, and thereafter beginning on the first
day of the calendar year, the price shall be increased or decreased by the
percentage increase or decrease in the U.S. Producer Price Index for Chemicals
and Allied Products (WPU006) for the immediately preceding calendar year. There
shall be no decrease in price below [*] dollars ($[*]) per kilogram.

 

3.                                       Section
3.4(b) shall be replaced in the entirety by the following:

3.4(b) From
the Amendment Date until December 31, 2003, ESP shall pay to Roche a royalty of
[*] percent ([*]%) of Net Sales. Beginning January 1, 2004, ESP shall pay Roche
a royalty on its Net Sales as follows, calculated on an annual basis using a
calendar year:

 

1)              On
the first $[*] of Net Sales, a royalty equal to [*] percent ([*]%) of Net Sales;

 

2)              On
the next $[*] of Net Sales, a royalty equal to [*] percent ([*]%) of Net Sales;

 

3)              On
Net Sales in excess of $[*], a royalty equal to [*] percent ([*]%) of such
excess;

 

4.                                       Section
3.4(c) shall be replaced in its entirety by the following:

3.4(c) Within
sixty (60) days after the end of each calendar Quarter, ESP shall calculate and
report to Roche for such previous quarter the (i) gross sales of Covered
Product made by ESP or its distributor, (ii) Net Sales (including those sales
to a distributor) of Covered Products, (iii) cumulative annual Net Sales for
the current calendar year, (iv) the amount of Bulk Product (at label strength)
contained in the Covered Products sold by ESP during such covered Quarter, and
(v) the calculation of payments due. With such report, ESP shall remit in U.S.
dollars to Roche the payment due pursuant to Section 3.4(b).

 

5.                                       Section
3.4(d) shall be deleted in its entirety and shall be replaced by the existing
3.4(e).

 

6.                                       Section
3.4(f) shall be renumbered to become Section 3.4(e).

 

7.                                       Sections
3.5(a), (b) and (c) and all of Section 3.6 shall be replaced in their entirety
by the following:

3.5(a) Roche
shall provide free Bulk Product to ESP on a quarterly basis at the rate of [*]
percent ([*]%) of the number of grams at label strength contained in the
Covered Product sold by ESP during the last Quarter for which ESP reported
sales pursuant to Section 3.4(c). Such free Bulk Product shall be added to
shipments of Bulk Product ordered by ESP, and if no such shipment is made
during any Quarter, the free Bulk Product shall be added to the next shipment made,
if there is one. Such free Bulk Product shall be all the material supplied by
Roche for samples, yield losses, overfill or other manufacturing issues; the
only exception shall be replacement pursuant to Section 3.2 for Bulk Product
that does not meet specifications set forth in Schedule A.

 

2

 

8.                                       The
transition from the old agreement pricing to the pricing above will be
accomplished in the following manner, which is exemplified in the model
attached as Exhibit A. Baxter (for inventory only) and ESP shall verify a
calculation of the Transitional Royalty Credit (as defined below) substantially
in the form of Exhibit A attached hereto which is provided as an example of how
such calculation is made.

 

8.1                                 ESP
and Baxter shall verify the amount of unsold inventory of Bulk Product, work in
process (“W-I-P”) and Covered Product on the day prior to the Amendment Date
(“Audit Date”) and determine the Total Grams of Bulk Product and Invoiced Grams
of Bulk Product as described herein.

 

(a)          The
grams of Bulk Product contained in the W-I-P and Covered Product on the Audit
Date shall be calculated by taking the number of individual ampoules in the
W-I-P and Covered Product multiplied by 0.025 grams (the “Raw Material Equivalent”).

 

The Raw Material Equivalent shall be added to the grams of Bulk Product
on hand as of the Audit date to determine the “Total Grams of Bulk Product.”

 

(b)         ESP
shall calculate a percentage (the “Invoiced Grams Percentage”) by taking 100%
minus (i) [*]% for Bulk Product acquired before September 1st, 2003, and (ii)
[*]% for Bulk Product acquired after September 1st, 2003.

 

(c)          ESP
shall multiply the Total Grams of Bulk Product by the applicable Invoiced Grams
Percentage to determine the total Invoiced Grams of Bulk Product.

 

These results
shall be reported to Roche within ten (10) days after the Audit Date. ESP shall
keep accurate records of such inventory and Roche shall have the option of
auditing such records and corresponding batch records.

 

8.2                                 The
parties agree to use [*] ($[*]) as the weighted average price for the previous
three quarters to be used for this calculation, provided that if the Average
Net Selling Price Per Gram for Q3 2003 varies from $[*], the actual Average Net
Selling Price Per gram for Q3 shall be used to calculate the weighted average
price according to the method in Exhibit A.

 

8.3                                 Multiply
the Invoiced Grams of Bulk Product by the weighted average price calculated in
accordance with 8.2 above.

 

8.4                                 Roche
shall credit the resulting number in 8.3 against the first payments due Roche
from ESP.

 

8.5                                 ESP
shall pay Roche $[*] times the Total Grams of Bulk Product from 8.1 as payment
for those grams ten (10) days after the Audit Date.

 

9.                                       Beginning
with the date of the signing of this letter and continuing until the earlier of
(i) the Amendment Date or (ii) December 31, 2003, Roche shall grant ESP on a
per Bulk Product shipment basis an additional [*] percent ([*]%) credit for
free goods, for a total

 

3

 

of [*] percent
([*]%) when added to the [*] percent ([*]%) now given pursuant to Section
3.6(a). This shall be the total of free goods available to ESP and ESP agrees
not to make any claim against Roche under Section 3.4(d) of the License and
Supply Agreement.

 

All other terms of the
Agreement remain in full force and effect.

 

	
  Sincerely,

  
	
   

  
	
  /s/ David R.
  Austin

  	
   

  
	
  David R.
  Austin

  
	
   

  
	
   

  
	
  AGREED

  
	
  ESP PHARMA,
  INC.

  
	
   

  
	
   

  
	
  By 

  	
  /s/ Howard
  Weisman

  	
   

  
	
  Name

  	
  Howard
  Weisman

  	
   

  
	
  Date

  	
  9-8-03

  	
   

  
					

 

4

 

EXHIBIT A

 

Example of Transition Arrangement
ESP Contract Change

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