Exhibit 10.1
* Portions marked with a "*" have been omitted pursuant to a request for
confidential treatment. Such portions have been filed separately with the SEC.
LICENSE, SUPPLY AND DISTRIBUTION AGREEMENT
THIS AGREEMENT is made the 1st day of July 2004 (the "Effective Date") by and
between NexMed, Inc., a corporation organized and existing under the laws of
Nevada having its principal place of business at 000 Xxxxxxxxx Xxxxxxxxx,
Xxxxxxxxxxxx, XX 00000, XXX (hereinafter referred to as "NexMed") and NexMed
International Limited, a corporation organized and existing under the laws of
the British Virgin Island having its principal place of business at Suite 2208
Windsor House, 000 Xxxxxxxxxx Xxxx, Xxxxxxxx Xxx, Xxxx Xxxx (hereinafter known
as "NexMed International") and SCHERING AG, a corporation organized and existing
under the laws of Germany having its principal place of business at 00000
Xxxxxx, Xxxxxxx (hereinafter referred to as "Schering"). NexMed, NexMed
International and Schering are sometimes referred to herein individually as a
"Party" and collectively as the "Parties".
WITNESSETH:
WHEREAS, NexMed is developing and will manufacture an
alprostadil cream formulation under the brand names Alprox TD;
WHEREAS, Schering is interested in the distribution,
marketing, promotion and the sale in the Territory (as defined below) of this
alprostadil cream product to be manufactured by NexMed;
WHEREAS, Schering, as a recognized pharmaceutical company, has
appropriate distribution partners and sales force along with adequate financial
resources for the distribution, marketing, promotion and sale of the Product (as
defined below);
WHEREAS, NexMed and Jenapharm GmbH and Co. KG an Affiliate of
Schering signed a Confidentiality Agreement on June 28, 2002; which was amended
to Schering on April 04, 2003 in order to govern the protection of confidential
information made available by the Parties in connection with the discussions
concerning this transaction;
WHEREAS, the Parties signed a Letter Agreement on December 1st
/ 10th, 2003, which contemplated that the Parties would negotiate a definitive
agreement which would incorporate certain terms and conditions set forth in such
Letter Agreement;
NOW, THEREFORE, in consideration of the foregoing recitals and
the mutual covenants and agreements contained herein, the Parties hereto,
intending to be legally bound, do hereby agree as follows:
ARTICLE I
DEFINITIONS
1.1 Definitions. The following terms, when capitalized, shall
have the following meanings (such meanings to be equally applicable to both the
singular and plural forms of the terms defined), when used in this Agreement.
"Affiliate" means any person, corporation, partnership, firm,
joint venture, or other entity which, directly or indirectly, by itself or
through one or more intermediaries, controls, is controlled by, or is under
common control with, NexMed or Schering, as the case may be. As used in this
definition, the term "control" means the possession of the power to direct or
cause the direction of the management and policies of an entity, whether through
the ownership of the outstanding voting securities or by contract or otherwise.
"Agreement" means this License, Supply and Distribution
Agreement and all schedules and exhibits attached hereto.
"Bankruptcy Event" shall have the meaning set forth in Section
14.2(d).
"Bulk Product" means the Product supplied in single use
disposable dispensers for final labeling and packaging, including outer
distribution and transport packaging, by Schering and released for the EU.
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"Business Day" means a day which is not a Saturday, a Sunday
or other day on which banks are required or authorized by law to be closed in
Robbinsville, New Jersey, USA or Berlin, Germany.
"CFR" means the US Code of Federal Regulations.
"Clinical Development" means all activities relating to
planning and execution of clinical studies in humans directed towards obtaining
Marketing Authorization of the Product in the Territory including, without
limitation, clinical studies and related Regulatory Approvals.
"CMC/Process Development" means the development of one or more
processes for the manufacture and packaging of the Product for Preclinical
Development, Clinical Development and Commercialization, and shall include,
without limitation, formulation, production, fill/finish, sourcing of
components, raw materials, and packaging supplies, development of methods and
controls appropriate for Regulatory Approval in the Territory, including assays,
quality control and quality assurance methodology and stability protocols.
"Commercialization" and "Commercialize" mean all activities
undertaken relating to the final packaging, pre-marketing, marketing, promotion,
distribution and sale of the Product.
"Confidential Information" shall have the meaning set forth in
Section 10.1.
"Control" or "Controlled" means the right to grant an
exclusive license or sublicense of Patents, know-how, Information or other
intangible rights as provided for herein without violating the terms of any
agreement or other arrangement with any Third Party.
"Development" and "Develop" mean all activities and
obligations relating to Existing Preclinical Development, Existing Trials,
Preclinical Development, Clinical Development and CMC/Process Development.
"ED" means erectile dysfunction.
"EMEA" means the European Medicines Evaluation Agency, or any
successor agency with responsibility for regulating the development, manufacture
and sale of human pharmaceutical products.
"EU cGMP" means the current Good Manufacturing Practices as
set out in Directive 2003/94 as effective of Nov. 2003, of the Commission of the
European Communities and further elaborated in The Rules Governing Medicinal
Products in the European Community, Volume IV - Guide to Good Manufacturing
Practice for Medicinal Products, Contract Manufacture and Analysis, as such may
be amended from time to time.
"European Marketing Authorization" means the Marketing
Authorization in the countries listed in Item 1 and Item 2 of Schedule 1
"European Union" means the countries listed under Item 1 of
Schedule 1
"Existing Development" means the Existing Preclinical
Development and the Existing Trials set out in Schedule 2 to this Agreement.
"Existing Preclinical Development" means the Preclinical
Development being carried out by NexMed as of the Effective Date, a description
of which is set out in Schedule 2 to this Agreement.
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"Existing Trials" means the ongoing (as of the Effective Date)
clinical studies of the Product.
"FDA" means the United States Food and Drug Administration, or
any successor agency.
"Field" means use of the Product in humans.
"Firm Order" shall have the meaning set forth in Section 8.3.1
(a).
"First Commercial Sale" means the date Schering or an
Affiliate or a sublicensee of Schering first sells commercially, pursuant to a
Regulatory Approval, a Product in any country of the Territory; provided,
however, that where such sale has occurred in a country for which pricing or
reimbursement approval is necessary for widespread sale, then such sale shall
not be deemed a First Commercial Sale until such pricing or reimbursement
approval has been obtained.
"GMP" means the Good Manufacturing Practices regulations
promulgated by the European Commission and/or the FDA and/or the GMP regulations
required by the local authorities of the countries where the Product will be
marketed including the EU cGMP and the US cGMP, as they may be amended from time
to time.
"Health Regulatory Authority" means EMEA, the national
competent authorities of the EU member states, FDA and other government entity
that has jurisdiction to grant Regulatory Approvals including, but not limited
to, Marketing Authorizations..
"Information" means (i) techniques, data and information
relating to the Product, including, but not limited to, inventions, practices,
methods, manufacturing processes, knowledge, know-how, skill, trade secrets,
experience, test data (including pharmacological, toxicological, preclinical and
clinical test data); data, records and information derived from Preclinical
Development, Clinical Development or CMC/Process Development, regulatory
submissions, adverse reactions, analytical and quality control data, marketing,
pricing, distribution, cost, sales and manufacturing data or descriptions, and
(ii) compounds, biologics, compositions of matter, viruses, assays and
biological materials within the Field relating to the Product.
"Losses" shall have the meaning set forth in Section 15.1.
"Major Countries" means Germany, France, Italy, Spain and
United Kingdom. Any of these countries is a "Major Country".
"Marketing Authorization" means the right to place a
proprietary medicinal product on a market in the Territory for commercial
exploitation.
"Marketing Authorization Application" means an application for
Regulatory Approval which is required before commercial sale, use or placing on
the market the Product as a proprietary medicinal product in a jurisdiction.
This includes, for the purposes of Regulatory Approval in the United States, a
Biologic License Application and all supplements filed pursuant to the
requirements of the FDA (including all documents, data and other information
concerning a Product which are necessary for, or included in, FDA approval to
market the Product), and, for the purposes of Regulatory Approval in the
European Union, applications pursuant to the current version of Directive
2001/83/EC or Council Regulation ECC/2309/81 as applicable. Any successor
legislation has to be followed accordingly.
