Exhibit 10.12
Dated JUNE 24, 1996
-------------------
ALFA WASSERMANN S.p.A
-and-
SALIX PHARMACEUTICALS. INC.
LICENCE AGREEMENT
Hewitson Xxxxx Xxxx
First Floor
Stuart House
City Road
Peterborough
PEI IQF
Xxxxxxxx Xxxxx+Xxxx
SOLICITORS
[*] CERTAIN INFORMATION IN THIS EXHIBIT HAS BEEN OMITTED AND FILED SEPARATELY
WITH THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS
BEEN REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
Article 1 - RECITALS.................................................... 1
Article 2 - DEFINITIONS................................................. 1
Article 3 - LICENSE TO MANUFACTURE AND SELL THE PRODUCTS................ 4
Article 4 - SUPPLY OF INFORMATION AND ASSISTANCE........................ 7
Article 5 - SUPPLY OF COMPOUND.......................................... 8
Article 6 - CONSIDERATION............................................... 8
Article 7 - DEVELOPMENT. REGULATORY APPROVALS AND MARKETING.............10
Article 8 - MARKETING...................................................13
Article 9 - COMMENCEMENT AND DURATION...................................14
Article 10 - TRADEMARK...................................................15
Article 11 - INDUSTRIAL PROPERTY RIGHTS..................................15
Article 12 - DEVELOPMENTS................................................15
Article 13 - CONFIDENTIALITY UNDERTAKING.................................17
Article 14 - PRODUCT LIABILITY - INDEMNIFICATION.........................18
Article 15 - NON COMPETITION.............................................19
Article 16 - FORCE MAJEURE...............................................19
Article 17 - TERMINATION OF THE AGREEMENT................................20
Article 18 - PERIOD SUBSEQUENT TO THE TERMINATION OF THE AGREEMENT.......21
Article 19 - ASSIGNABILITY...............................................21
Article 20 - ENTIRE AGREEMENT AND MODIFICATION...........................22
Article 21 - LANGUAGE AND GOVERNING LAW..................................22
Article 22 - WAIVER......................................................22
Article 23 - NOTICES.....................................................23
Article 24 - LITIGATION..................................................23
30
LICENCE AGREEMENT
-----------------
BETWEEN:
ALFA WASSERMANN S.p.A., a corporation organized and existing under the laws
of Italy, with registered office at Contrada S. Emidio, 65020 Alanno
(Pescara), Italy, represented herein by Xx. Xxxxxx Xxxxxxxxx, in his
capacity as Int'l Gen. Manager (hereinafter "ALFA"); and SALIX
PHARMACEUTICALS, INC. corporation organized and existing under the laws of
California, United States of America, with registered office is at 0000 X.
Xxxxxxxx Xxxx, Xxxxx 000, Xxxx Xxxx, Xxxxxxxxxx 00000, represented herein
by Xx. Xxxxx X. Xxxxxxxx in his capacity as President (hereinafter "SALIX")
WHEREAS
(A) ALFA has developed a Compound known as "rifaximin", and Products
(hereinafter defined) which exhibit antibacterial activity and therefore
can be used in the treatment of bacterial diseases;
(B) The Compound and/or the Products are the subject of patents and/or patent
applications owned by ALFA ( the "Patents", as hereinafter defined);
(C) SALIX wishes to obtain from ALFA an exclusive licence to exploit the
Patents and the Technology Rights (hereinafter defined) and to use the
Compound in order to develop, make, have made, use, sell and have sold
therapeutic products for the treatment of gastrointestinal and respiratory
tract diseases and conditions (the "Products", as hereinafter defined)
under the Trademark in the Territory (both hereinafter defined);
(D) ALFA is willing to grant SALIX such licence on the terms and conditions
contained in this Agreement.
NOW THEREFORE, for and in consideration of the premises and the understandings
herein contained, it is hereby agreed as follows;
Article I - RECITALS
--------------------
It is acknowledged and agreed that the recitals to this Agreement and the
schedules and annexures to this Agreement form an integral part hereof and are
expressly incorporated herein..
Article 2 - DEFINITIONS
-----------------------
1
The following words and expressions used in this Agreement shall have the
following meanings:
"Affiliate(s)" shall mean any corporation, joint-venture or
other entity which directly or indirectly
controls, is controlled by or is under common
control with a party to this Agreement. "Control"
shall mean the possession of the power to direct
or cause the direction of the management and
policies of a person or business entity, whether
through ownership of voting securities, by
contract or otherwise;
"Compound" shall mean the raw material known as "rifaximin",
which is 2,7-(Epoxypentadeca [1,11,13]trienimino)
benzofuro [4,5-e]-pyrido[1,2-a]benzimidazole-
1,15(2H)-dione, 25-(acetyloxy)-5,6,21,23-
tetrahydroxy-27-methoxy-2,4,11,16,20,22,24,26-
octamethyl-,[2S-(2R*, 16Z, 18E,20R*,21R*,
22S*,23S*,24S*,25R*,26S*,27R*,28E)]-(Chemical
Abstract No. 80-621-81-4-together with all
products analogs and isomers thereof and any
improvements or developments to any of the
foregoing owned by or controlled by or licensed to
ALFA in respect thereof during the term of this
Agreement.
"FDA" shall mean the United States Food and Drug
Administration or any successor agency performing
a similar function or an equivalent foreign
regulatory agency (including without limitation,
the Health Protection Branch in Canada);
"NDA" shall mean applications filed with the FDA
requesting approval to market a new drug,
including but not limited to New Drug Applications
and Product License Applications (PLA), as
applicable. As used herein, the term "NDA" is
inter-changeable with the term "PLA" depending on
the regulatory approval process applicable to the
product under the provisions of the United States
Code 21 CFR or any equivalent foreign regulatory
provisions;
"Net Sales" shall mean the gross invoiced amount received by
SALIX (or any of its sub-licensees or
distributors) for
2
commercial sales to third parties (who shall not
be Affiliates or distributors of SALIX or its
Affiliates) of the Products in the Territory, net
of all normal trade and cash discounts and net of
all refunds, rebates, returns, transportation and
insurance charges, sales, value added or other
direct taxes charged on any invoice, customs
duties and surcharges allowed to the purchasers as
deductions from the purchase price of the Products
or otherwise as specified on the invoice;
"Patents" shall mean the patents and/or patent applications
listed in Part I of the Schedule and any other
patent rights in the Territory now existing or
hereafter acquired by or licensed to ALFA
pertaining to the subject matter of such patents
and patent applications or otherwise to the
Compound and/or the Product and any divisions,
continuations and continuations-in-part of any
such patents or patent rights and any patent
granted in respect thereof for the full terms
thereof including any reexaminations, renewals,
extensions and reissues thereof and including any
supplementary protection certificates;
"Products" shall mean those pharmaceutical products for human
use in the treatment and/or prevention of
gastrointestinal and respiratory tract diseases
and conditions containing the Compound as an
active ingredient;
"Putting into Commerce" shall mean the date of the first commercial
sale of Products to third parties (who shall not
be Affiliates or Sublicensees or distributors of
SALIX or its Affiliates) by or on behalf of SALIX
or any sublicensees or distributors of SALIX or
its Affiliates under the terms of this Agreement
made in any part of the Territory after all
relevant marketing and pricing approvals shall
have been granted by the relevant regulatory
authorities in respect of the Product in such part
of the Territory;
"Schedule" shall mean the Schedule hereto, comprising Parts 1
to 4 thereof;
"Supply Agreement" shall mean an agreement between the parties of
even date herewith relating to the supply of the
Compound by ALFA to SALIX;
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"Technology Rights" shall mean all intellectual property and other
proprietary rights and all confidential
information and know-how pertaining to the
Compound and/or the Products or otherwise to the
Patents in any respect (including without
limitation all improvements, inventions,
derivatives, formulation data, specifications,
manufacturing procedures and technology, technical
information, know-how, trade secrets,
pharmacology, toxicology and other preclinical
data, clinical data, regulatory information and
marketing data) within the possession or control
of ALFA (whether developed by or licensed to ALFA)
(and all such rights and information within the
possession or control of any other licensee of
ALFA having rights in respect of the Compound or
the Products) in existence as at the date hereof
or arising during the term of this Agreement which
are available to ALFA for the Territory.
