PORTIONS OF
THIS EXHIBIT MARKED “[* * *]” HAVE BEEN OMITTED
PURSUANT TO A REQUEST FOR CONFIDENTIAL TREATMENT PURSUANT TO RULE
24b-2 UNDER THE SECURITIES EXCHANGE ACT OF 1934, AS AMENDED, AND
THE OMITTED PORTIONS HAVE BEEN FILED SEPARATELY IN PAPER FORM WITH
THE SECURITIES AND EXCHANGE COMMISSION.
EXCLUSIVE LICENSE
AGREEMENT
This EXCLUSIVE
DIFLUPREDNATE LICENSE AGREEMENT (hereinafter called this
“Agreement”) is made and effective as of the 3rd day of
April, 2006 by and between:
SENJU
Pharmaceutical Co., Ltd., a legal entity duly organized and
existing under the laws of Japan, having its principal office of
business at 5-8, Hiranomachi 2-chome, Chuo-ku, Osaka 541-0046,
Japan (hereinafter called “SENJU”);
SIRION
Therapeutics, Inc., a legal entity duly organized and existing
under the laws of the State of Florida, U.S.A., having its
principal office of business at 3110 Cherry Palm Drive,
Suite 340, Tampa, Florida 33619, U.S.A. (hereinafter called
“SIRION”);
WHEREAS, SENJU
is the joint owner with Mitsubishi Pharma Corporation, a Japanese
corporation having its principal place of business at 2-6-9,
Hiranomachi, Chuo-ku, Osaka 541-0046, Japan (hereafter referred to
as “MITSUBISHI”), of patent rights in certain areas of
the world, including the United States, to topical ophthalmic
products containing Difluprednate (hereinafter defined in detail),
as well as compositions containing Difluprednate; and
WHEREAS, SENJU
is an exclusive licensee, throughout the world except for Japan,
including the United States, of sub-license granting rights to an
ophthalmic product containing Difluprednate for the treatment of
all ophthalmic diseases in humans by way of an agreement
(Kaigainiokeru kaihatsu oyobi Syougyoukanikannsuru Keiyaku-syo)
entered into as of February 22, 2005, by and between SENJU on
one hand; and MITSUBISHI on the other hand (said agreement
hereafter referred to as “SENJU-METSUBISI{I License
Agreement”); and
WHEREAS, SENJU
desires to grant SIRION a license, based on its rights under the
SENJU-MITSUBISHI License Agreement, to develop, use, obtain
governmental approval for, manufacture, sell, distribute, and
promote an ophthalmic emulsion and/or suspension containing
Difluprednate in the Territory (hereinafter defined), according to
the terms and conditions set forth herein, and SIRION wishes to
receive such license and the obligations therein; and
WHEREAS, SENJU
and SIRION understand and acknowledge that the exercise of this
Agreement by either Party may result in the creation of new
inventions or discoveries.
NOW THEREFORE,
in consideration of the foregoing, the mutual covenants contained
herein and for other good and valuable consideration, the receipt
and sufficiency of which are hereby acknowledged, SENJU and SIRION
(SENJU and SIRION collectively called “Parties” and/or
individually called “Party”, and all other entities not
hereto named will be referred to as “Third Parties”)
hereby agree as follows:
The following
terms used in this Agreement shall have the meanings set forth in
this Article 1, unless the context clearly requires otherwise,
and the singular shall include the plural and vice versa. All other
terms shall be afforded their generally accepted legal
definitions.
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1.01
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“Compound” shall mean a
certain chemical substance having the chemical structure of
6á, 9-Difluoro- 11 â, 17, 2 1-trihydroxy-1,
4-pregnadiene-3, 20-dione 21-acetate 17-butyrate. The Compound as
also referred to as “Difluprednate.”
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1.02
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“Product” shall mean the
topical corticosteroid ophthalmic emulsion and/or suspension
containing the Compound as an active ingredient for the treatment
of ophthalmic diseases in humans only. Combination products
containing the Compound and other active ingredients, whether
patented or not, are initially excluded from this definition, but
may be included only with the express prior written consent of
SENJU, such consent not to be unreasonably withheld. Furthermore,
SENJU has the right to amend Article 10 of this Agreement in
exchange for the grant of permission to allow a patented
combination product into this definition, provided however, that
for the term of this Agreement, as defined in Article 3, there
shall be a royalty on sales of combination products identical to
those on the Product under Article 10. After the term of this
Agreement ends, the Parties shall negotiate in good faith for the
future terms of such a grant.