,,Mutual Recognition" or ,,mutually recognized" shall have
meaning as set out in current version of Directive 2001/83/EC or Council
Regulation ECC/2309/81 as applicable. Any successor legislation has to be
followed accordingly.
"Necessary Patents" shall have the meaning set forth in
Section 11.1.
"NexMed" means NexMed, Inc., NexMed International and all
other Affiliates of NexMed, except as otherwise specifically stated herein.
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"NexMed Domain Names" shall have the meaning set forth in
Section 12.2.2.
"NexMed Information" means Information within the Control of
NexMed as of the Effective Date or which comes within the Control of NexMed
during the term of this Agreement and relates to the manufacture, use or sale of
the Product. Notwithstanding anything herein to the contrary, NexMed Information
shall exclude NexMed Patents.
"NexMed Patents" means any Patents in the Territory owned or
Controlled by NexMed or its Affiliates as of the Effective Date or which comes
within the Control of NexMed or any of its Affiliates during the term of this
Agreement covering the use, importation, sale or offer for sale of the Product.
"NexMed Trademark" means the trademark "Alprox-TD" owned by
NexMed.
"Non-Commercialized Country" shall mean any European Union
country where Schering Commercialized the Product and determined to cease to
actively Commercialize the Product in such country.
"Non-Commercialized Ratio" shall mean the quotient received by
dividing (i) the total net sales for the Product generated in each
Non-Commercialized Country during the twelve (12) complete calendar months
immediately preceding the cessation of significant marketing activities in such
Non-Commercialized Countries, by (ii) the average annual net sales for the
Product in all European Union countries other than Non-Commercialized Countries
during the thirty-six (36) complete calendar months immediately preceding such
measurement date.
"Patents" means all existing patents and patent applications
and all patent applications hereinafter filed, including any continuation,
continuation-in-part, division, provisional or any substitute applications, any
patent issued with respect to any such patent applications, any reissue,
reexamination, renewal or extension (including any supplemental patent
certificate) of any such patent, and any confirmation patent or registration
patent or patent of addition based on any such patent, and all foreign
counterparts of any of the foregoing. "Patents" also includes a Supplementary
Certificate of Protection of a member state of the European Union and any other
similar protective rights in any other country.
"Patent Expenses" means the fees, expenses and disbursements
and outside counsel and agent fees incurred in connection with the preparation,
filing, prosecution and maintenance of NexMed Patents or Joint Patents including
NexMed' and Schering's costs of patent interference and opposition proceedings.
"Preclinical Development" means all activities relating to the
planning and execution of non-human studies conducted in in vitro or in relevant
in vivo animal models directed toward obtaining Regulatory Approval of a Product
in each jurisdiction in the Territory. This includes preclinical testing,
pharmacokinetics, toxicology, documentary and medical writing directly related
to Preclinical Development activities, and related regulatory affairs.
"Product" means a prescription pharmaceutical product for ED
containing NexMed's proprietary formulation of alprostadil as topical cream for
the transdermal use including the single use disposable dispenser and all
further improvements within the area of ED.
"QAA" shall mean the Quality Assurance Agreement attached
hereto as Schedule 3, which forms an integral part of this Agreement.
"Quality Specifications" means those specifications for
release of starting materials, packaging materials and the Bulk Product as set
forth in the QAA as amended from time to time.
"Registration Dossier" means any and all information,
processes, techniques and data relating to the Product owned and prepared by
NexMed and submitted to Health Regulatory Authorities in the format required by
the regulations applicable in the particular jurisdiction to obtain Regulatory
Approvals, including, but not limited to Marketing Authorizations.
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"Regulatory Approval" means all approvals, product and
establishment licenses, registrations or authorizations of any federal, state or
local Health Regulatory Authority, department, bureau or other governmental
entity, necessary for the manufacture, use, storage, importation, export,
transport, sale or placing on the market of the Product in a jurisdiction in the
Territory.
"Regulatory Correspondence" means all correspondence including
but not limited to letters with Health Regulatory Authorities.
"Schering Trademark" means the trademarks selected and owned
by Schering which it uses for the marketing of the Product, other than the
NexMed Trademark.
"Specifications" means all the specifications for the Product
as contained (i) in the technical files (ii) in the Registration Dossiers
prepared by NexMed and as has been approved by the Health Regulatory
Authorities.
"Shipment Date" shall have the meaning set forth in Section
8.5.2.
"Steering Committee" means the coordinating committee
established by the Parties in Section 5.1.
"Supply Price " shall have the meaning set forth in Section
9.1.
"Territory" means the countries listed in Schedule 1.
"Third Party" means any entity other than NexMed or Schering
and their respective Affiliates.
"US cGMP" means the FDA's current Good Manufacturing Practice
regulations as promulgated under the Act at 21 CFR (chapters 210, 211, 600 and
610), and as further defined by FDA guidance documents, as such may be amended
from time to time.
ARTICLE II
LICENSES AND TRANSFER OF INFORMATION
2.1 Exclusive Patent and Information License to Schering
(a) NexMed International hereby grant to Schering an exclusive
(even as to NexMed) license, with a right to sublicense
(subject to Section 2.1(d)), under the claims contained in the
NexMed Patents and the NexMed Information to final package,
use, market, sell, import for sale and distribute the Product
in the Territory, subject to the terms and conditions hereof.
NexMed hereby represents and warrants to Schering that NexMed
International owns all rights held by NexMed and its
Affiliates to license the NexMed Patents and NexMed
Information in the Territory.
(b) A list of the NexMed Patents identified as of the Effective
Date is attached hereto as Schedule 6. If at any time during
the course of this Agreement any additional Patents in the
Territory are acquired by or come under the control of NexMed
that include any claims that cover the final packaging, use,
marketing, importation, sale, offer for sale or distribution
of the Product, such shall be added to the list attached
hereto as Schedule 6.
(c) Promptly following the Effective Date, NexMed shall disclose
and provide to Schering all Information relating to the
Product that is necessary for Schering to Commercialize the
Product in the Territory. If at any time during the course of
this Agreement any additional Information is acquired by
NexMed that is necessary for Schering to Commercialize the
Product in the Territory, NexMed shall promptly, upon such
acquisition, disclose and provide to Schering all such
additional Information; the disclosure and provision of such
additional Information is subject to any then existing Third
Party rights or confidentiality obligations with the exception
of safety data.
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(d) Sublicensing. Schering shall be permitted to sublicense or
subcontract to Affiliates and Third Parties any of Schering's
rights to Commercialize the Product in the Territory without
the prior written consent of NexMed; provided, however,
Schering shall provide NexMed within five (5) days after
execution with a copy of each executed sublicense agreement
with sublicensees. Schering is not obliged to provide NexMed
with such copy if such sublicense agreement is concluded
between Schering and one of its Affiliates or Partners in the
customary distribution chain. Schering shall ensure that each
of its Affiliates and sublicensees accepts and complies with
all of the terms and conditions of this Agreement as if such
Affiliates or sublicensees were a party to this Agreement and
Schering shall guarantee and be responsible for its
Affiliates' and sublicensees' performance under this
Agreement.
(e) Exclusivity. Neither Schering nor any of its Affiliates shall
during the Term, market, commercialize, sell, offer for sale
or have sold, or in-license or otherwise acquire any
prescription PDE5-inhibitor for the treatment of ED without
the prior written consent of NexMed which consent shall not be
unreasonably denied so long as such additional product will
not materially interfere with Schering's commercialization
efforts for the Product pursuant to this Agreement.
(f) NexMed Retained Rights. Any rights of NexMed not expressly
granted to Schering under the provisions of this Agreement
shall be retained by NexMed. In furtherance of the foregoing
and not in limitation thereof, NexMed shall retain the right
(a) to exploit NexMed Patents and NexMed Information to
Develop and Commercialize the Product outside the Territory,
without any duty to account to Schering or obtain Schering's
consent for such exploitation, (b) to exploit NexMed Patents
and NexMed Information for purposes unrelated to the Product,
without any duty to account to Schering or obtain Schering's
consent for such exploitation, and (c) to exploit the NexMed
Patents and NexMed Information outside the field of ED.