"Territory" shall mean the United States (its territorial
possessions, territories and the Commonwealth of
Puerto Rico) and Canada;
"Trademark" shall mean the trademark to be chosen and agreed
by the parties to be used by SALIX for the
marketing of the Products in the Territory , such
trademark to be registered and maintained by ALFA
in its name under the terms of this Agreement;
"Valid Claim" shall mean a claim of an issued and unexpired
patent included within the Patents, which has not
been held permanently revoked, unenforceable or
invalid by a decision of a court or other
governmental agency of competent jurisdiction
unappealable or unappealed within the time allowed
Or appeal and which has not been admitted to be
invalid or unenforceable through reissue or
disclaimer or otherwise.
Article 3 - LICENCE TO MANUFACTURE AND SELL THE PRODUCTS
--------------------------------------------------------
3.1 For good and valuable consideration set forth herein, ALFA hereby grants to
SALIX and SALIX hereby accepts;
3.1.1 an exclusive licence under the Patents and all Technology Rights to
develop, make, have made, use, market, promote, sell and have sold
Products within the Territory;
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3.1.2 a non exclusive Licence under the Patents and all Technology Rights
(and under any similar rights existing outside the Territory) to
manufacture and have manufactured on its behalf Products in any part
of the world solely for use and sale within the Territory;
3.1.3 an exclusive Licence to use and exploit the Trademark within the
Territory in connection with the sale of the Products only;
3.1.4 the right to sublicence to third parties and Affiliates all or any
part of the rights granted under Articles 3.1.1, 3.1.2 and 3.1.3
above, under the provisions of Article 3.2.
Such Licences to be continuing and irrevocable, save only as expressly provided
under the terms of this Agreement.
3.2 The right to sublicence granted under Article 3.1.4 shall be subject to the
following terms:
3.2.1 the terms of any such sublicence shall be in accordance with the
terms of the Licence granted to SALIX hereunder and shall be subject
to the prior approval of ALFA, such approval not to be unreasonably
withheld or delayed;
3.2.2 SALIX will be entitled to grant sublicences in each of the three
indications selected under Article 7.1 only after the Products have
been adequately developed and the relevant NDA has been filed with
the FDA for each such indication.
3.2.3 notwithstanding the appointment of any such sublicensee SALIX shall
remain solely responsible to ALFA for the performance of its
obligations under the terms hereof and for any breach of such
obligations, whether such breach shall be caused by SALIX or any
sublicensee.
For be avoidance of doubt it is hereby acknowledged that the appointment by
SALIX of any distributor for the Products within the Territory, of any
manufacturer to manufacture the Products for and on behalf of SALIX or of
any third party to assist in the development and approval of the Products
shall not be deemed to constitute the appointment of any sublicensee or the
sublicense by SALIX of any rights hereunder.
3.3 ALFA shall procure and maintain all export and other licences and permits
required for the grant to SALIX of the rights and Licences granted under
Article 3.1 and for the supply to SALIX of all documentation under Article
4 and shall comply with all other laws regulations and government
directives relating to the grant of rights under the terms of this
Agreement to ensure that SALIX shall be entitled to exercise the rights
granted to it free of any restriction.
3.4 ALFA hereby represents, warrants and undertakes to SALIX;
5
3.4.1 that it has full right and authority to grant the Licences contained
in this Agreement and to perform its obligations hereunder;
3.4.2 that the exercise by SALIX of the rights granted to it hereunder
within the Territory shall not infringe the rights of any third
party;
3.4.3 that ALFA has not (and will not during the term of this Agreement)
make any commitment or incur any obligation in conflict with the
rights and Licences granted to SALIX hereunder;
3.4.4 that ALFA is the sole legal and beneficial owner of the patents and
patent applications set out in Part I of the Schedule and that Part
I of the Schedule contains accurate details of all patents and
patent applications existing in the Territory in respect of the
Compound and/or the Products.
3.4.5 that during the term of the Trademark Licence granted under Article
3.1.3 ALFA shall not use or permit the use of the Trademark within
the Territory on or in connection with any pharmaceutical product.
3.5 SALIX undertakes, during the term of this Agreement, not to sell or
otherwise supply the Compound and/or the Products to any third party
outside the Territory (save only for the supply of Compound to
manufacturers of Products for sale within the Territory) and shall not
knowingly, sell or otherwise supply the Compound and/or the Products to any
third party within the Territory for the purpose of sale or supply to any
third party outside the Territory. ALFA confirms and acknowledges that
restrictions in substantially the form of this Article 3.5 have been and
will be imposed upon third party licensees of Compound, Patent and/or
Technology Rights in respect of territories outside the Territory when and
where legally enforceable. For the proper protection of the rights granted
to SALIX hereunder ALFA undertakes to use all reasonable endeavours to
prevent any breach or continuation of any breach by any such licensee of
such terms and ALFA confirms and acknowledges that it shall also be bound
by such restrictions in respect of the exploitation of the Compound and/or
the Products outside the Territory.
3.6 SALIX acknowledges that ALFA has represented to it that the Patents, the
Compound, the Products, the Technology Rights, the Trademark and the
relevant exploitation rights in the Territory are all the exclusive
property of ALFA. SALIX acknowledges that save as expressly provided
herein it shall acquire no right title or interest in any such proprietary
rights of ALFA and that nothing contained herein shall be construed as
granting SALIX any rights whatsoever in the Patents, the Compound, the
Products, the Technology Rights, the Trademark and the relevant
exploitation rights in connection with products other than the Products.