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1.03
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“Effective Date” shall
mean the date first above written on which this Agreement was
signed by the Parties and shall become effective.
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1.04
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“First
Commercialization” shall mean the date of the first
commercial offer for sale by SIRION of the Product in commercial
quantities to a Third Party in the Territory according to the terms
of this Agreement.
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1.05
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“Governmental Approval”
shall mean any kind of approvals by the United States Food and Drug
Administration (“U.S. FDA”) or equivalent future
governmental authority in the Territory, necessary to commercialize
the Product in the Territory, including, without limitation, any
approvals necessary for the development, manufacture, distribution,
and sale of the Product in the Territory.
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1.06
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“Territory” shall mean
the United States of America as well as Puerto Rico, Guam, the U.S.
Virgin Islands, and any other U.S. territories and
possessions.
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1.07
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“Cumulative Net Sales”
shall mean the total Net Sales made according to this Agreement,
that start to accumulate from the First Commercialization and may
be calculated at any given time during the term of this
Agreement.
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1.08
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“Net Sales” shall mean
the gross invoiced amount charged by SIRION to sell the Product to
Third Parties in the Territory, less (a) all normal and
customary deductions of any type or nature
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2
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(such as, e.g., returns, credits,
refunds, discounts, allowances, rebates, chargebacks and
adjustments); and (b) freight, shipping, insurance costs,
customs, duties, taxes and other governmental charges and
surcharges imposed upon the sale or distribution of the Product.
However, the deductions under this definition may not exceed [* *
*] of the gross invoiced amount. For the purpose of clarification,
the gross invoiced amount and deductions thereof apply to
aggregate, rather than individual, sales of the Product, and do not
apply to sales of anything other than the Product, even if sold
simultaneously with the Product.
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1.09
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“Patent Rights” shall
mean that granted under U.S. Patents No. 5,556,848, issued
September 17, 1996; and No. 6,114,319, issued
September 5, 2000; as well as any and all reissues,
re-examinations, and patent term extensions thereof.
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1.10
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“Semi-Annual Period”
shall mean each of the six (6) month periods commencing April
1st and October 1st and running through, respectively, the
following September 30th and March 31st.
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1.11
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“Technical Information &
Know-How” shall mean any and all scientific and clinical data
and knowledge which relate to the Product or the Compound, which
are necessary or useful for the practice of the Patent Rights and
the grant of this Agreement, including without limitation, the
development of the Product, obtaining Government Approval, and the
manufacture and sale of the Product in the Territory.
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1.12
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“Development Activity”
shall mean any and all tests, studies and other activities for
SIRION to research and develop the Product, including but not
limited to activities to obtain and maintain the Governmental
Approval in the Territory.
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1.13
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“Financial Year” shall
mean the annual twelve-month period that begins on April 1 in a
given year and runs through March 31 of the next
year.
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1.14
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[*
* *]
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1.15
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[*
* *]
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1.16
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“Generic Product” shall
mean a substance identical with Product that is legally
commercialized in the Territory after First Commercialization, and
that satisfies all of the following conditions:
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(i)
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contains the Compound as its active
pharmaceutical ingredient;
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(ii)
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has
the same strength, dosage, and administration as the
Product;
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(iii)
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has
the same indication as the Product; and
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(iv)
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has
the same bioavailability and bioequivalence as the
Product;
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OR any
substance the United States Food and Drug Administration (U.S. FDA)
has defined as a drug product that is the ‘Pharmaceutical
Equivalent’ and ‘Bioequivalent’ of the Product,
and has assigned an ‘AB’ or ‘AT’ evaluation
code.