ARTICLE III
DEVELOPMENT
3.1 Development
(a) NexMed shall solely be responsible for the cost and control of
all Development of the Product.
(b) The Development to be conducted by NexMed pursuant to Section
3.1 (a) above shall be set out in the development plan
attached hereto as Schedule 4. NexMed shall be solely
responsible for preparing the development plan and making any
amendments to such development plan.
(c) NexMed shall use commercially reasonable efforts to
distinguish any product it sells that contains alprostadil
from the Product and shall use commercially reasonable efforts
to discourage and prevent any off-label use for ED of any such
other products that NexMed sells that contains alprostadil.
3.2 NexMed shall not conduct or support any clinical studies for the
Product in a country of the Territory after obtaining Regulatory
Approval in such country of the Territory without Schering's prior
written consent.
ARTICLE IV
REGISTRATION, PHARMACOVIGILANCE
4.1 In accordance with this Article IV, NexMed shall be solely responsible
for the preparation of Marketing Authorization Applications including
the Registration Dossiers to achieve Marketing Authorizations in the
countries listed in Item 1 and 2 of Schedule 1. Schering will support
NexMed in the performance of such activities in that Schering will
assist in the development of the submission strategy, consult on the
development of the submission plan and guide in the regulation
interpretation.
4.2 A copy of each such Marketing Authorization Application for the
countries listed in Item 1 and Item 2 of Schedule 1 and the respective
Registration Dossier including respective amendments and updates shall
be promptly provided to Schering. In connection with all Marketing
Authorization Applications being prosecuted by NexMed in the countries
listed in Item 1 and Item 2 of Schedule 1 NexMed agrees to provide
Schering with a copy (which may be wholly or partly in electronic form)
of all filings to Health Regulatory Authorities that it makes
hereunder, such copy to be provided at the same time as NexMed makes
the filing with the Health Regulatory Authority.
4.3 Registration in the countries listed in Item 1 and 2 of Schedule 1
4.3.1 Subject to Section 4.1, NexMed shall submit Marketing Authorization
Application initially to all countries listed in Item 1 and 2 of
Schedule 1, conduct and be solely responsible for the Marketing
Authorization Application for the Product in all countries listed in
Item 1 and 2 of Schedule 1 until the Product is mutually recognized.
All such Marketing Authorization Applications shall be filed in the
name of NexMed or its Affiliates and Schering shall be named as the
distributor of the Product.
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4.3.2 In case NexMed will submit the Marketing Authorization Application
under the MR-procedure, as set out in the current directive 2001/83/EC,
NexMed shall within ninety (90) days after the Marketing Authorization
in the Reference Member State apply for Marketing Authorization in the
Concerned Member States.
4.3.3 Independently of the regulatory route followed to achieve Mutual
Recognition, NexMed shall within five (5) Business Days after Mutual
Recognition of the Product transfer the Marketing Authorization
Applications to Schering or its Affiliates as indicated by Schering.
4.3.4 After Mutual Recognition of the Product Schering shall be responsible
to obtain the national Marketing Authorizations in the Concerned Member
States. NexMed shall be obliged to provide all Information and
documents necessary to achieve this without undue delay. As a rule the
Information and documents shall be provided within three (3) Business
Days following request by Schering.
4.3.5 In the case a country listed in Item 1 and 2 of Schedule 1 refuses to
Mutually Recognize the Marketing Authorization of the Product, Schering
has the right to decide whether the Marketing Authorization Application
is withdrawn in this Concerned Member State or whether the procedure is
to be referred to arbitration by the CPMP according to the provisions
of the Directive.
4.3.6 Until European Marketing Authorization of the Product, the fees for the
Marketing Authorizations in the countries listed in Item 1 and 2 of
Schedule 1 shall be born by NexMed. Thereafter and outside of the
countries listed in Item 1 and 2 of Schedule 1, Schering shall bear all
costs and expenses associated with preparing, obtaining and maintaining
all Marketing Authorizations.
4.4 Registration in all other Countries of the Territory
4.4.1 Schering shall have the right, but not the obligation to apply in it's
own name for the Marketing Authorization in all other countries of the
Territory. Schering will prepare, obtain and maintain the Marketing
Authorizations in all such other countries during the term of this
Agreement at its own cost and in its name.
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4.4.2 Subject to any Third Party Rights and/or confidentiality obligations,
NexMed shall grant Schering access to any information on the Product
reasonably necessary to obtain and maintain the Marketing
Authorizations in such other countries of the Territory of the Product
and will answer as soon as possible the questions of the Health
Regulatory Authorities related to the registration of the Product in
such other countries of the Territory.
During the term of this Agreement, NexMed and Schering shall cooperate
in all regulatory activities in good faith.
4.5 Mutual Exchange Product Safety related Information; Recalls. NexMed and
Schering will regularly inform each other of any information relating
to the safety of the Product, including any serious unexpected and
expected side effects of which the Parties shall inform each other
expeditedly and in accordance with the relevant and current legislation
of the countries of the Territory. Schering shall promptly notify
NexMed of any material actions to be taken by Schering with respect to
any recall or market withdrawal or other corrective action related to
the Product in the Territory prior to such action so as to permit
NexMed a reasonable opportunity to consult with Schering with respect
thereto and Schering agrees to consider NexMed's consultation.
Within a period of six (6) months of execution of the Agreement, and
before the First Commercial Sale in one of the countries of the
Territory and before enrollment of the first patient in a Schering
sponsored phase IV study, the Parties agree to enter into a standard
operating procedure which should be set up by both Parties to govern
safety information exchange including but not limited to collection,
investigation and reporting to Regulatory Authorities of
Product-related adverse drug experience reports, such that each of the
Parties can comply with its legal obligations worldwide. The standard
operating procedure will encompass individual case safety reports from
all sources as well as periodic reporting (e.g. Periodic Safety Update
reports). The standard operating procedure will be promptly amended as
changes in international legal obligations require. Each party shall
provide to the other Party all data and results obtained from such
phase IV studies and other studies regarding the safety of the Product.
NexMed shall be free to utilize such data and results outside of the
Territory; Schering shall be free to utilize such data and results for
commercializing the Product in the Territory.
4.6 Participation by NexMed in Regulatory Affairs.
4.6.1 Notwithstanding anything to the contrary contained in this Article IV,
within a reasonable time prior to making any regulatory filings or
Marketing Authorization Applications with respect to a Product in the
Territory and during any such Regulatory Approval or Marketing
Authorization approval process, Schering will provide copies of any
proposed filings and consult with, and consider in good faith any
comments of, NexMed with respect to any filings to be made or other
actions to be taken by Schering in the Territory.
4.6.2 If either Party is advised by its counsel that it must communicate with
any Health Regulatory Authority in the Territory with respect to the
subject matter hereof, it shall promptly, but not later than two (2)
Business Days, advise the other Party of the same and provide the other
Party in advance with a copy of any proposed written communication with
such Health Regulatory Authority and comply with any and all reasonable
requests of the other Party concerning any meeting or written or oral
communication with such Health Regulatory Authority.
4.6.3 Each Party shall promptly and in accordance with applicable law provide
to the other Party copies of any documents or correspondence received
from any Health Regulatory Authority, but not later than two (2)
Business Days after such receipt, that pertains to the Product
(including without limitation any minutes from a meeting with respect
thereto). Each Party shall provide the other Party with any documents
or correspondence to be submitted to any Health Regulatory Authority in
the Territory that relate to the Product in time sufficient to allow
for a reasonable time to comment.
4.7 Change Management:
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4.7.1 Applicability. Sections 4.7.2 through 4.7.4 below shall apply from and
after the time that the Marketing Authorization in the Territory has
been transferred to Schering or its Affiliates and agents as
contemplated by Section 4.3.3.
