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Glycyx Pharmaceuticals, Ltd.
Xxxxxxx Xxxxxxxx, 0xx Xxxxx
00 Xxxx Xxxxxx
Xxxxxxxx, Xxxxxxx XX00
February 5, 1999
Fujirebio Inc.
FR Bldg., 62-5,
Xxxxxxxxxx-xxxxxxx 0-xxxxx
Xxxx-xx, Xxxxx 000-0000
Xxxxx
Gentlemen:
This letter (the "Letter of Intent") is intended to confirm our agreement
concerning a license arrangement between Fujirebio Inc. ("Fujirebio") and Glycyx
Pharmaceuticals, Ltd. ("Glycyx") with respect to compounds covered by the
patents and patent applications listed on Exhibit A hereto, including without
limitation the compound {(+)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-
pyridyl]oxy-(z)-2-butenyl]acetamide}, and prodrugs, analogs, isomers, salts
and/or metabolites thereof (hereinafter collectively referred to as
"Lafutidine"), together with (i) the inventions described in the patents and
patent applications listed on Exhibit A hereto together with any other patents
and patent applications worldwide relating to Lafutidine which are owned or
controlled by, or licensed together with a right to sublicense to, Fujirebio
during the term of the agreement (collectively, the "Patent Rights"), and (ii)
all related improvements, inventions, derivatives, formulation data,
specifications, manufacturing procedures and technology, technical information,
know-how, trade secrets, tradenames, trademarks, pharmacology, toxicology and
other pro-clinical data, clinical data, regulatory information, marketing data
and other intellectual property rights relating thereto owned or controlled by,
or licensed together with a right to sublicense to, Fujirebio during the term of
the agreement (collectively, the "Technology Rights"), on the terms and
conditions set forth below.
1. The parties shall proceed promptly and in good faith to negotiate the
terms of, and when agreement is reached, to execute, deliver and perform, a
definitive license agreement (the "License Agreement") regarding the grant by
Fujirebio to Glycyx of an exclusive license (with right to grant and authorize
sublicense) to Lafutidine, the Patent Rights and Technology Rights in order to
develop, make, have made, use, import, have imported, offer for sale, sell and
have sold pharmaceutical preparations containing Lafutidine (collectively, the
"Product") for all indications throughout the world, excluding Japan, Taiwan,
Korea, Brazil and Argentina (the "Territory"). The License Agreement shall be
consistent with the terms set forth in Exhibit B attached hereto, and shall
contain such other covenants, conditions, indemnities, representations and
warranties as are usual and customary in a license arrangement of this type.
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2. In consideration of Fujirebio's obligations hereunder and in an effort
to obtain additional information necessary to determine the economic terms of
the License Agreement and to promptly commercialize Lafutidine, Glycyx agrees to
perform the tasks set forth in Exhibit C and Glycyx further agrees to make the
following payments to Fujirebio as provided in Exhibit B, II.1.(1) and (2):
(i) US Dollars *** upon signing of this Letter of Intent, namely, at
latest, within one week after the date on which Glycyx signed this Letter of
Intent and,
(ii) US Dollars *** within one week after Fujirebio's delivery to
Glycyx of the first package of the Information which includes all the available
documents regarding technical, manufacturing, preclinical matters and some
clinical documents (excluding an English translation of the clinical tests) as
specified in Exhibit B, I.8.(I).
Such payments shall be made by cable transfer to Fujirebio's bank account in
Japan without holding any tax.
3. Fujirebio represents and warrants that it has not entered into any
other agreement or understanding concerning Lafutidine, the Patent Rights and/or
the Technology Rights in any part of the Territory. In consideration of the
significant effort to be incurred by Glycyx in fulfilling its obligations
hereunder, Fujirebio agrees that neither it nor any of its agents or employees
shall, for six months from signing of this Letter of Intent (the "Exclusivity
Period"), directly or indirectly, encourage, initiate, engage in or enter into
solicited or unsolicited discussions, negotiations, arrangements or
understandings with any other party regarding the license of Lafutidine and/or
any Patent Rights and/or the Technology Rights in the Territory. In the event
that the parties have not executed the License Agreement prior to the end of the
Exclusivity Period, this Letter of Intent shall terminate and Fujirebio shall
have the right to negotiate and enter into such an arrangement with a third
party; provided, that Fujirebio has negotiated in good faith with Glycyx during
the Exclusivity Period.