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2.01
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SENJU hereby grants by way of a
license to SIRION, and SIRION hereby accepts, a sole and exclusive,
running royalty-bearing license under the Patent Rights and using
the Technical Information & Know-How to make or have the
Product made, develop, manufacture, use, market, offer to sell, and
sell the Product, in the Territory. This license shall not include
the right for SIRION to sell the Product from the Territory to any
party outside of the Territory. The license granted to SIRION
herein shall not include the right to grant further licenses or
sub-licenses to any third party without the prior written consent
of SENJU, such consent not to be unreasonably withheld. Nothing in
this Agreement shall affect, and SENJU shall retain the right to
grant, other sub-licenses to the Product outside of the
Territory.
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2.02
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SENJU hereby represents that it has
the full right and authority to enter into this Agreement, to grant
the licenses provided herein and to perform its obligations
hereunder. SENJU further represents and warrants that neither it,
nor any of its affiliates or subsidiaries, shall assert the rights
granted to SIRION under this article in the Territory for the term
of this Agreement. SENJU additionally represents and warrants that
as of the Effective Date it has not licensed the right to import
the Product into the Territory from outside the Territory to a
Third Party, nor will it do so itself or by way of a license to a
Third Party for the term of this Agreement.
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2.03
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SIRION represents and warrants that
SIRION will comply, with all applicable governmental laws and
regulations relating to the development, manufacture, marketing,
sale, distribution, promotion to sell of the Product in the
Territory.
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2.04
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Notwithstanding Paragraph 2.01
above, SIRION shall have a right to contract manufacture the
Product in whole or in part to any Third Party but only upon
obtaining the prior written consent of SENJU, which shall not be
unreasonably withheld, provided, however, that SIRION shall
promptly notify SENJU in writing of any such contract manufacture
that it enters into and the name of contract manufacturer, and that
SIRION shall require the contract manufacturer to undertake the
same obligations undertaken by SIRION under this Agreement that are
applicable to the manufacture of the Product. For the purpose of
clarification, this paragraph shall not affect the rights of either
Party under Article 13.
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2.05
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SENJU further grants to SIRION a
right of first refusal for the exclusive use of the Technical
Information & Know-How, as well as any future patents covering
the Compound or Product, or the use thereof, individually in
Canada, the United Mexican States, and the countries or areas of
Central America and the continent of South America. Accordingly, in
the event that SENJU receives an offer from a Third Party for the
rights mentioned in this paragraph, it shall immediately notify
SIRION of this fact. SIRION will then have [* * *] to match said
Third Party offer. Any rights granted to SIRION by SENJU as a
result of this paragraph would then be reduced to an agreement to
be executed in the future according to those terms. SIRION
acknowledges that as of the Effective Date, SENJU has no rights to
patents covering the Compound or Product, or the use thereof, in
the areas stated in this paragraph, nor is it under any obligation
to obtain such rights under this Agreement.
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2.06
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To
the extent of its actions that affect the grant to SIRION of this
Agreement, SENJU shall deploy and conduct itself under the
SENJU-MITSUBISHI License Agreement in a
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4
manner that
will enable SIRION to exercise its rights under this Agreement. In
this regard, and without limiting the foregoing, SENJU shall
(a) comply in all respects with and perform all of its duties
and obligations under the SENJU-MITSUBISHI License Agreement,
(b) not take or fail to take any action under the
SENJU-MITSUBISHI License Agreement that could have a materially
adverse effect on S1RION’s rights under this Agreement,
(c) enforce the provisions of the SENJU-MITSUBISHI License
Agreement against MITSUBISHI if failure to do so could have a
materially adverse effect on SIRION’s rights under this
Agreement, and (d) not modify, amend or terminate the
SENJU-MITSUBISHI License Agreement if to do so would effect
SIRION’s rights under this Agreement without the prior
written consent of SIRION, which consent shall not unreasonably be
withheld.
Article 3— Term of
Agreement
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3.01
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This Agreement and the license
granted therein shall become effective as of the Effective Date and
shall continue in effect until the later of 1) ten (10) years
from the First Commercialization, or 2) the expiration or
invalidation of all of the Patent Rights. At the expiration of the
term of this Agreement as stated in this article, but not its
termination according to Article 18, SIRION shall have a fully
paid-up, perpetual right to the Technical Information &
Know-How.