4.7.2 During the course of this Agreement, if either Schering or NexMed
wishes to or is required to make a change to: (i) the Bulk Product or
Bulk Product Specifications; or (ii) the manufacturing process for the
Bulk Product; or (iii) the sites of manufacture of the Bulk Product; or
any other aspects, which may have an influence or impact on the
Regulatory Approval or approved Marketing Authorization of the Product
in any country of the Territory (a "Change"), it shall submit to the
other Party in writing details of the requested Change for prior
written approval. Such Change may be initiated by Schering or NexMed or
may be mandated by the appropriate Regulatory Authority in such
country.
Costs within this Section 4.7 shall include the costs for implementing
a Change as well as all costs for the filing of a Change.
4.7.3 NexMed Change request:
If NexMed requests a Change as a result of any change in governmental
or Regulatory Requirements, Schering shall not unreasonably withhold or
delay consent to it. The responsibility for and the costs arising out
of such a Change shall be borne by NexMed.
Where NexMed requests a Change due to NexMed voluntarily changing its
manufacturing processes or otherwise, e.g. technical necessities at
NexMed, both Parties shall discuss any such change. The responsibility
for and the costs arising out of such a Change shall be borne by
NexMed.
4.7.4 Schering Change request:
If Schering voluntarily requests a Change, NexMed shall as soon as
practicable review such proposed Change and provide Schering with its
likely effect on NexMed's production systems together with the
investments and/or the costs necessary to implement such a Change. If
Schering wishes to proceed, and NexMed has no reasonable objections,
NexMed shall use its commercially reasonable endeavors to achieve such
Changes as quickly as possible. The responsibility for and the costs
arising out of such a Change shall be borne by Schering.
If Schering requests a Change as a result of any change in governmental
or Regulatory Requirements in the Territoy, NexMed shall not
unreasonably withhold or delay consent to it. The responsibility for
and the costs arising out of such a Change shall be borne by NexMed.
In any event, Schering shall be responsible for any subsequent
regulatory submissions in the Territory, and NexMed will provide
Schering with all Information necessary to compile the Registration
Dossier to meet the respective governmental and/or regulatory
requirements to change the particulars of the Marketing Authorization.
ARTICLE V
STEERING COMMITTEE / WORKING TEAM
5.1 Establishment. The Parties hereby agree that promptly after execution
of this Agreement or as the Parties decide as appropriate, they will
form the Steering Committee composed of four (4) members (the "SC
Members") with functions more fully described in Section 5.2 below.
Each Party shall have the right to appoint two (2) SC Members to serve
on the Steering Committee each of whom shall be (i) a member of the
respective Party's senior management and (ii) duly authorized by such
Party to transact the business of the Steering Committee. Upon written
notice to the other, each Party shall be entitled to appoint substitute
SC Member(s), provided that, such substitute(s) belong to the senior
management of its respective Party. SC Members shall be allowed to be
represented by proxy. The Parties hereby agree that the Steering
Committee shall meet at least semi-annually at mutually agreeable dates
and places and that, upon invitation of either Party, other
representatives of Schering, NexMed, or both, shall be allowed to
attend such meetings. The Parties further agree that each shall bear
all expenses of its respective SC Members and representatives with
respect to their participation in the Steering Committee.
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5.2 General Functions of the Steering Committee. The Parties agree that the
functions of the Steering Committee shall be to exchange information
and to jointly plan activities with respect to the Product, including
marketing plans and promotional materials for the Territory. The
Steering Committee shall also appoint a Working Team, as more fully
described in Section 5.4 below and a Manufacturing and Supply Team, as
more fully described in Section 8.2 below.
5.3 Decision-Making. The Parties hereby agree that all decisions and/or
actions taken by the Steering Committee shall be taken exclusively by
the unanimous express consent of all the SC Members. In the event the
Steering Committee is unable to reach an agreement on any matter, then
such matter shall be referred to the Chief Executive Officer of NexMed
and to the Chief Executive Officer of Schering's Region Europe for
their consideration and resolution. The Parties however agree that, in
the event of any issue arising in connection with the marketing and the
final packaging of the Product in the Territory, Schering's decision
shall constitute the final decision, and in the event of any issue
arising in connection with the Development of the Product, NexMed's
decision shall constitute the final decision, and that any such
decision shall be binding upon both Parties. Notwithstanding the
foregoing, no Party shall be entitled to exercise its casting vote to
require, in any way, that the other Party expend additional
consideration or resources than such Party has expressly agreed to
commit in this Agreement.
5.4 Working Team. Shortly following its formation, the Steering Committee
shall appoint not more than five (5) representatives from each Party,
(the "WT Members") one of whom shall necessarily be a project manager
of its respective Party, to serve on the Working Team. Upon written
notice to the other, each Party shall be entitled to appoint substitute
WT Member(s). WT Members shall be allowed to be represented by proxy.
5.5 General Functions of the Working Team. The Parties agree that the
Working Team's functions shall be to set up a life cycle management
plan and dealing with all issues in the context of marketing of the
Product and submit it for review by the Steering Committee, it being
understood that such plan is not meant to encompass the NexMed Patents
and/or NexMed Information. The Working Team shall be responsible for
the implementation of the life cycle management plan and co-ordination
of each Party's respective activities. The Parties agree that the
Working Team shall meet at least once every four (4) months at mutually
agreeable dates and places, and that, upon invitation of either Party,
other representatives of Schering, NexMed, or both, shall be allowed to
attend such meetings. The Parties further agree that each Party shall
bear all expenses of its WT Members and representatives with respect to
their participation in the Working Team.
5.6 Retention of Powers. The Parties hereby agree that, notwithstanding the
creation of the Steering Committee and/or the Working Team and/or
Manufacturing and Supply Team, each Party to this Agreement shall (i)
at all times retain the rights and powers granted to it pursuant to the
terms and conditions of this Agreement, and that (ii) except as
otherwise expressly provided in this Agreement or expressly agreed to
by the Parties in writing to that effect, neither the Steering
Committee nor the Working Team nor the Manufacturing and Supply Team
thereof shall be delegated or vested with any such rights or powers.
Neither the Steering Committee nor the Working Team nor the
Manufacturing and Supply Team shall have at any time the power to amend
or modify this Agreement in any way, as such may only be amended or
modified as provided in Section 16.13 of this Agreement.
ARTICLE VI
MILESTONE PAYMENTS
6.1 Milestone Payments. Schering shall make the following payments ("Milestone
Payments") to NexMed. Each of these Milestone Payments shall be paid only
once regardless of the number of times the milestones are achieved by the
Product. The payments shall be due within fifteen (15) Business Days after
NexMed presents copies of the * to Schering; the payment for the sale of *
units or more of the Product in a calendar year shall be due within
fifteen (15) business day after the first achievement.
10
------------- -------------------------------------------------------------------------- ------------------
No. MILESTONES PAYMENT in (euro)
------------- -------------------------------------------------------------------------- ------------------
1 (a) _________*____________ of Alprox TD 2,000,000.00
_____________*______________before December 31, 2006, or
(b) __________*___________ of Alprox TD ________*_________
------------- -------------------------------------------------------------------------- ------------------
2 ________*____________ European Authorities or _______*_______ the 5,000,000.00
reference member state ______*_________.
--------------------------------------------------------------.
------------- -------------------------------------------------------------------------- ------------------
3 Marketing Authorization in the first Major Country other than the 2,500,000.00
reference member state subsequent to the reference member state for
indication moderate to severe ED without specific tox warning
------------- -------------------------------------------------------------------------- ------------------
4 Marketing Authorization in the second Major Country other than the 2,500,000.00
reference member state subsequent to the reference member state for
indication moderate to severe ED without specific tox warning
------------- -------------------------------------------------------------------------- ------------------
5 Marketing Authorization in the third Major Country other than the 2,500,000.00
reference member state subsequent to the reference member state for
indication moderate to severe ED without specific tox warning
------------- -------------------------------------------------------------------------- ------------------
6 Marketing Authorization in the fourth Major Country other than the 2,500,000.00
reference member state subsequent to the reference member state for
indication moderate to severe ED without specific tox warning
------------- -------------------------------------------------------------------------- ------------------
7 One time payment if Schering sells _____*______units or more of the 3,000,000.00
Product in a calendar year
------------- -------------------------------------------------------------------------- ------------------
ARTICLE VII
COMMERCIALIZATION
7.1 Schering as Sole Marketing Party. Subject to Section 2.1(d), Schering
shall have the exclusive right to Commercialize the Product, either by
itself or through its Affiliates or sublicensees, in the Territory.