4. During the Exclusivity Period, Fujirebio will provide Glycyx with all
information reasonably requested by Glycyx and available to Fujirebio regarding
Lafatidine, the Patent Rights and the Technology Rights. Further, Fujirebio
agrees to provide Glycyx with a reasonable quantity of Product and/or its
placebo that have been already manufactured at its own manufacturing site free
of charge for the purpose of a human pharmacology study mentioned in Exhibit C
if Glycyx wishes to receive such products.
5. Glycyx agrees that any human study mentioned in Exhibit C shall be
performed in accordance with terms and conditions mentioned in Exhibit B III R&D
Works, Article 2, 3, 4, 6, 7 and 8. Further, Glycyx agrees to hold Fujirebio
harmless from any damage, loss, cost or expenses arising out of any third
person's claim relating to any human study mentioned in Exhibit C, except due to
negligence or willful misconduct of Fujirebio.
6. The parties hereto acknowledge that the secrecy agreement executed on
June 10, 1997 between Fujirebio and Salix Holding, Ltd., Glycyx's parent company
(the "Secrecy
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Agreement") shall remain effective as it is, and the same secrecy obligations as
set forth in the Secrecy Agreement shall be applicable to and binding Glycyx.
Glycyx shall use neither Lafutidine nor Product for any other purpose than those
set forth herein, and shall keep in confidence any information, results and data
arising from the tasks set forth in Exhibit C.
7. This Letter of Intent shall be governed by and construed in accordance
with the laws of Japan, without giving effect to any conflict of laws, principle
or rules. In the event that a dispute hereunder cannot be settled through a good
faith discussion among the parties hereto within a reasonable period, such a
dispute shall be finally settled by an arbitration in accordance with the United
States -- Japan Trade Arbitration Agreement of September 16, 1962. The
arbitration shall be held in San Francisco, CA if initiated by Fujirebio, and in
Tokyo, Japan if initiated by Glycyx. All correspondence and proceedings
hereunder shall be in English.
8. Each party shall use its good faith efforts to promptly carry out the
terms of this Letter of Intent. If either party fails to perform a material
obligation of this Letter of Intent, the other party may terminate this Letter
of Intent upon written notice to the defaulting party if the nondefaulting party
has notified the other party in writing of such failure and such failure has not
been corrected within thirty (30) days after receipt of such notice.
9. Upon the termination hereof, Glycyx shall return to Fujirebio all the
information on Lafutidine provided from Fujirebio under this Letter of Intent or
that provided by Fujirebio to Salix Holdings, Ltd. under the Secrecy Agreement
and all unused Sample and/or its placebo, if any, and Glycyx agrees that data
from a human study to be performed in accordance with Exhibit C shall be
transferred to Fujirebio free of charge and Fujirebio has the right to use such
data in any country for obtaining governmental approvals and commercialization
of the Product and Compound. The terms of Article 5 (Glycyx's obligation to hold
Fujirebio harmless) and the Article 6 survive the termination of this Letter of
Intent. Unless it is necessary for Fujirebio's filing for approval and
commercialization, Fujirebio agrees not to disclose to any third party any
Glycyx's trade secret received from Glycyx during the Exclusivity Period without
prior written consent of Glycyx, which shall not be withheld unreasonably, and
this clause survives the termination of this Letter of Intent.
10. Notices and all other communications in connection with this Letter of
Intent shall be in writing (in English language) sent to the addresses set forth
above or as otherwise specified by the parties, and shall be sent simultaneously
by air express service and by facsimile to the other party. Such notices shall
be deemed given when received.