3.7 In order to protect the rights granted by ALFA to SALIX under the terms of
this Agreement:-
3.7.1 ALFA undertakes that it shall not without the prior consent of SALIX
either
6
directly or indirectly (through any third party or sublicensee)
develop, manufacture or market within the Territory any
pharmaceutical product containing the Compound as an active
ingredient, such consent not to be unreasonably witheld or delayed
where ALFA can show to SALIX that such development, marketing or
manufacture would not adversely affect the exploitation by SALIX of
its rights hereunder, and
3.7.2 in the event of any development of any pharmaceutical product
containing the Compound as an active ingredient, within the
Territory (whether by ALFA or any licensee) the development thereof
shall be effected in close consultation with SALIX and SALIX shall
be kept fully informed and shall have the right to rescind any
consent given under Article 3.7.1 in the event that in the course of
such development it is shown that such development and/or subsequent
marking is adversely affecting the exploitation by SALIX of its
rights hereunder; and
3.7.3 ALFA undertakes and warrants that any exploitation of any
rights in the Compound within the Territory (whether by ALFA or any
third party) will not adversely affect the exploitation by SALIX of
its rights hereunder, in any material manner.
3.8 SALIX is aware that ALFA has developed formulations of the Compound which
may find a use for the treatment of topical and vaginal infections and also
in the veterinary area. SALIX accepts the fact that the activities which
ALFA or its Licensees may undertake in such areas (save for activities in
the case of veterinary formulations which fall within the definition of
Product) are to be considered in connection with the provisions of Article
3.7, not in contrast with SALIX's interests and not adversely affecting the
exploitation by SALIX of its rights in the Compound under the terms of this
Agreement.
Article 4 - SUPPLY OF INFORMATION AND ASSISTANCE
------------------------------------------------
4.1 ALFA undertakes to supply to SALIX forthwith upon execution of this
Agreement copies of all documentation constituting the Patents and the
Technology Rights existing as at the date hereof and thereafter during the
term of this Agreement to supply to SALIX all documentation in respect of
any further or additional Patents or Technology Rights promptly upon the
same becoming available to ALFA.
4.2 ALFA undertakes promptly to supply to SALIX during the twin of this
Agreement such information and documentation in connection with and
relating to the completion of the clinical development and applications for
regulatory approvals for the Compound and/or Products in respect of other
territories (whether prepared by ALFA or any licensee of ALFA and which are
available to ALFA) as Salix may reasonably require in connection, with the
clinical development and regulatory approvals required for the Products
within the Territory or otherwise in connection with the performance by
SALIX of its obligations under Article 7.
7
4.3 Each party undertakes throughout the term of this Agreement to supply free
of charge to the other all such pharmaceutical pre-clinical and clinical
data and information as may be developed or obtained by it or any
sublicensee with respect to the Compound and/or Products and to permit the
other party to use all such information in connection ,with the continued
exploitation of the Products.
4.4 Representatives of either party may upon reasonable notice and at times
reasonably acceptable to the other party visit any facilities where any pre
clinical or clinical tests or trials are being carried out in respect of
the Products and any facilities where the Compound or Products are being
manufactured and shall be entitled to consult informally during any such
visit or by telephone or facsimile communication with personnel at any such
facilities Provided That SALIX shall inform ALFA of the substance and
content of all such consultations and communications.
4.5 All documentation supplied to SALIX under the terms of this agreement
necessary. to enable SALIX to fulfill its regulatory obligations hereunder
or necessary to enable SALIX to exercise its right to manufacture under
Article 9 of the Supply Agreement shall be supplied in the English Language
and ALFA shall at its sole cost obtain translations of any such
documentation for such purpose, save where SALIX shall notify ALFA in
writing that a summary of the same in the English language will suffice..
Article 5 - SUPPLY OF COMPOUND
------------------------------
5. In order to safeguard the quality standards of the Compound and of the
Products, it is understood that subject to the terms of me Supply Agreement
ALFA will be the sole and exclusive supplier of the Compound to SALIX and
SALIX undertakes to purchase the Compound exclusively from ALFA subject to
the provisions contained in the Supply Agreement.
Article 6 - CONSIDERATION
-------------------------
6.1 In consideration of all the rights and licences granted hereunder SALIX
agrees to pay ALFA the following amounts:
6.1.1 [*]
6.1.2 [*]
8
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
[*]
6.1.3 [*]
6.1.4 [*]
QUANTITY Of COMPOUND SOLD IN EACH CALENDAR YEAR ROYALTY RATE, AS A %
OF NET SALES
[*]
6.2 In the event that SALIX is required to pay to any third party royalties
calculated by reference to Products sold in respect of any technology of
such third party incorporated in the Products there shall be deducted from
the calculation of Net Sales (in connection with the calculation of
royalties due hereunder) a sum equal to [*] in respect of the Products.
6.3 Within 60 days of the end of each calendar quarter after the date of
Putting into Commerce (such quarters to end on the last days of March,
June, September and December in each calendar year) SALIX shall submit to
ALFA a written report setting out details of all Net Sales in such calendar
quarter together with its calculation of such Net Sales) and with such
statement SALIX shall pay to ALFA the sum due in respect of royalty on such
Net Sales.
6.4 In the event that any payment due hereunder shall not be paid by the due
date such payment shall from the due date until the date of payment bear
interest at the rate of 4 % (four per-cent) above the official prime rate
published by the Bank of America in the Territory.
6.5 Each of SALIX and ALFA shall use all reasonable endeavours to minimise any
sum required to be deducted by way of withholding tax from any sums payable
under this agreement to ALFA and shall use all reasonable endeavours to
procure for ALFA the
9
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
benefit of any present or future treaty against double taxation in force
between Italy ,and the Territory in respect of such sums payable and any
tax so withheld. Provided That for the avoidance of doubt SALIX shall
deduct any such withholding tax required to be deducted by it under any
applicable law.
6.6 All payments to be made by SALIX to ALFA hereunder shall be made in US
Dollars by SWIFT (international communications) wire transfer to such bank
as ALFA shall designate in writing.
6.7 SALIX shall maintain during the term of this Agreement normal accounting
books (in accordance with normal US accounting practice) containing
accurate details of all sales of Products and of the calculation of Net
Sales (in accordance with the definition thereof contained in Article 2)
and the royalty due to ALFA hereunder. ALFA will have the right upon
reasonable notice during normal working hours to cause qualified
professional accountants of its choice to inspect the books and records and
any other documentation and records maintained by SALIX relevant to the
calculation of any royalty hereunder. The cost of the above accountants'
inspections shall be borne by ALFA save only where any such inspection
reveals a discrepancy in excess of 5% of royalties due and payable, in
which event the costs shall be borne by SALIX Provided Always;
6.7.1 that such inspection shall not take place more than once in each
calendar year;
6.7.2 that such inspection shall only be in respect of records and
accounts for the period of three years preceding the date of such
inspection and SALIX shall not be required to retain records for any
period exceeding three years
6.8 For the avoidance of doubt, sales of Products made by SALIX to an Affiliate
or any sub-licensee or distributor for the purpose of resale to non-
Affiliated parties shall be specifically excluded from Net Sales
calculations for royalty determinations.