7.2 Commercialization Efforts. Schering agrees to use commercially reasonable
efforts with respect to the Commercialization of the Product in the
Territory as provided hereunder. Commercialy reasonable efforts means the
same efforts like for other propriatary products with the same commercialy
potential. Such commercially reasonable efforts will be consistent with
the efforts used by Schering in preparing commercialization plans and
commercializing its own pharmaceutical products, and may include
sub-licensing, subject to Section 2.1(d). Without limiting the generality
of the foregoing, Schering shall determine the pricing and marketing
strategy for the Product in its sole discretion, provided, however, that
Schering shall not sell the Product as a loss leader and shall not set the
price of the Product at less than fair market price.
7.3 Schering shall not be obligated to Commercialize the Product in any non
EU-country where Schering does not believe on reasonable commercial
grounds, that it would be commercially reasonable to do so; provided that
in such circumstance, all rights to the Product in such country shall on
request of NexMed revert to NexMed and Schering shall transfer all
Regulatory Approvals and applications in such country to NexMed. NexMed
shall reimburse to Schering all external costs to obtain and maintain
Regulatory Approval in such countries.
11
7.4 In addition to and without limiting, defining or otherwise qualifying the
standards of conduct set forth elsewhere in this Agreement, Schering
shall: (i) use its commercially reasonable efforts to launch the Product
in each country as soon as practicable following receipt of Regulatory
Approval for the Product in such country; (ii) conduct Commercialization
in compliance with all requirements of applicable laws, rules and
regulations; (iii) consult with and keep NexMed and the Steering Committee
informed of all such activities; and (iv) assure appropriate reporting of
adverse events.
ARTICLE VIII
MANUFACTURE AND SUPPLY
8.1 Manufacture and Supply
8.1.1 Subject to the following terms and conditions, NexMed will manufacture
the Product and shall supply Schering with all of Schering's
requirements of the Product for sale in the Territory and Schering
shall purchase its requirements of the Product exclusively from NexMed.
Product shall be supplied by NexMed as Bulk Product.
8.1.2 NexMed will manufacture the Bulk Product pursuant to the processes
described in the relevant documents provided for in the Regulatory
Approval and in accordance with the Quality Assurance Agreement (the
"QAA") attached hereto as Schedule 3, which forms an integral part of
this Agreement. NexMed will adhere to these processes and instructions.
8.1.3 NexMed represents and warrants that it will obtain all material
approvals of Regulatory Authorities necessary for the manufacture of
Product prior to the first delivery of the Bulk Product. Each Party
covenants that during the term of this Agreement, it shall comply in
all material respects with all applicable laws and regulations in
carrying out its obligations pursuant to this Agreement. A Party will
inform the other Party if it happens that the competent Health
Authorities notify to such Party any non compliance with applicable
laws and regulations.
8.2 Manufacturing and Supply Team
8.2.1 The Steering Committee shall form as a sub-committee, the Manufacturing
and Supply Team, to act as a forum for effectively addressing issues
brought to the attention of the Steering Committee by either Party
relating to the manufacture and supply of the Product, the failure to
supply Product in a timely manner resulting from increases in demand
that exceed manufacturing capacities, quality issues or other
logistical issues.
8.2.2 The Manufacturing and Supply Team shall consist of 2 (two)
representatives from each Party. Substitutes may be appointed at any
time upon written notice. The Manufacturing and Supply Team shall meet
at mutually agreed dates and places. Additional representatives of
Schering and NexMed or both, in addition to members of the
Manufacturing and Supply Team, may attend such meetings at the
invitation of either Party. Schering and NexMed shall bear all expenses
of their respective members related to the participation in meetings of
the Manufacturing and Supply Team.
8.2.3 The Manufacturing and Supply Team shall serve as an advisor to the
Steering Committee with respect to issues described in Section 8.2.1
and shall have no right to exercise the rights of the Parties under
this Agreement. The Manufacturing and Supply Team shall not have the
power to amend or modify this Agreement, which may be amended or
modified only as provided in Section 16.13.
8.2.4 Advice given by the Manufacturing and Supply Team to the Steering
Committee shall only be given following unanimous agreement of the
members of the Manufacturing and Supply Team. Should it prove
impossible to obtain such agreement then the disputed matter will be
referred to the Steering Committee for resolution.
12
8.3 Ordering and Forecast
8.3.1 At least six (6) months prior to the first distribution of the Product
in a country of the Territory, and once per calendar quarter
thereafter, by the last day of such calendar quarter at the latest,
Schering will provide NexMed with:
(a) an order for Product for each month of the three-month period
commencing on the first day of the over-next calendar quarter
("Firm Order"),
(b) a non-binding forecast ("First Forecast") for Product for each
month of the three-month period immediately following the over
next calendar quarter,
(c) a non-binding month-by-month forecast of anticipated orders
for the Product (a "Second Forecast"), for the three (3) month
period following the period covered by the Firm Order plus the
First Forecast.
Schering will take into consideration the batch sizes and minimum order
sizes as set forth in Exhibit 2. Each Firm Order will be binding on
Schering and Schering shall be obligated to purchase those amounts set
forth in each Firm Order.
8.3.2 The operation of the foregoing provisions is illustrated in the
following example:
Example: On March 31, 2005, at latest, Schering shall place its Firm
Order for Product to be delivered in July, August and September 2005,
and shall provide: a First Forecast on a monthly basis from October to
December 2005 and a Second Forecast on a monthly basis from January
2006 up to March 2006.
8.3.3 Within two (2) weeks upon receipt of the First Forecast, NexMed will
submit to Schering a written confirmation that it is able to supply
Schering with its requirements according to the First Forecast. If no
confirmation is given by NexMed within the two (2) weeks period, the
Forecast shall be deemed to have been accepted.
8.3.4 NexMed is obliged to reserve manufacturing capacities and materials
sufficient to fulfill the Firm Orders. NexMed is obliged to fulfil the
Firm Orders. However, Schering's Firm Orders should not exceed by more
than 30% or be less than 30% of the First Forecast of this quarter. In
case of greater variations between Firm Order and Forecast, the Parties
will meet and negotiate in good faith in order to find a suitable
solution.
8.3.5 The Firm Orders shall specify the Arrival Dates for each month of the
Firm Order. The Arrival Dates and quantities specified in Firm Orders
will be confirmed by NexMed in writing within two (2) weeks of receipt.
If no confirmation is given by NexMed within the two (2) weeks period,
the Firm Orders shall be deemed to have been accepted. NexMed shall use
the Schering item number and the purchase order system for all
deliveries. All invoices, delivery documentation and delivery notes
have to contain the corresponding purchase order number and P.O.
position.
8.3.6 If Schering desires to alter any quantities set forth in a Firm Order
or to accelerate the Shipment Dates, then NexMed shall undertake, but
shall be under no obligation to do so, to use its commercially
reasonable efforts to comply with any changes of ordered quantities or
acceleration of Shipment Dates, especially with regard to changes to
prevent the interruption of market supply or to cuts in ordered
quantities or cancellations where the non-fulfillment of changes would
require to destroy or re-pack the Product.
8.3.7 In case that Schering rejects a lot of Bulk Product, NexMed will
provide a replacement lot within four (4) weeks of written notice from
Schering of such a rejection, subject to the provisions of Section 8.6.
This replacement shipment will be made independent of a final agreement
on the rejection.
13
8.3.8 NexMed shall maintain continuously a safety stock of the starting
materials including active pharmaceutical ingredients equal to the
average of three (3) months Firm Order for the applicable period or
capacity of three (3) months.