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Article 4— Technical Information and
Know-How
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4.01
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Within a reasonable period after the
Effective Date, SENJU shall provide SIRION with documentation of
all Technical Information and Know-How, known to and reasonably
available to SENJU at the Effective Date, already translated into
the English language. Excluded from the obligations of this Article
will be any material that SENJU is required by contractual
obligation to keep confidential. SIRION will be required to conduct
any translations of the Technical Information and Know-How of this
paragraph into a language other than English at its own expense and
risk. Specific items to be transferred include, but are not limited
to: manufacturing processes, non-clinical study data, and clinical
study data.
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4.02
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SENJU represents and warrants that
the Technical Information and Know-How provided to SIRION according
to this article shall be reasonably sufficient for SIRION to
effectively exercise the rights granted to it by this
Agreement.
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4.03
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SIRION shall not use any Technical
Information and Know-How provided under this Agreement for any
purpose other than the development, and the manufacture or
commercialization of the Product during the term of this Agreement
or anytime thereafter.
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4.04
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SIRION agrees and acknowledges that
clinical data and information of the Technical Information and
Know-How may not comply with applicable regulatory requirements,
codes and regulations including Good Laboratory Practice and Good
Clinical Practice, and that any failure to apply and utilize for
the Development Activities for obtaining
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5
Governmental
Approval shall not be deemed a breach by SENJU of this Agreement.
Accordingly, if SIRION were to be requested or required to conduct
an additional clinical study, re-clinical study, or re-non-clinical
study for the clinical data, non-clinical data, and information
involved in Technical Information and Know-How, SIRION shall
conduct them at its sole cost and risk.
Article 5— Product Development and
Governmental Approval
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5.01
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SIRION represents and promises that
it will make a commercially diligent and reasonable effort to, at
its own expense and risk, develop, market, and promote the sale of
the Product in the Territory, including but not limited to,
performing all activities and preparation, filing, and support of
the application documents necessary to obtain Governmental
Approvals in the Territory. Specifically, SIRION shall responsible
for any and all clinical trials required to obtain Governmental
Approval, including those done on humans, at its sole cost and
risk.
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5.02
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SENJU shall provide SIRION with
access to any and all documents in its possession that might be
required by SIRION to obtain Governmental Approval and not
otherwise provided by this Agreement, upon SIRION’s request,
and in the English language if possible.
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5.03
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Occasionally, but at least [* * *],
SIRION shall provide SENJU with the written report concerning the
progress of all Development Activities and of obtaining
Governmental Approval. Further, SIRION shall promptly notify SENJU
upon obtaining any Governmental Approval in a country of the
Territory.
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5.04
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Soon after the Effective Date,
SIRION shall provide SENJU with a development plan and schedule of
the Product in the Territory (hereafter referred to as
“Development Plan and Schedule”) for SENJU’s
review and comment. SENJU shall provide SIRION with SENJU’s
comments and advice, and SIRION shall take SENJU’s comments
and advice into consideration for the Development Plan and
Schedule. In the event that SIRION renews or updates the
Development Plan and Schedule, above procedure shall again be
applied. SIRION agrees and acknowledges that SENJU will provide
MITSUBISHI with Development Plan and Schedule provided by SIRION
subject to Paragraph 19.03.
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5.05
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Notwithstanding anything else to the
contrary stated herein, in the event that the schedule of the
Development Plan and Schedule is delayed due to SIRION’s
complete omission and gross negligence, SENJU shall have a right to
notify SIRION thereof and if SIRION fails to remedy the situation
in all material respects within [* * *] days after receiving
SENJU’s notice then SENJU shall have the option, upon notice
to SIRION, to terminate this Agreement.
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5.06
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Upon the request of SENJU, SIRION
shall provide SENJU or MITSUBISHI and their respective affiliates,
subsidiaries, or sub-licensees with any data, information and
result (hereinafter called “Results”) generated from
the Development Activities. SIRION agrees and acknowledges that
SENJU and its affiliates, subsidiaries, or sub-licensees shall
have
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the
right to use the Results for the sole purposes of development,
manufacture, obtaining the governmental approval and sale of the
Product outside of the Territory without any compensation to
SIRION, and that MITSUBISHI, its affiliates or subsidiaries shall
have the right to use or have its sub-licensees use the Results for
the sole purposes of development, manufacture, obtaining the
governmental approval and sale of the product containing the
Compound outside the ophthalmic field throughout the world without
any compensation to SIRION. SIRION shall provide SENJU with the
reliability assurance certificates that the Results would be
generated by SIRION in compliance with applicable GLP (Good
Laboratory Practice), GCP (Good Clinical Practice).