6.9 Save as expressly stated in this Agreement, SALIX shall not be entitled in
any circumstances to withhold any money due to ALFA under the terms of this
Agreement in respect of any possible (justified or unjustified) claims
against ALFA, related to this Agreement or to the Supply Agreement.
Article 7 - DEVELOPMENT, REGULATORY APPROVALS AND MARKETING
------------------------------------------------------------
7.1 SALIX shall use all reasonable endeavours to develop at least [*]
indications for the Products. It is acknowledged that it is the present
intention of SALIX to first develop a Product as a treatment for antibiotic
associated colitis as per the Development Plan contained in Part 3 of the
Schedule. The [*] indications will be identified within the first [*] the
date hereof. The development of these latter indications shall not start
later than [*] from the date hereof.
7.2 SALIX shall perform and complete (or procure the performance or completion
on its behalf) diligently and expeditiously at its sole expense and
direction (except as
10
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
hereinafter set forth) all work studies and formalities necessary to
complete all Phase II and III clinical requirements for the initial
indication and pre-clinical and clinical requirements, as appropriate, for
additional indications for the Products within the Territory, shall file
the NDA and shall obtain (in its own name or that of its nominee(s)) the
permits, approvals, (including NDA approval(s)) and any other
authorizations necessary to market the Products in the Territory.
7.3 SALIX shall provide ALFA with semiannual reports describing in reasonable
detail its progress in all the above activities, until the Putting into
Commerce.
7.4 ALFA undertakes to perform and complete diligently and expeditiously the
studies listed in Part 4 of the Schedule at its sole responsibility for
covering all cost and expense. All such studies shall be conducted and
completed in such manner and to such standard (including without
limitation, US Good Laboratory Practice and Good Clinical Practice) as may
be required for the use of such study results and documentation in
connection with any regulatory approvals required for the Products within
the Territory and to supply SALIX with full details and information
concerning the same under the provisions of Article 4.
7.5 Each of ALFA and SALIX undertakes to cooperate and liaise with the other
party in such manner as may reasonably be required in connection with the
timing and conduct of trials in order to prevent any avoidable delays and
to ensure the commitment of each party as may be appropriate under the
terms of this Agreement.
7.6 ALFA shall use its best efforts to supply, or arrange for others to supply,
all such quantities of the Compound and/or Products as may reasonably be
required by SALIX for all required preclinical tests, stability and human
clinical trials and for samples or placebos for clinical trials such
quantities to be supplied at ALFA's expense free of charge to SALIX
(Provided Always that in this Article 7.6 "Products" shall mean bulk
(tablets) for the active drug and for the placebo).
7.7 ALFA undertakes to supply to SALIX copies of all preclinical or clinical
reports and protocols relating to the Compound and/or the Products obtained
or prepared by ALFA or any licensee of ALFA of the Compound in any
territory. The parties shall use their best efforts in order that all
preclinical and clinical studies are obtained and produced in accordance
with US Good Laboratory Practice and Good Clinical Practice standards and
comply in all material respects with the requirements of the FDA in respect
of reports and protocols filed in support of or otherwise in connection
with any NDA.
7.8 Immediately after the signature hereof, ALFA and SALIX will establish a
"Product Development Committee" consisting of three representatives from
each of the parties. It is acknowledged that the Product Development
Committee as at the date hereof will be constituted by;
ALFA; Xx Xxxxxxx Xxxxxxxxx
Dr XX. Xxxxxx Xxxxxxxx
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and one other to be appointed
SALIX; Xxxxxxxxx XxXxxxx
Xxxxxx Xxxxxx-Xxxx
Xx Xxxxx Xxxxxxx
The primary aim of the Product Development Committee will be the discussion
and the recommendation of indications which SALIX shall develop; it shall
also discuss and suggest to the parties any additional form of cooperation,
under Article 7.8 below. The Product Development Committee shall endeavour
to meet at least two times in each year, at locations alternating between
California and Italy. Each party shall bear the costs and expenses incurred
by its own representatives in connection with the Product Development
Committee and attending any meetings. Notwithstanding the foregoing it is
acknowledged and confirmed that in its role of developer and marketer SALIX
will retain the final decision to determine all aspects of the development
and commercialization of the Products in the Territory, in its sole
discretion, acting in the best interest of the Products in the Territory.
7.9 SALIX will be responsible in its sole discretion for determining which
indication(s) of the Products, within the treatment of gastrointestinal and
respiratory tract diseases and conditions, to develop, taking into
consideration the recommendations of the Product Development Committee
(subject always to the final decision of SALIX under Article 7.8), and for
designing all related clinical protocols, conducting clinical studies,
preparing, filing for and obtaining regulatory approvals required to
market, and commence commercial sales for such indication(s) in the
Territory. SALIX undertakes to market the Products in compliance with all
such regulatory approvals obtained.
7.10 In addition to the exchange of information and obligations in respect
thereof contained in this Agreement and without limiting and or affecting
in any way the generality of such provisions, the parties agree that they
are prepared to negotiate specific forms of cooperation for carrying out
additional studies and/or tests, and for exchanging respective proprietary
information in addition to what is already subject to the provisions
hereof, for the most efficient preparation of pre-clinical and clinical
regulatory packages; the parties shall then agree on law and in what
portion they will share the related costs; the parties shall furthermore
from time to time exchange marketing information for the purpose of
homogenizing worldwide strategies and marketing policies.
7.11 SALIX shall notify ALFA of any material step which has been undertaken with
the purpose to have the Products approved and shall promptly send to ALFA
by courier or by similar means copies of the following documentation;
IND annual reports
Final reports of all clinical studies undertaken
the NDA
ALFA shall be allowed to use and to make available such documentation to
its
12
Licensees free of charge.
SALIX acknowledges that it shall not in the Territory or elsewhere publish
any data or information concerning the Products or any clinical trials of
the Products without the prior consent in writing of ALFA such consent to
be provided within a maximum period of 60 days and not to be unreasonably
withheld or delayed.
7.12 In the event that SALIX abandons development of the Compound and/or
Products for any indication (after commencing development in respect of
such indication) in a defined part of the Territory and does not recommence
such development within 90 days of any notice in writing served on it by
ALFA Licence granted hereunder in connection with the Patents and the
Technology Rights relating solely to such indication shall be deemed (upon
the expiry of such 90 day period) to have terminated in respect of such
specified indication only and all rights in such indication shall revert to
ALFA and SALIX shall deliver to ALFA all information within its possession
relating to such indication Provided Always that ALFA undertakes that it
shall not either directly or indirectly (through any third party or sub
licensee) market within the Territory any Product for any such indication
without the prior consent of SALIX such consent not to be unreasonably
withheld where ALFA can show that such marketing would not adversely affect
the exploitation by SALIX of its rights hereunder. For the avoidance of
doubt the provisions of this Article 7.12 shall not affect in any manner
the obligations of SALIX under Article 6.
7.13 The parties further undertake to maintain throughout the terms of this
Agreement a system (and obligations as required) concerning the prompt
reporting of all and any adverse events relating to the Compound and/or the
Products and the prompt supply to the other party of any information
concerning any such adverse event, in such manner as may required by the
FDA and European Union authorities..