8.3.9 Schering shall provide at least six (6) months prior to the first
distribution of the Product in a country of the Territory, and annually
thereafter, by the end of June, a long-term requirements plan for the
Product to NexMed covering the next two (2) years. NexMed shall confirm
in writing to Schering, the existence of capacity sufficient for
manufacturing in accordance with the long-term requirement plan, or if
the existing capacity is incompatible with meeting the long-term
requirements, NexMed will use commercially reasonable efforts to
increase its capacity accordingly.
8.4 Packaging
The packaging of the Bulk Product shall be consistent with the
Specifications.
8.5 Shipment
8.5.1 NexMed will prepare the Bulk Product for shipment to Schering according
to the shipping instructions set forth in the QAA, as amended from time
to time. Shipments will be made FCA as defined in INCOTERMS 2000, at
NexMed's designated shipment point in a country in the EU. Carrier will
be chosen by Schering and coordinated by NexMed.
8.5.2 Shipment will be made early enough to meet the arrival date specified
in the Firm Orders (the "Arrival Date"), and in the quantities
specified in the Firm Orders. Quantities shipped may vary within the
range of +/- 10% of the quantities specified in the Firm Orders. NexMed
will immediately inform Schering of any circumstances that could result
in any shipment delay or a significant variation (greater than +/- 10%)
of the quantities set forth in the Firm Orders. Shipment delays which
exceeds 15/30/45 days will allow Schering to deduct 2/5/10% of the
invoiced amount. This compensation does not replace any further rights
of Schering.
8.5.3 Unless otherwise agreed in writing the manufacturing date of the
Product shall not be more than four (4) months prior to the Shipment
Date. Product shall not have a remaining shelf life of less than twenty
(20) months upon shipment unless Schering has requested delayed
delivery.
8.5.4 Should any quantities of the Product supplied by NexMed, in Schering's
opinion not conform with the Specifications, Schering will notify
NexMed in writing within thirty (30) days from the date of delivery of
the Product. Schering will supply NexMed with details of the allegedly
non-conforming Product including samples thereof and will cooperate in
any investigation NexMed should wish to carry out. Even if such
determination is disputed by NexMed, NexMed shall as soon as possible
and not later than thirty (30) days, subject to availability, replace
such non-conforming Products free of charge, provided Schering has paid
for the rejected Product.
8.5.5 Notwithstanding the above, if a dispute arises between NexMed and
Schering concerning the non-conformity of the Product to the
Specifications, and said dispute is not resolved within thirty (30)
days from the receipt by NexMed of the notification mentioned in
Section 8.5.4, the matter shall be submitted to an independent
laboratory chosen in common agreement between the Parties (or,
failing such agreement, by the Chamber of Commerce and Industry of
Frankfurt am Main, Germany) whose decision will be final. The
expenses incurred for said determination shall be paid by the Party
whose position is found erroneous by the said decision and if the
Products are found to be conforming, Schering shall immediately pay
NexMed for all Product that was shipped to Schering.
8.5.6 NexMed represents and warrants to manufacture the Product in the
quality according to the QAA. The Product will conform in all material
respects to the Quality Specifications as set forth in the QAA. Product
found not to be manufactured in accordance with the QAA will not
satisfy the obligations of NexMed as set forth in this Agreement.
14
8.5.7 In the event rejected Bulk Product can not be reworked and must be
destroyed, all destruction shall be performed by NexMed or, if mutually
agreeable, by Schering. The Party, which has caused the defective or
otherwise nonconforming Bulk Product will pay the costs of such rework
and destruction. Following destruction, the applicable Party will send
to the other a certificate of destruction indicating the following:
name of the Bulk Product, batch number, quantity, and name of the
company that destroyed the Bulk Product.
15
8.6 Shortage of Supply
If there is any shortage in the supply of the Product, NexMed shall
deliver the Product to Schering at least at the same level as to
NexMed's other customers or NexMed themselves resulting in a similar
(then percentile) reduction of the Product supply in relation to the
forecasted amounts for Schering and NexMed's other customers.
8.7 Alternative Manufacturing
8.7.1 Should NexMed be unable to supply (i) at least seventy-five percent
(75%) of Schering's Firm Orders for three (3) consecutive calendar
months or (ii) should NexMed fail to supply Schering in six (6)
calendar months within the immediately preceding, consecutive
twenty-four (24) calendar months at least seventy-five percent (75%) of
Schering's Firm Order in accordance with the terms of this Agreement,
NexMed shall inform Schering without delay and discuss with it about
said inability and shall authorize Schering to manufacture or have
manufactured quantities of the Product and shall provide Schering with
all necessary know-how, technology, information and assistance for such
manufacturing.
8.7.2 If Schering assumes the manufacturing of the Product in accordance with
the terms of Section 8.7.1 hereof, Schering shall pay NexMed for each
unit manufactured an amount equal to * less Schering's Cost of
Manufacturing.
8.7.3 NexMed shall organize an alternative supplier for the Product prior to
the first delivery of the Bulk Product to Schering. Schering shall have
the right of first refusal to be the alternative supplier on the same
terms and conditions as a commercially reasonable third party
alternative supplier.
ARTICLE IX
SUPPLY PRICE, PAYMENTS
9.1 Supply Price. NexMed will supply all of Schering's Product
requirements as Bulk Product at the price of * per single
dose unit ("Supply Price"). This Supply Price represents NexMed's
total share in the sales of the Product.
9.2 Samples. NexMed will supply clinical samples at * per single
dose unit and commercial samples at * per single dose unit.
9.3 NexMed shall not supply Third Parties for countries reverted to
NexMed according to Section 7.3 at more favorable supply price
conditions than Schering.
9.4 Invoice; Payments. NexMed shall invoice to Schering upon delivery of
the Product. Schering shall pay to NexMed the invoices within thirty
(30) days from the date such invoices are received by Schering.
9.5 Payments; Interest. Payments due under this Agreement shall be due on
such date as specified in this Agreement and, in the event such date is
not a Business Day, then the next succeeding Business Day, and shall be
made by wire transfer of immediately available funds to a bank account
designated by NexMed, at least ten (10) days before payment is due. Any
failure by a Party to make a payment within ten (10) Business Days
after the date when due shall obligate such Party to pay computed
interest to the receiving Party, the interest period commencing on the
due date and ending on the payment day, to the other Party, at a rate
per annum equal to the one month EURIBOR as quoted on the due date on
REUTERS screen (EURIBOR01). The interest calculation shall be based on
the act/360 computation method. The interest rate shall be adjusted and
interest shall be compounded monthly in arrears. Such interest shall be
due and payable on the tender of the underlying principal payment.
9.6 Taxes. NexMed shall pay any and all taxes levied on account of all
payments it receives under this Agreement. If laws or regulations
require that taxes be withheld, Schering will (i) deduct those taxes
from all remittable payments, (ii) timely pay the taxes to the proper
taxing authority, and (iii) send proof of payment to NexMed within
thirty (30) days of receipt of confirmation of payment from the
relevant taxing authority. Schering agrees to make all lawful and
reasonable efforts to minimize such taxes to NexMed.
16
9.7 Payment Currency. Payments by Schering under this Agreement shall be
paid to NexMed in Euro by wire transfer of immediately available funds
to an account at a commercial bank such bank account being designated
by NexMed at least ten (10) Business Days before payment is due.
ARTICLE X
CONFIDENTIALITY
10.1 Confidentiality; Exceptions. Except to the extent expressly authorized
by this Agreement or otherwise agreed in writing, the Parties agree
that the receiving Party shall keep confidential and shall not publish
or otherwise disclose or use for any purpose other than as provided for
in this Agreement any Information and other information and materials
furnished to it by the other Party pursuant to this Agreement or any
Information developed during the course of the collaboration hereunder,
or any provisions of this Agreement that are the subject of an
effective order of the Securities Exchange Commission granting
confidential treatment pursuant to the Securities Act of 1934 as
amended (collectively "Confidential Information"), except to the extent
that it can be established by the receiving Party that such
Confidential Information:
(a) was already known to the receiving Party, other than under an
obligation of confidentiality, at the time of disclosure by
the other Party; or
(b) was generally available to the public or otherwise part of the
public domain at the time of its disclosure to the receiving
Party; or
(c) became generally available to the public or otherwise part of
the public domain after its disclosure and other than through
any act or omission of the receiving Party in breach of this
Agreement.