11. This Letter of Intent shall constitute a binding agreement between the
parties, contains the entire agreement between Fujirebio and Glycyx concerning
the subject matter hereof, and supersedes all prior agreements (except for the
Secrecy Agreement) and understandings concerning the subject matter hereof. No
amendment, modification or waiver of this Letter of Intent shall be valid or
binding unless set forth in writing signed by both parties. This Letter of
Intent may not be assigned or otherwise transferred by a party without the prior
written consent of the other party. This Letter of Intent may be executed in
counterparts, all of which when taken together shall constitute one agreement
binding on all parties.
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If the above correctly reflects our mutual agreement, please sign and
return one copy of this Letter of Intent. We look forward to a long and mutually
beneficial relationship between Fujirebio and Glycyx.
Very truly yours,
GLYCYX PHARMACEUTICALS, LTD.
/s/ XXXX XXXXXX
Xxxx Xxxxxx, President
Accepted and agreed this
9th Day of February, 1999
FUJIREBIO INC.
By: /s/ XXXXXXXX XXXXXX
---------------------------------
Xxxxxxxx Xxxxxx, M.D., Ph.D.
Title: President
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EXHIBIT A
LIST OF LAFUTIDINE PATENTS
--------------------------------------------------------------------------------
Application Number Patent Number
(date) (date) Countries
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Substance Patent US166022 US4912101 USA
(Mar. 9, 1988) (Mar. 27, 1990)
--------------------------------------------------------------------------------
Substance Patent EP88103890.5 EP282077 CH, DE, FR, GB, IT,
(Mar. 11, 1988) (Nov. 11, 1993) NL
--------------------------------------------------------------------------------
Process Xxxxxx XX00/000000 XX0000000 XXX
(Aug. 6, 1993) (Apr. 1, 1997)
--------------------------------------------------------------------------------
Process Patent EP93112595.9 EP582304 AT, BE, CH, DE, DK,
(Aug. 5, 1993) (Apr. 0, 0000) XX, XX, XX, XX, XX,
IT, LI, LU, MC, NL,
PT, SE
--------------------------------------------------------------------------------
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EXHIBIT B
SUMMARY OF LICENSE TERMS
The parties acknowledge and agree that, during the Exclusivity Period, they will
work together to gather additional information to determine and negotiate in
good faith the elements of the License Agreement. The parties agree that such
terms will be subject to the following general parameters:
I. OVERVIEW
-----------
1. SUBJECT: Lafutidine and related Patent Rights and Technology
Rights
2. LICENSOR: Fujirebio Inc.
LICENSEE: Glycyx Pharmaceuticals, Ltd.
3. TERRITORY: All territories outside of Brazil, Argentina, Japan,
Taiwan and Korea.
4. PRINCIPAL MARKETS: USA, United Kingdom, Germany and France.
5. COMPOUND: Active ingredient (Lafutidine)
PRODUCT: Pharmaceutical/therapeutic and/or prophylactic
preparations containing COMPOUND
6. INDICATIONS: All indications
7. GRANT OF LICENSE: An exclusive license to Lafutidine, the Patent Rights
and Technology Rights in order to develop, make, have
made, use, import, have imported, offer for sale, sell
and have sold Products within TERRITORY. LICENSEE
shall have right to grant and authorize sublicenses
with prior consent of LICENSOR, not to be unreasonably
withheld (use of a distributor shall not be considered
a sublicense). LICENSEE shall have option to obtain a
royalty free license to applicable trademark of
LICENSOR.