Article 8 - MARKETING
---------------------
8.1 SALIX shall use all reasonable endeavours to introduce, promote and
maximize the sales of the Products throughout the Territory; SALIX shall
carry out such activities under the Trademark and in accordance with the
usual practice in the pharmaceutical field of the Territory .
8.2 SALIX and ALFA shall consult and exchange information concerning marketing
strategies and market information within the Territory and elsewhere in
respect of any territory in which the Products may be marketed to endeavour
to produce homogeneity in the marketing of the Products worldwide. The
parties will exchange marketing information; for this purpose each party
shall provide to the other samples of all promotional literature,
pamphlets, booklets, and advertising material for the Products and all data
which support promotional claims for them. ALFA and/or ALFA'S licensees,
at their own cost, may translate and reproduce such promotional materials
or publications and distribute them, at their sole discretion, in the
course of its promotional and marketing activities Provided Always that
SALIX shall not be liable in any manner whatsoever in respect of any such
translations or reproductions
13
and shall be indemnified and held harmless against any loss or claim
arising in connection with the same. SALIX may at its own cost
translate and reproduce any such promotional materials or publications
and distribute them in the course of its promotional and marketing
activities Provided Always that ALFA shall not be liable in any manner
whatsoever in respect of any such translations or reproductions and
shall be indemnified and held harmless against any loss or claim
arising in connection with the same.
8.3 SALIX undertakes to print on the packaging of and on all promotional
and advertising material relating to the Products the words "Licensed
by Wassermann S.p.A" or similar language to the extent permitted under
any applicable law and ALFA licenses SALIX to use is corporate name in
such form for such purpose.
8.4 Putting into Commerce of the Products shall be effected by SALIX in
any country in the Territory within and not later than six (6) months
from the date of the obtaining of the NDA and/or of the regulatory
approvals to market the Products in such country within the Territory
(including if applicable all pricing and reimbursement approvals),
unless postponements of said deadline be agreed upon in writing by the
parties Provided Always that SALIX shall not be in breach of its
obligations under this Article in the event that any failure to meet
such deadlines shall be caused by any failure by ALFA to Supply
Compound in accordance with the provisions of the Supply Agreement.
SALIX shall promptly notify ALFA in writing of the date of the Putting
into Commerce in the Territory.
Article 9 - COMMENCEMENT AND DURATION
-------------------------------------
9.1 This Agreement shall come into force and effect from the last date of
execution of these presents and shall continue thereafter unless and
until terminated in accordance with the provisions set out below.
9.2 The obligations of SALIX to pay royalties in respect of Products under
the provisions of Article 6 shall commence upon Putting into Commerce
of such Products and shall continue until whichever shall be the later
of.-
9.2.1 the expiry of the period in which the manufacture, use or
sale of the Products by any unlicensed third party would
constitute an infringement of any Valid Claim within the
Patents; and
9.2.2 the expiry of a period of ten years from the date of Putting
into Commerce of the first Product
For the avoidance of doubt this Agreement shall continue thereafter in
accordance with its terms and the licences granted under Article 3.1 shall
continue thereafter as irrevocable royalty free paid up licences (with the right
to sublicence), and save only as expressly provided under Article 10.3 in
respect of the Trademark thereafter.
14
ARTICLE 10 - TRADEMARK
----------------------
10.1 As soon as possible after execution of this Agreement the parties will
select and agree the most suitable trademark for the Products (the
Trademark) to be used by SALIX hereunder in the Territory. Forthwith
upon agreement of the Trademark ALFA undertakes to take all such steps
as may be required at its own expense to obtain registration of the
Trademark throughout the Territory for use of the Trademark on the
Products and thereafter to maintain and renew such registration(s) as
required throughout the period in which SALIX shall be exploiting the
Products.
10.2 ALFA hereby grants SALIX to exclusive licence to use the Trademark to
identify the Products to be manufactured, promoted and sold in the
Territory hereunder. The parties agree and undertake to execute such
Trademark User Agreements as may be required to note and register the
Licence granted under this Agreement in respect of the Trademark
within the Territory.
10.3 It is understood that the Trademark Licence granted to SALIX hereunder
does not involve the acquiring of ownership of the Trademark on the
part of SALIX; upon expiry of the obligation to pay royalties under
the terms of Article 9.2 SALIX shall thereafter retain an exclusive
licence of the Trademark in respect of the continued sale and
exploitation of the Products. If so required by SALIX ALFA shall
execute a separate Trademark Licence in respect of the Trademark in
favour of SALIX permitting the continued use of the Trademark on the
Products, such licence to be irrevocable provided that SALIX shall pay
royalties on the continued use of the Trademark thereafter at the rate
of [*] of Net Sales. In the event that SALIX notifies ALFA in writing
at any time thereafter that it wishes to terminate such Trademark
Licence SALIX acknowledges that it shall have no continuing right to
use the Trademark Provided Always that ALFA under takes not thereafter
(either directly or indirectly) to use the Trademark within the
Territory upon any products competitive in any material respect with
the Products.
1O.4 In the event the parties shall agree and select as the Trademark any
trademark already in the possession of SALIX as at the date hereof,
SALIX shall transfer said trademark to ALFA within and not later than
three (3) months after the date of agreement of the Trademark and such
trademark shall fall within the definition of "Trademark" for all
purposes hereunder. In such circumstances SALIX shall take all such
steps as may reasonably be required to vest ownership of such
trademark in ALFA
Article 11 - INDUSTRIAL PROPERTY RIGHTS
---------------------------------------
11.1 In the event that SALIX shall become aware of any infringement or
violation of the rights of ALFA in the Patents or the Technology
Rights by any third party within the Territory it shall forthwith
notify ALFA. SALIX undertakes to use all reasonable endeavours to
prevent any such infringement or violation.
11.2 ALFA, undertakes promptly and at its sole expense, either directly or
indirectly through a duly authorized agent, to take all such steps as
may reasonably be required
15
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
to prevent any violation or infringement of any of the Patents or the
Technology Rights or the Trademark within the Territory and to procure
that any such infringement or violation is discontinued . SALIX shall
provide to ALFA such assistance as it may reasonably requite in
connection therewith provided always that ALFA shall reimburse to
Salix all reasonable costs incurred by SALIX in providing such
assistance or otherwise in the performance of its obligations under
Article II 1.1. In the event that ALFA shall fail to take such steps
SALIX shall be entitled to take such steps in its own name or in be
name of ALFA as it considers appropriate to prevent any such
Infringement or violation or otherwise as it may consider appropriate
to protect the market for the Products within the Territory provided
always that SALIX shall be entitled to deduct from royalties due to
ALFA hereunder all costs, charges, expenses and damages suffered or
incurred by it.
11.3 In the event that the exercise by SALIX of the rights granted under
Article 3.1 shall infringe the rights of any third party or in the
event that any allegation is made in respect of any such infringement
ALFA shall take all such steps and action at its sole cost and expense
to defend or otherwise settle any such claim and to procure for SALIX
the right to continue to exercise the exclusive and other rights
granted hereunder and shall indemnify and hold harmless SALIX against
all costs expenses claims losses or damages suffered or incurred in
connection with any such claim or allegation.