(d) was disclosed to the receiving Party, other than under an
obligation of confidentiality, by a Third Party who had no
obligation to the disclosing Party not to disclose such
information to others; or
(e) was independently discovered or developed by the receiving
Party as documented in its corporate records.
10.2 Authorized Disclosure. Each Party may disclose Confidential Information
hereunder to the extent such disclosure is reasonably necessary in
filing or prosecuting patent applications, prosecuting or defending
litigation, filing or updating any Marketing Authorization Application,
complying with applicable governmental laws, rules and regulations or
conducting Development, provided that, if a Party is required by law or
regulation to make any such disclosures of the other Party's
Confidential Information it will, except where impracticable for
necessary disclosures, for example in the event of medical emergency,
give reasonable advance notice to the other Party of such disclosure
requirement and, except to the extent inappropriate in the case of
patent applications, will use its reasonable efforts to secure
confidential treatment of such Confidential Information required to be
disclosed. In addition, and with prior written notice to the other
Party of each Third Party with whom a confidential disclosure agreement
is being entered into, each Party shall be entitled to disclose, under
a binder of confidentiality, Confidential Information to any Third
Party for the purpose of carrying out the purposes of this Agreement.
Nothing in this Article X shall restrict any Party from using for any
purpose any Confidential Information independently developed by it
during the course of the collaboration hereunder, or from using
Confidential Information that is specifically derived from pre-clinical
or clinical trials to carry out Regulatory Approval, marketing, sales
or professional services support functions as is customary in the
pharmaceutical industry. Where materiality of disclosure requires a
press release or other disclosure pertaining to this Agreement by one
Party, the disclosing Party shall give at least three (3) Business
Days' advance notice to the other Party.
17
10.3 Survival. This Article X shall survive the termination or expiration
of this Agreement.
ARTICLE XI
OWNERSHIP OF INTELLECTUAL PROPERTY, PATENT RIGHTS AND USE OF NAME
11.1 Ownership. Each Party shall solely own, and it alone shall have the
right to apply for, Patents within and outside of the Territory for any
inventions made solely by that Party's employees or consultants in the
course of performing work under this Agreement; provided, however, if
Schering is the owner of any inventions relating to the Product,
Schering shall grant NexMed a non-exclusive and royalty-free license to
use the invention during the term of the Agreement. If Schering decides
not to apply for a patent, Schering shall assign these invention to
NexMed, and NexMed shall have the right to apply for Patents relating
to any such inventions subject to the applicable German statute for
employee inventions.
To the extent NexMed has not obtained the Patents necessary for
Schering's license pursuant to Article II 1 (a) ("Necessary Patents")
at the time of first commercialization, NexMed shall continue to use
all commercially reasonable efforts to obtain these outstanding
Patents.
11.2 Third Party Patent Rights. Each Party agrees to bring to the
attention of the other Party any Third Party Patent it discovers, or
has discovered, and which relates to the subject matter of this
Agreement.
11.3 Enforcement Rights.
(a) Notification of Infringement. If either Party learns of any
infringement or threatened infringement by a Third Party of
the NexMed Patents such Party shall promptly notify the other
Party and shall provide such other Party with all available
evidence of such infringement.
(b) Enforcement in the Territory. NexMed shall have the right, but
not the obligation, to institute, prosecute and control at its
own expense any action or proceeding with respect to
infringement of any NexMed Patents covering the manufacture,
use, importation, sale or offer for sale of the Product being
developed or marketed in the Territory, by counsel of its own
choice. Schering shall have the right, at its own expense, to
be represented in any action by counsel of its own choice. If
NexMed fails to bring an action or proceeding or otherwise
take appropriate action to xxxxx such infringement within a
period of one hundred eighty (180) days of notice by Schering
to NexMed requesting action, Schering will have the right to
bring and control any such action or proceeding relating to
NexMed Patents by counsel of its own choice and NexMed will
have the right to be represented in any such action by counsel
of its own choice and at its own expense. If one Party brings
any such action or proceeding, the other Party agrees to be
joined as a party plaintiff if necessary to prosecute the
action or proceeding and to give the first Party commercially
reasonable assistance and authority to file and prosecute the
suit. Any damages or other monetary awards recovered pursuant
to this Section 11.3(b) shall be allocated first to the costs
and expenses of the Party bringing suit, then to the costs and
expenses, if any, of the other Party. In the event that
Schering brings such action, any amounts remaining shall be
distributed as follows: compensatory damages seventy percent
(70%) shall be payable to Schering and the remaining thirty
percent (30%) to NexMed, and punitive and exemplary damages
shall be paid equally to Schering and NexMed. In the event
that NexMed brings such action, seventy percent (70%) of any
amounts remaining shall be payable to NexMed and the remaining
thirty percent (30%) to Schering.
18
(c) Settlement with a Third Party. The Party that controls the
prosecution of a given action shall also have the right to
control settlement of such action, provided however, that if
one Party controls, no settlement shall be entered into
without the written consent of the other Party (which consent
shall not be unreasonably withheld or delayed) if such
settlement would materially and adversely affect the interests
of such other Party.
11.4 Defense and Settlement of Third Party Claims. If a Third Party asserts
that a patent or other intangible right owned by it is infringed by any
Product in the Territory, NexMed will be solely responsible for
defending against any such assertions at its cost and expense (subject
to the provisions of Section 11.3(b)), and if a Third Party asserts
that a trademark owned by it is infringed by any Product in the
Territory, Schering will be solely responsible for defending against
any such assertions at its cost and expense. No settlement may be
entered into without the written consent of the other Party, which
shall not be unreasonably withheld. The costs of any such settlement
(including, without limitation, damages, expense reimbursements,
compliance, future royalties or other amounts) shall be paid by the
Party defending such action. If any Third Party is successful in any
such claim and the non-defending Party is ordered to make any payments
to such Third Party in connection therewith, any such payments shall be
promptly paid by the defending Party.
11.5 Licenses under Third Party Patents.
(a) Determination. Upon mutual agreement, the Parties may seek
to obtain a license or right under one or more Third Party Patents
covering any Product in the Territory in order to avoid infringement.
In the event that Schering determines that it is beneficial for the
Parties to obtain a license or right under one or more Third Party
Patents covering any Product in the Territory and NexMed objects to
such determination within thirty (30) days after such determination is
made, the Parties shall suspend action for a period of one (1) month
(the "Deferral Period") to allow NexMed to present its position to and
discuss its position with Schering. Such discussion shall involve
senior management of each Party.
(b) NexMed may present such facts, findings, conclusions and
other information as it deems necessary to Schering during the Deferral
Period. Upon the earlier of the end of the Deferral Period or NexMed's
presentation of all of its information, Schering shall evaluate such
information and make a final determination, in its reasonable judgment,
as to the desirability of obtaining a license or right under such Third
Party Patents. The decision reached by Schering shall thereafter be
final and binding on the Parties.
(c) Licensing. In the event that the Parties agree to seek to
obtain a license or right under any Third Party Patents or in the event
of final determination by Schering of the desirability to obtain a
license or right under any Third Party Patents, Schering and NexMed
will make reasonable efforts to obtain such license or right.
(d) Royalties. Any royalties and fees to be paid to the Third
Party in consideration of the license or right under the Third Party
Patents with respect to the Product sold by Schering, its Affiliates or
its sublicensees shall be shared equally by the Parties.
11.6 Patent Expenses. All Patent Expenses with respect to NexMed Patents
shall be borne by NexMed.
11.7 Use of Names. Neither Party shall use the name of the other Party in
relation to this transaction in any public announcement, press release
or other public document without the written consent of such other
Party, which consent shall not be unreasonably withheld or delayed;
provided however, that either Party may use the name of the other Party
in any document filed with any Health Regulatory Authority, including
the FDA and the Securities and Exchange Commission, in which case
Schering shall be referred to as "Schering AG, Germany". Each Party
agrees not to use the other Party's name in relation to this
transaction in any press release, public announcement or other public
document without the approval of the other Party, which approval shall
not be unreasonably withheld or delayed.