8. INFORMATION TRANSFER: LICENSOR (i) to provide, within thirty (30) days after
the date of Letter of Intent, LICENSEE with (at
LICENSOR's costs without charge) ENGLISH translation
of all then available documents regarding
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technical, manufacturing, pre-clinical matters and
some clinical documents necessary for the tasks
mentioned in Exhibit C as the first package (except
for an ENGLISH translation of the clinical test
documents) and, (ii) to provide LICENSEE with
remaining ENGLISH translation of documents regarding
clinical tests and regulatory filings prior to
LICENSEE's FDA consultation during the period of
Letter of Intent, and thereafter from time to time as
developed by LICENSOR or its licensees. LICENSEE's
license shall include right to use any such documents
to support LICENSEE's regulatory filings. LICENSOR to
provide reasonable technical assistance requested by
LICENSEE. LICENSOR to procure and maintain all export
and other licenses and permits required to transfer
the technology and to grant the license, and shall
comply with all other laws, regulations and
governmental directives relating thereto.
9. R&D WORKS: Additional works, at LICENSEE's risk, sole
discretion (after consulting with LICENSOR) and
expense, necessary for registration.
10. NET SALES: ***
11. UNIT: One tablet (which means Product) containing 10mg of
Compound
12. Net Sales Price: Net Sales divided by Unit sold on a country-by-country
basis
II. ECONOMICAL CONDITIONS
-------------------------
1. LICENSE FEES (US$): The following License Fees are non-creditable and
non-refundable in any case.
***
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***
2. ROYALTY (US$)
a) Countries of exclusive license
(1) Patented Countries: ***
(2) Other Countries: ***
b) Countries of non-exclusive
license: ***
c) Launch obligations in LICENSEE to launch Product within 9 months
exclusive-license Principal following receipt of all necessary marketing and
Markets pricing approvals in a given Principal Market.
d) Failure to launch in Failure to launch within specified period shall,
Principal Market if not cured within Market 60 days notice to
LICENSEE, cause license in such Principal Market
to become non-exclusive.
3. SUPPLY
---------
a) Exclusive Purchase LICENSEE shall purchase Compound or Product
exclusively from LICENSOR for sale in Territory;
provided LICENSOR can supply same under
applicable GMP for sale in a given country (and
meeting all applicable regulatory requirement)
and
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for so long as patent exists preventing others
from manufacturing Compound for sale or until
the tenth anniversary of the sales of Product,
whichever is longer, on a country-by-country
basis, provided that if any generic product is
launched in a given country, the parties shall
reconsider the export price for such country.
LICENSOR shall provide at least one regulatory
certified site to supply each of Compound and/or
Product, as applicable, and shall make its best
effort to secure the second regulatory certified
site. Notwithstanding such effort, if LICENSOR
fails to find any candidate of the second site
one year before the estimated date of the first
New Drug Application of the Product in a given
country of the Principal Markets, LICENSEE may
secure it with LICENSOR's prior consent which
shall not be unreasonably withheld.
b) Price (FOB Tokyo): *** on a country-by-country basis, or bottom
(1) In case of Compound: price (which shall be agreed upon during the
license agreement negotiation), whichever is
higher.
(2) In case of Product: *** on a country-by-country basis, or bottom
price (which shall be agreed upon during the
license agreement negotiation), whichever is
higher.
4. MINIMUM PURCHASE The parties shall decide the Minimum Annual
Purchase Quantity of Product or Compound during
the license agreement negotiation.
5. SUBLICENSE PAYMENTS LICENSEE to pay LICENSOR *** of upfront license
fees received by LICENSEE from third parties for
sublicense right hereunder (excluding payments
paid by third parties for research/development
funding and/or reimbursement of expenses, or
payments which relate to the issuance of debt or
equity securities of LICENSEE or its affiliate).
III. R & D WORKS
---------------- LICENSEE to be responsible for all aspects of
R&D Works within Territory in accordance with
the following terms and conditions.
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1. TIMETABLE: LICENSEE shall submit to LICENSOR proposed
development timetables including estimated
milestones of each steps in Principal Markets
for LICENSOR's review. LICENSOR may give
comments on it and LICENSEE shall take into
account such comments as far as it is
practically feasible. LICENSEE further agrees to
discuss from time to time with LICENSOR possible
timetables for Product launch in other countries
than Principal Markets.