Article 12 - DEVELOPMENTS
--------------------------
12.1 In the event that SALIX shall discover or identify any new uses or
applications outside the field of gastrointestinal and respiratory
tract diseases and conditions for the Compound or any pharmaceutical
product which may use the Compound or otherwise any new indications
for the Products or the Compound outside the field of gastro
intestinal and respiratory tract diseases and conditions (an
"Invention") it shall notify ALFA in writing of be same and shall use
all reasonable endeavours to procure that the same shall remain
strictly confidential and shall not be disclosed to any third party
during a period of 180 days from the date of notification or if
earlier until ALFA and SALIX shall have agreed the manner in which the
same may be exploited. Thereafter it shall only be disclosed either
upon terms agreed between the parties or by SALIX in such manner as it
considers appropriate. The parties shall negotiate in good faith terms
relating to the protection and exploitation of any such Invention
Provided Always that
12.1.1 SALIX shall have the right to exploit any Invention
throughout the Territory free of any further or additional
payment to ALFA.
12.1.2 ALFA shall have the right to exploit any such invention in
all other parts of the world and to sublicense any such
rights, subject to the negotiation in good of faith such
payments (including royalties) as may be reasonable and
appropriate to compensate SALIX for its rights in any such
Invention
12.1.3 Any patent rights applied for in respect of any such
Invention shall be applied
16
for in the sole name of SALIX
12.2 In the event that ALFA (or any licensee of ALFA) shall discover or
identify any new uses or applications for the Compound or any
pharmaceutical product which may use the Compound or otherwise any new
indications for the Products or the Compound (an "ALFA invention")
within or relating to the field of gastro intestinal or respiratory
tract diseases or conditions ALFA shall notify SALIX in writing of the
same and SALIX is hereby granted an option to obtain an exclusive
licence in respect of all rights existing in any ALFA Invention to
exploit the same within the Territory the terms of such licence to be
negotiated in good faith between the parties.
12.3 ALFA hereby grants SALIX a first option to enter into good faith
negotiations concerning the grant to SALIX of a licence to exploit
within the Territory any future compounds and/or pharmaceutical
products developed or identified by ALFA of potential application
within the field of gastro intestinal and respiratory tract diseases
and conditions.
Article 13 - CONFIDENTIALITY UNDERTAKING
----------------------------------------
13.1 During the term of this Agreement and for a period of ten (10) years
after the expiry of the obligation to pay royalties, SALIX shall keep
secret and confidential and shall use all reasonable endeavours, to
procure that the same is kept confidential all technical and
scientific data, information and know-how and documentation disclosed
to it by ALFA under the terms of this Agreement and shall not disclose
the same to any third party save only as may be required in connection
with the performance of its obligations hereunder or in connection
with any sublicence granted or to any potential investor in SALIX.
13.2 During the term of this Agreement and for a period of ten (10) years
after the expiry of the obligation to pay royalties. ALFA shall keep
secret and confidential and shall use all reasonable endeavours to
procure that the same is kept confidential all technical and
scientific data, information and know-how and documentation disclosed
by it to SALIX under the terms of this Agreement together with all
information developed by it from any such information or documentation
and all information data and documentation supplied to it by SALIX in
connection with this Agreement and shall not disclose the same to any
third party save only as may be required in connection with the
performance of its obligations or otherwise to any other licensee of
the rights hereunder in respect of any territory outside the Territory
Provided such Licensees agree to be bound by the same obligations of
confidentiality accepted by ALFA in this Article 13.
13.3 The obligations contained in Articles 13.1 and 13.2 shall not apply to
any part of such data information or documentation which
13.3.1 shall otherwise than by reason of the default of the
recipient after the date hereof enter the public domain;
17
13.3.2 the recipient can show was in its possession free of any
obligation of confidentiality prior to the date of receipt in
connection with this Agreement
13.3.3 the recipient is obliged by or statutory or regulatory
authority to disclose
Article 14 - PRODUCT LIABILITY - INDEMNIFICATION
------------------------------------------------
14.1 ALFA shall be solely liable for all costs claims damages and expenses
arising out of the use of the Compound in the Product and the
exploitation of the Product Within the Territory where any such costs
claims damages and expenses are suffered or incurred by any third
party or by SALIX by reason of;
14.1.1 any default by ALFA of its obligations under this Agreement
or under the Supply Agreement;
14.1.2 any negligent act or omission of ALFA in connection with the
performance of its obligations under this Agreement or the
Supply Agreement
14.1.3 any inherent defect in the Compound as determined by the
Specifications (as defined in the Supply Agreement);
and ALFA shall idemnify, and hold SALIX harmless against all and any
such costs claims damages and expenses and shall effect and maintain
adequate and appropriate insurance cover in respect of all such risks
and shall if and when required by SALIX produce to SALIX evidence of
such insurance cover .
14.2 Save as expressly provided in Article 14.1 SALIX shall be solely
liable to third parties and shall hold ALFA harmless from all actions
for compensation by third parties for any damages whatsoever, either
direct or indirect or consequential, deriving from the Products
manufactured and sold by SALIX or from the studies made by SALIX under
the terms of this Agreement and undertakes to effect and maintain
appropriate and adequate insurance cover against any such liability
and shall if and when required by ALFA produce to ALFA evidence of
such insurance cover.
14.3 In the event of any claim, action or proceeding for which a person is
entitled to indemnity hereunder, the person seeking indemnity
("Claimant") shall promptly notify the relevant party ("Indemnitor")
of such matter in writing. Indemnitor shall then promptly assume
responsibility for and shall have full control of such matter,
including settlement negotiations and any legal proceedings and
Claimant shall fully cooperate in Indemnitor' s handling and defence
thereof. Provided Always that Indemnitor shall keep Claimant fully
informed of the progress and conduct of any such negotiations or legal
proceedings and shall not in any settlement defence of the same make
any admission or otherwise act in such manner as may prejudice the
continuing business or reputation of Claimant without the prior
consent in writing of Claimant (such consent not to be unreasonably
withheld or delayed).
14.4 Notwithstanding any provision of this Agreement which might otherwise
be to the
18
contrary, neither party shall under any circumstances be liable to the
other for any indirect loss, lost profits, economic loss or other
consequential damages and in the event of any breach by either party
of the teens of this Agreement or otherwise in the event of the
negligence of either party the damages recoverable shall be limited to
such damages as may be suffered as a direct consequence of any such
breach of negligence Provided Always that such limitation shall not
apply to the indemnity provisions contained in Articles 14.1 and 14.2
and any such indemnity shall extend to the full amount of any sums
paid by the Claimant to any third party in connection with such
matters (whether or not such sums paid to the third party include
consequential or indirect loss).