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5.07
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Upon the request of SENJU, SIRION
shall provide SENJU or MITSUBISHI and their respective affiliates,
subsidiaries, or sub-licensees with any and all copies of the New
Drug Application Dossier (hereafter referred to as
‘NDA’) submitted to the US FDA for obtaining the
Governmental Approval and copy of certificate of Governmental
Approval. SIRION agrees and acknowledges that SENJU and its
affiliates, subsidiaries, or sub-licensees shall have the right to
use, free of charge, such copies of the NBA and copy of certificate
of Governmental Approval for the sole purposes of development,
manufacture, obtaining the Governmental Approval and sale of the
Product outside of the Territory without any compensation to
SIRION. SIRION agrees and acknowledges that MITSUBISHI, its
affiliates or subsidiaries shall have the right to use or have its
sub-licensees use, free of charge, such copies of the NBA and copy
of certificate of Governmental Approval for the sole purposes of
development, manufacture, obtaining the governmental approval and
sale of the product containing the Compound outside the ophthalmic
field throughout the world without any compensation to
SIRION.
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5.08
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If
SIRION, in its bona fide business judgment, no longer wishes to
develop, obtain Governmental Approval for, or commercialize the
Product according to this Agreement as a result of a significant
and unforeseen problem, it shall notify SENJU of this fact and the
Parties shall discuss a resolution thereof. In such a case, with
the express written permission of SENJU, such permission not to be
unreasonably withheld, the terms of this Agreement may be altered
or the entire Agreement terminated according to the terms of
Paragraph 18.04. In the event of a termination of the
Agreement under this paragraph, SIRION shall have [* * *] to pay
SENJU any outstanding debts remaining under this
Agreement.
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6.01
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Within [* * *] of obtaining
Governmental Approval, SIRION shall use commercially reasonable and
diligent efforts to launch, promote, and sell the Product in the
Territory.
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6.02
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SIRION shall, in advance of any
sales or distribution, furnish SENJU with a copy of the package
inserts included with the Product, and thereafter, any revised
version thereof.
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6.03
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SIRION shall prepare, at its own
costs and expenses, appropriate marketing, advertising and
promotional material for the Product. SIRION shall, in advance of
any use, furnish SENJU with those materials for SENJU’s
review.
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6.04
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Alliance indication to the
Product’s bottle, outer package, brochure, insert leaflet,
advertising and/or promotional materials shall be discussed and
decided between SENJU and SIRION; provided that, SIRION may use any
alliance indication required by law.
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6.05
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At
least [* * *] before the occurrence of First Commercialization,
SIRION shall submit to SENJU a sales forecast of the Product
covering the [* * *] Financial Years after the Financial Year of
the First Commercialization, addressing each subsequent Financial
Year separately, including a forecast of a sales peak of the
Product and its timing, for SENJU’s review and approval. Any
sales forecast submitted by SIRION shall be deemed approved by
SENJU [* * *] after its submission, unless SIRION receives from
SENJU written objections to such forecast within such [* * *]
period. If SENJU disagrees with SIRION’s sales forecast
within the aforementioned [* * *] period, SENJU and SIRION shall
have an independent market research agent, which is acceptable to
both SENJU and SIRION, calculate the sales forecast for such [* *
*] Financial Years after the Financial Year of the First
Commercialization. SIRION and SENJU shall bear equally the cost of
such market research agent. SENJU and SIRION agree and acknowledge
that the sales forecast submitted by SIRION or the sales forecast
calculated by such independent market research agent, will be
subject to minimum annual sales forecast for calculation of minimum
royalties under Paragraph 11.01.
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6.06
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Should SIRION’s actual sales
amount of the Product be far below the sales forecast adopted by
the Parties under this article due to the occurrenc
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