2. PROTOCOL: LICENSEE shall submit to LICENSOR for its review
of the protocol of each study in R&D Work, and
LICENSOR may give comments on it and LICENSEE
shall take into account such comments as far as
it is practically feasible, and LICENSEE
reserves the right to make a final decision on
the protocol.
3. INDICATIONS: Initial indication proposed to be for
NSAID-induced ulcers. Additional indications to
be determined by LICENSEE after discussion
between LICENSOR and LICENSEE.
4. PERFORMANCE: LICENSEE (or its sublicensees) shall be fully
responsible for studies of R&D Works at
LICENSEE's own risk and expense.
5. CLINICAL SUPPLIES: LICENSOR shall provide LICENSEE free of charge
with EU and US cGMP grade Product or Compound
sufficient to enable LICENSEE to perform R&D
Works as agreed between LICENSOR and LICENSEE,
currently estimated to be equivalent to 120,000
10mg tablets or 2 kilograms of Compound, which
shall be solely used for the clinical trials in
order to obtain the approval of the first
indication in the Territory, and any extra
quantity for other purposes, e.g. the validation
manufacturing for sample sales or other
commercial sales, etc., shall be supplied with a
price to be agreed.
6. ADVERSE EVENTS: LICENSEE shall perform and shall have its
sublicensee or its partner for clinical trials
of Lafutidine perform the Adverse Drug Event
(ADE)
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monitoring in Territory and shall send written
report to LICENSOR in accordance with the ICH
guidelines. LICENSOR agrees to provide LICENSEE
with safety information on Lafutidine in
accordance with the same. Details of method and
procedure to be described in a separate
agreement.
7. WITHDRAWAL: Except as required by applicable law or
regulatory authority, LICENSEE shall not
withdraw any Product approval without first
discussing same with LICENSOR.
8. RESULTS AND DATA: LICENSEE shall provide LICENSOR with written
report of each study of R&D Works. LICENSOR may
use such data without any payment to LICENSEE in
any countries other than those where LICENSEE
retains exclusive license.
9. DELAY IN R&D WORK: Subject of Force Majeure or fault of LICENSOR,
unreasonable delay in R&D Works beyond
LICENSEE's development timetable (unless
relating to issues of safety or efficacy) may,
if not cured within 90 days of notice to
LICENSEE, be cause of early termination in a
given Principal Market.
10. COOPERATION: LICENSEE, LICENSOR and LICENSOR's other
development partners/licensees for Lafutidine
will keep each other informed regarding clinical
trials and development plans, commercial
activities and similar matters.
IV. IMPROVEMENT Each party to promptly disclose to the other in
--------------- writing improvements to subject matter covered
by Patent Rights.
1. LICENSOR's IMPROVEMENT: LICENSEE may use it in TERRITORY without
additional payment to LICENSOR.
2. LICENSEE's IMPROVEMENT: LICENSOR may use it without any payment outside
TERRITORY.
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V. MARKETING AND DISTRIBUTIONS
------------------------------
1. COMPETING PRODUCTS: Prohibition of directly competing products by
LICENSEE. If LICENSOR or an affiliate launches a
competing product in a country in the Territory,
the exclusive purchase obligation and minimum
obligation will be deleted on a
country-by-country basis where a competing
product is launched by LICENSOR or its
affiliate, sublicensee or distributor.
2. ADVERSE EVENTS: LICENSEE and LICENSOR shall perform safety
monitoring of Lafutidine in the same way as
mentioned in Article III-6 ADVERSE EVENTS.
VI. AUDITING AND INSPECTION
---------------------------
1. AUDITING: LICENSOR's right to audit LICENSEE's sales
records used to substantiate royalty payments,
including its Affiliate. LICENSEE shall audit
sales record of its sublicensee or distributors,
if applicable, and report the result to LICENSOR
for the same purpose.
2. INSPECTIONS: LICENSEE's right to inspect LICENSOR's
manufacturing facilities, including its
Affiliates and contract suppliers only for the
purpose of ensuring that Compound and/or Product
is manufactured under applicable GMP for sale in
a given country.