14.5 Each party undertakes to notify the other: -
14.5.1 forthwith in the event that it becomes aware of any serious
or previously unknown adverse reaction or contra indications
to the Compound and/or the Products in any part of the
Territory or elsewhere; and
14.5.2 within three months, on a quarterly basis, of other adverse
reactions or contra indications to the Compound and/or the
Product (other than those specified in Article 14.5. 1) in
any part of the Territory or elsewhere.
Article 15 - NON COMPETITION
----------------------------
15.1 SALIX undertakes that it shall not for a period of 5 (five) years from
the first date of Putting into Commerce of any Product promote,
distribute or otherwise sell, directly or indirectly, any antibiotic
products in the Territory competitive in any material respect with the
Products developed and sold by SALIX hereunder.
15.2 ALFA undertakes that it shall not for a period of 10 (ten) years from
the date hereof be involved directly or indirectly in the promotion,
distribution or sale of any antibiotic products within the Territory
competitive in any material respect with the Products to be developed
and sold by SALIX hereunder.
15.3 ALFA undertakes that during the period in which royalties may be due
hereunder it shall use all reasonable endeavours to procure that any
product incorporating the Compound sold and exploited in the Territory
shall be sold and exploited in such manner as shall not prejudice or
otherwise affect in any material manner the ability of SALIX to
exploit the rights granted hereunder in the best commercial interests
of SALIX.
Article 16 - FORCE MAJEURE
---------------------------
Neither party shall be liable in any manner in respect of any breach by such
party of its bligations hereunder (other than any breach of any obligation to
make payment on the due date) where such breach raises from any circumstance
outside such party's reasonable control. Amongst said circumstances are
included, by way of example only and not implying any limitation, fires, floods,
earthquakes, accidents, explosions, quarantine restrictions, strikes,
19
labour shortages, shortages of raw materials for the manufacturing of Products
and acts of any public authority, including foreign ones.
Article 17 - TERMINATION OF THE AGREEMENT
------------------------------------------
17.1 Either party may terminate this Agreement following the material
breach of any material provision hereof if the party in breach shall
have failed to remedy such breach within sixty days of receipt of
written notice from the other party specifying such breach and
requesting remedy.
17.2 ALFA shall have the right to terminate this Agreement, by sending
SALIX by registered airmail return (receipt requested) a three (3)
months advance notice in writing
17.2.1 should SALIX fail to use its best efforts to develop the
Products for the [*] indications selected under Article 7.1
in particular SALIX shall use its best efforts to file the
IND for the first indication in the US within six (6)
months from the date of execution of this Agreement and the
NDA within twenty-four (24) months from the filing of the
IND.
17.2.2 should SALIX fail to effect the Putting into Commerce
within the six (6) months term provided for in Article 8.4
above subject to the proviso in Article 8.4; or
17.2.3 should SALIX fail to sell the Products for a period of at
least six (6) consecutive months after the Putting into
Commerce of the Products, save where such failure is due:
(a) in whole or in part to any failure of ALFA to perform
its obligations under this Agreement or the Supply
Agreement; or
(b) the discontinuance or suspension of sales by reason of
any government regulations relating to the Products or
otherwise by any delays or restrictions caused or
imposed by government or by reason of any concern
relating to safety, efficacy or quality of the Products.
(c) SALIX being affected by force majeure circumstances
(that is, circumstances outside its reasonable control).
17.2.4 should SALIX become the subject of proceedings involving
bankruptcy, receivership, administration, insolvency,
moratorium of payment, reorganization or liquidation, or make
any assignation for the benefit of the creditors or any
equivalent measures in any relevant jurisdiction;
Provided Always that such notice shall not be effective in the event
that SALIX shall during such three month period remedy any breach or
failure specified above such that the circumstances giving rise to any
such notice shall no longer apply. In the event of
20
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
termination by ALFA under the provisions of this Article such
termination shall be ALFA's sole remedy in respect of any such failure
or otherwise any alleged breach by SALIX.
17.3 SALIX shall have the right to terminate this Agreement in whole or in
part, in respect of any indication or any part of the Territory by
giving ninety (90) days' notice in writing to ALFA whereupon the
rights of SALIX under this Agreement to exploit such indication or
exploit Product in such part of the Territory shall cease.
Article 18 - PERIOD SUBSEQUENT TO THE TERMINATION OF THE AGREEMENT
------------------------------------------------------------------
18.1 Upon the termination or expiration of this Agreement by reason of
service of notice under Article 17.1 or 17.2 (and not otherwise);
18.1.1 SALIX shall cease any activity and any use of material
consequent to or connected with this Agreement and shall
return to ALFA, at its own expense and within one (1) month
from the effective date of termination, all the Technology
Rights supplied to it by ALFA hereunder, as well as any and
all documents and materials referring to it, and shall (save
only as specified below) cease any and all use of be
Technology Rights and of the Trademark for any purpose
whatsoever; and
18.1.2 ALFA may at its sole discretion require SALIX to:
(a) transfer to ALFA or to a company named by ALFA the IND,
the NDA, the PLA and/or other regulatory approvals for
the Product Provided That upon any such transfer SALIX
shall be entitled to reimbursement of all provable
government fees incurred by SALIX in connection with the
NDA and/or other regulatory approvals or the
applications therefor;
(b) transfer to ALFA or a company named by ALFA, at cost,
all unsold quantities of the Products Provided Always
that SALIX shall have the right to continue its selling
activities in order to dispose of said Products (and in
such a case SALIX shall continue to pay the royalties
due in respect thereof);
(c) accept delivery of any quantities of Compound ordered
from ALFA prior to the date of termination under the
terms of the Supply Agreement.
Article 19 - ASSIGNATION
------------------------
19.1 ALFA shall have the right to assign this Agreement, in whole but not
in part, to any Affiliate of its choice to whom the Patents and
Technology Rights may have been transferred and SALIX hereby
acknowledges and accepts any such assignation but
21
ALFA shall not otherwise assign or purport to assign this Agreement
(in whole or in part) without the prior consent in writing of SALIX
such consent not to be unreasonably withheld or delayed.
19.2 SALIX shall have the right to assign this Agreement, in whole but not
in part, to any Affiliate of its choice and ALFA hereby acknowledges
and accepts any such assignation but SALIX shall not otherwise assign
or purport to assign this Agreement (in whole or in part) without the
prior consent in writing of ALFA such consent not to be unreasonably
withheld or delayed.
19.3 This Agreement shall be binding upon the successors and assignees,
(and any subsequent assignee) of each of the parties.
Article 20 - ENTIRE AGREEMENT AND MODIFICATION
----------------------------------------------
20.1 This Agreement together with the Supply Agreement constitutes the
final and complete understanding existing between ALFA and SALIX
relating to the subject matter hereof The terms of this Agreement
cannot be substituted, superseded, waived or modified in any manner
except by written agreement executed for and on behalf of each of ALFA
and SALIX.
20.2 This Agreement supersedes the letter of intent dated February 2, 1995.
This Agreement supersedes the Nondisclosure Agreement dated Number 11,
1991 between SALIX and ALFA provided that such agreement shall
continue in accordance with its terms in respect of any breach by
either party of the terms thereof occurring prior to the date hereof.
Article 21 - LANGUAGE AND GOVERNING LAW
---------------------------------------
21.1 This Agreement is written and executed in two originals in the English
language.
21.2 This Agreement shall be governed by and construed in accordance with
the laws of Scotland, without giving effect to any conflict of laws
principles or rules. All communications notices and proceedings
required to be given hereunder shall be in the English Language.
Article 22-WAIVER
-----------------
No waiver of any default by either party shall be deemed to constitute a waiver
of any subsequent default with respect to the same or any other provision
hereof. No waiver shall be effective unless made in writing with specific
reference to the relevant provision(s) of this Agreement and signed by a duly
authorized representative of the party granting the waiver.
22
Article 23 - NOTICES
--------------------
Except as otherwise herein provided, all notices to be served or notified to the
parties hereunder shall be mailed by registered airmail return receipt requested
to their respective addresses listed below or to any other address subsequently
communicated in writing, and shall be deemed to have been given seven working
days after the date of mailing.
Party By Mail
----- -------
to SALIX SALIX HOLDINGS Ltd
0000 X. Xxxxxxxx Xxxx,
Xxxxx 000, Xxxx Xxxx,
Xxxxxxxxxx 00000
to ALFA: ALFA XXXXXXXXX S.p.A
Attn. Xx. Xxxxxx Xxxxxxxxx
--------------------------
Xxx Xxxxxxx xxx '00 xx 0
00000 Xxxxxxx, Xxxxx
Article 24 - LITIGATION
-----------------------
The parties hereby agree that any legal action or proceeding arising out of or
in connection with this Agreement shall be brought in the Scottish Courts and
the parties hereby prorogate the non-exclusive jurisdiction of the Court of
Session, Edinburgh. IN WITNESS WHEREOF, these presents consisting of this and
the twenty one preceding pages together with the Schedule hereto, are executed
as follows:-.
23
For and on behalf of
ALFA WASSERMANN S.p.A
at MILANO
on the 24 day of June 1996
By /s/ signature unreadable
---------------------------
Director
in the presence of
/s/ Xxxxxxx Xxxxxxx
-------------------------------
XXXXXXX XXXXXXX Name of Witness
-------------------------
c/o ALFA WASSERMANN Address of Witness
-------------------------
MILANO
-------------------------
For and on behalf of
SALIX PHARMACEUTICALS, INC.
at Palo Alto
on the 24 day of June 1996
By /s/ Xxxxx Xxxxxxxx
------------------------
Director
in the presence of
/s/ XXXXXXXXX X. XxXXXXX
------------------------
XXXXXXXXX X. XxXXXXX Name of Witness
------------------------
c/o SALIX PHARMACEUTICALS Address of Witness
------------------------
Palo Alto, CA
------------------------
24
This is the Schedule referred to in the foregoing Licence Agreement between
Alfa Wassermann S.p.A and Salix Pharmaceuticals, Inc., dated June 24, 1996
SCHEDULE
--------
PART 1
PATENTS
--------------------------------------------------------------------------------
Case Filing date Filing no. Granting date No. of the Expiry date
granted patent
S34 05/11/1981 262,123 07/27/1982 4,341,785 05/11/2001
S50 04/26/1985 727,521 12/10/1985 4,557,866 04/26/2005
S73 06/28/1993 083,453 10/04/1994 5,352,679 06/28/2013
Case S 34 (product patent): Imidazo-rifamycin derivatives with antibacterial
utility
Case S 50 (processing patent): Process for the synthesis of pyrido-imidazo
rifamycins
Case S 73 (patent for therapeutical use) : Use of rifaximin and pharmaceutical
formulations containing it in the treatment of gastric dyspepsia caused by
helicobacter pylori.
All as filed for the Territory.
------------------------------
25
PART 2
COMPOUND SPECIFICATION
[*]
26
[*] CERTAIN INFORMATION ON THIS PAGE HAS BEEN OMITTED AND FILED SEPARATELY WITH
THE SECURITIES AND EXCHANGE COMMISSION. CONFIDENTIAL TREATMENT HAS BEEN
REQUESTED WITH RESPECT TO THE OMITTED PORTIONS.
PART 3
SALIX DEVELOPMENT PLAN
----------------------
--------------------------------------------------------------------------------
ACTIVITIES
--------------------------------------------------------------------------------
A. ANIMAL PHARMACOLOGY
Al Treatment of clindamycin-induced colitis with rifaximin in hamsters
B HUMAN PHARMACOKINETICS
B1 Absorption/excretion in patients with C difficile colitis (assay of
samples taken from phase III efficacy studies)
C CLINICAL EFFICACY
C1 Two phase III pivotal efficacy studies in patients with
antibioticassociated colitis (to include evaluation of dose-response)
27
PART 4
ALFA DEVELOPMENT PLAN
-------------------------------------------------------------------------------
-------------------------------------------------------------------------------
ACTIVITIES
-------------------------------------------------------------------------------
A. TOXICOLOGY
A.1 Validation chemistry pre-study stability and homogeneity of
suspension.
A.2 Analytical method development LC-MS/N4S (rat/dog/rabbit/human)
(including validation)
A.3 4 week preliminary toxicity rat
A.4 26 week toxicity rat
A.5 4 week preliminary toxicity dog (including supporting toxicokinetics)
A.6 52 week toxicity dog (including supporting toxicokinetics)
A.7 Formulation chemistry rabbit (repro)
A.8 Pregnant preliminary rabbit
A.9 Teratology rabbit (ICH 413) (including supporting toxicokinetics)
A.10 Formulation chemistry rat (repro)
A.11 Fertility rat (ICH 411)
A.12 pre- and post natal rat (ICH 412)
A.13 Teratology rat (ICH 413) (including supporting toxicokinetics)
A.14 Acute studies in two rodent species (mouse, rat)
B ADME (dog-rat)
B.1 Preparation of 14C-Rifaxmin
B.2 Absorption excretion (AE) 14C-R, in dog after single administration
B.3 Absorption distribution excretion (ADE) 14C-R in rat after single
administration
B.4 ADME alter multiple doses in rat or dog (if required)
B.5 Identification of metabolites (if required)
C SAFETY (general) PHARMACOLOGY STUDIES
C.1 General signs and behavior
C.2 Central nervous system
C.3 Respiration and cardiovascular system
C.4 Autonomic nervous system and smooth muscle
C.5 Skeletal muscle
C.6 Gastrointestinal system
C.7 Water and electrolyte excretion
C.8 Drug interaction studies.
28
D MICROBIOLOGY
D.1 R on C Difficile vs Vancomicin and Metronidazole
D.2 R induction of resistance in NH4 pr.b.vs Neomycin
E CLINICAL DEVELOPMENT
E.1 Single ascending dose in healthy volunteers
E.2 Single dose radiolabelled study in healthy volunteers (including
determination of metabolites, as necessary)
E.3 Multiple dose in healthy volunteers (if required)
E.4 Absorption study in patients with ulcerative colitis.
29