VII. TERM AND TERMINATION
-------------------------
1. TERM: 10 years from starting sales in the first
launched country or the expiration of the
last-to-expire Patent in a given country,
whichever is longer. Thereafter, continue unless
LICENSEE's one (1) year prior written notice to
LICENSOR.
2. EARLY TERMINATION: Either party may terminate the License Agreement
in whole or in part upon 30 days notice, if
either of the following is not cured within 60
days from a
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written notice:
a) the other party's bankruptcy, liquidation.
b) the other party's defaults and no remedy.
LICENSOR may terminate the License Agreement in
whole or in part upon 30 days notice, if either
of the following is not cured within 60 days
from a written notice:
a) Unreasonable delay in R&D Works (The
mechanism for providing extension of time shall
be agreed in the License Agreement).
b) Cease or suspension of the Product sale for
six (6) months in a given country (unless
suspension caused by regulatory authorities or
applicable law).
If any difficulty in future commercialization
with Lafutidine is confirmed with the results of
R&D Works, LICENSEE may notify LICENSOR of an
intention to terminate the License Agreement in
whole or in part, with simultaneously submitting
a reasonable report in writing of the said
results. Upon the receipt of said notice,
LICENSOR and LICENSEE shall in good faith
negotiate and discuss the results of R&D Works
within 90 days. The termination by LICENSEE may
become effective upon LICENSOR's consent in
writing, which consent shall not be unreasonably
withheld.
3. POST TERMINATION: a) Terminate sales of the Product within 6
months.
b) Return Information and transfer data and the
Product Approval in Territory free of charge to
LICENSOR.
c) Obligations incurred prior to termination
shall remain.
VIII. GOVERNING LAW The provisions shall be set forth in the
------------------- License Agreement.
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IX. PRODUCT LIABILITY a) LICENSEE agrees to hold LICENSOR harmless
--------------------- from, and undertakes the entire product
liability (including latent side effects) of,
damage, loss, cost or expenses arising out of
any third party's claims attributable to
LICENSEE's manufacture (if applicable), sale,
distribution, labeling and/or warning of the
Product and other activities, including those by
Affiliates, sublicensees, contract
manufacturers, and/or distributors, under the
License Agreement, except to the extent provided
in b) below.
b) LICENSOR agrees to hold LICENSEE harmless
from, and undertakes the entire product
liability, damages, loss, cost or expenses
arising out of any third party's claim
attributable to LICENSOR's workmanship or
materials of Compound or Product supplied by
LICENSOR to LICENSEE.
c) LICENSEE and LICENSOR shall each purchase
insurance policy for Product Liability to cover
their respective obligations mentioned above.
X. PATENT INFRINGEMENT
----------------------
1. INFRINGEMENT BY A THIRD The provision shall be set forth in the License
PARTY: Agreement.
2. INFRINGEMENT OF A THIRD The provision shall be set forth in
PARTY'S PATENTS: the License Agreement.
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EXHIBIT C
SUMMARY OF GLYCYX OBLIGATIONS
Glycyx will, at its sole expense and discretion, use its commercially reasonable
efforts to:
1. Conduct a human pharmacology study to evaluate the prevention of
NSAID-induced erosions by Lafutidine versus placebo, omeprazole and misoprostil.
2. Prepare a detailed background document on Lafutidine and an outline of
the studies required for a New Drug Application ("NDA") submission for one
indication for Lafutidine, and submit such outline to the US Food and Drug
Administration (the "FDA") for comment.
3. Based upon the comments received from the FDA, to prepare a
development plan for the first NDA submission for Lafutidine, including
anticipated costs and timelines.
4. Conduct GMP inspections of the existing Lafutidine chemical production
facility and the Lafutidine tablet production facility.
5. Based upon the outcome of the GMP inspections, prepare a detailed list
of items required to ensure that the Lafutidine chemical and tablet production
plants and processes meet GMP regulations for production of clinical trial
material.
CONFIDENTIAL TREATMENT REQUESTED