19
ARTICLE XII
TRADE XXXX RIGHTS AND INFRINGEMENT
12.1 Trademarks.
12.1.1 Schering shall be responsible for the selection, registration,
maintenance and defense of all Schering Trademarks, which are employed
in connection with the marketing and selling of the Product in the
Territory and shall own and control such Schering Trademarks and pay
any costs in connection therewith.
12.1.2 Each Party recognizes the exclusive ownership by the other Party of any
proprietary name, logotype or trademark furnished by such Party
(including Affiliates) for use in connection with the marketing, sale
or distribution of the Product. Neither Party shall, either while this
Agreement is in effect, or at any time thereafter, register, use or
challenge or assist others to challenge the trademarks of the other
Party or attempt to obtain any right in or to any such name, logotype
or trademark or in and to any name, logotype or trademarks confusingly
similar to the Product or any other goods and products, notwithstanding
that such goods or products have a different use or are dissimilar to
the Product.
12.1.3 Schering shall be responsible for the registration, hosting,
maintenance and defense of the Schering Trademarks as domain names.
NexMed shall empower Schering to act on behalf for filing and
maintaining the NexMed-Trademarks and Domain Names during the term of
this Agreement and in connection with the marketing and selling of the
Product in the Territory.
12.2.1 NexMed hereby grants to Schering the right to use the NexMed Trademark
in the Territory for the duration of this Agreement free of charge.
Schering may use the NexMed Trademark or any other Schering Trademark
in connection with the marketing, sale or distribution of the Product.
12.2.2 In the event that Schering decides to use the NexMed Trademark, the
Parties shall discuss the transfer to Schering of all domain names
similar to the NexMed Trademark ("NexMed Domain Names"). If, however,
NexMed is using or plans to use the NexMed Trademark outside the
Territory, the NexMed Domain Names shall not be transferred to
Schering. In that event
(i) Nexmed shall be responsible for the registration, hosting,
maintenance and defense of a switching internet page with one of the
NexMed Domain Names; and
(ii) NexMed shall grant Schering a right to link to such switching
internet page; and
(iii) the Parties will discuss allowing Schering to use a domain name
similar to the NexMed Domain Names (e.g., "NexMed Trademark
Xxxxxx.xxx").
12.2.3 The Parties agree that the ownership and use of the NexMed Trademark
shall be governed by the following provisions:
(a) NexMed shall retain any and all rights, title and interests in
and to the NexMed Trademarks, and no rights therein are
licensed and/or transferred to Schering hereunder, except as
expressly set forth in this Agreement.
(b) NexMed shall, at its costs and expenses, and whenever
necessary for the performance of the terms of this Agreement,
(i) file and undertake in good faith to obtain and then
maintain the NexMed Trademarks' registration in the Territory,
and (ii) inform Schering of the status of such NexMed
Trademarks. A list on the legal status of the Trademarks and
domain names for all countries of the Territory is attached as
of Effective Date as Schedule 5.
12.3 Trademarks infringement:
(a) Upon being aware of any of the following within the Territory,
either Party shall promptly notify the other of, (i) any
infringement, (ii) threatened infringement, (iii) deceptive
use of any Trademarks, (iii) any adverse claim asserted by a
Third Party with respect to the NexMed Trademark or Schering
Trademarks and/or to any labels affixed to any of the Product,
20
and the Parties shall render each other any assistance as may
be requested for the purpose of restraining such infringement
or deceptive use and for taking any other appropriate action.
NexMed and Schering shall consult at to possible courses of
action, but NexMed hereby agrees that Schering's final
determination with respect to such courses of action shall be
final. In the event Schering or any of its Affiliates
institute any proceedings for the infringement or deceptive
use of any NexMed Trademark or Schering Trademark in the
Territory, NexMed hereby agrees that it shall, at Schering's
cost and expense, assist Schering or its Affiliates with any
assistance that may be reasonably requested.
(b) In the event of any Third Party claim that any trademarks
utilized by Schering infringe such Third Party's intellectual
property right in the Territory, Schering and/or its
Affiliates shall, at their own costs and expenses, do what
they consider appropriate and necessary to defend such claim
and NexMed hereby agrees that, upon Schering's request, it
shall provide Schering with full assistance. Schering hereby
agrees to indemnify NexMed including reasonable attorneys fees
in case of any Third Party claiming that any trademarks
utilized by Schering infringe such Third Party's right in the
Territory.
12.4 In the event that this Agreement is terminated in its entirety in
accordance with Article XIV or in the event that Schering reverts a
country upon NexMed's request in accordance with Section 7.3, Schering
shall, upon NexMed's request, transfer any rights it may have in the
NexMed Trademark to NexMed. In addition, Schering shall, at NexMed's
request, transfer any Schering or NexMed Trademark used in connection
with the Product to NexMed, and NexMed shall pay for such transfer a
royalty in the amount of fifty percent (50%) of the total sales of
Product under the Schering Trademark in the Territory during the last
full calendar month preceding the effective date of expiration or
termination. NexMed has the right but not the obligation to pay such
royalties by installments extending up to one year after such transfer.
ARTICLE XIII
REPRESENTATIONS AND WARRANTIES
13.1 Representations and Warranties
(a) Each of the Parties represents and warrants to the other Party as follows:
(i) The Agreement is a legal and valid obligation binding upon
such Party and enforceable in accordance with its terms. The
execution, delivery and performance of the Agreement by such
Party does not conflict with any agreement, instrument or
understanding, oral or written, to which it is a party or by
which it is bound, nor to such Party's knowledge, violate any
law or regulation of any court, governmental body or
administrative or other agency having jurisdiction over it.
(ii) NexMed has not granted, and during the term of this Agreement
neither Party will grant, any right to any Third Party
relating to the NexMed Patents and/or NexMed Information which
would conflict with the rights granted to either Party
hereunder.
(iii) There are no actions, suits, proceedings or unsatisfied
judgments outstanding, pending or threatened against or
affecting either Party, which may impair the ability of this
Party to perform its obligations under this Agreement, and
this Party is not aware of any existing ground on which any
such action, suit or proceeding might be commenced with any
reasonable likelihood of success.
(b) NexMed hereby represents and warrants to Schering that NexMed:
21
(i) To the best of its knowledge, it has provided to Schering all
material information in its possession or control or of which
it is aware as of the Effective Date, concerning efficacy,
side effects, injury, toxicity, or sensitivity, reaction and
incidents or severity thereof, associated with any clinical
use, studies, investigations or tests with the Product (animal
or human), whether or not determined to be attributable to the
Product.
(ii) To the best of its knowledge, NexMed has not employed, or used
a contractor or consultant that employs, any individual or
entity debarred by the FDA (or subject to a similar sanction
of EMEA), or, to the best knowledge of NexMed, any individual
who or entity which is the subject of an FDA debarment
investigation or proceeding (or similar proceeding of EMEA),
in the conduct of the preclinical or clinical studies of the
Product.
(iii) As of the Effective Date, except as it may have previously
disclosed to Schering in writing, NexMed has not received any
notices of infringement or any written communications relating
in any way to a possible infringement with respect to the
Product, and, to its knowledge, it is not aware that the
manufacture, use or sale of the Product infringes any Third
Party patent rights.
(iv) As of the Effective Date, NexMed is not aware of any prior act
or any fact which causes it to conclude that any NexMed Patent
is invalid or unenforceable.
(v) As of the Effective date, NexMed has not received any notice
that any opposition or cancellation proceedings or other legal
disputes have been initiated against the NexMed Trademark in
any country in the Territory where applications for
registration of the NexMed Trademark have been filed and/or
where the NexMed Trademark has been registered.
(vi) To the best of its knowledge, NexMed has obtained all right,
title and interest in and to all rights to the NexMed Patents
and NexMed Information, free and clear of any liens,
encumbrances or rights to repurchase; and
(vii) NexMed has conducted, or has caused its contractors or
consultants to conduct, and will in the future conduct, the
preclinical and clinical studies for the Product, in all
material respects in accordance with applicable laws,
published standards of the FDA and the European Commission,
and regulatory standards applicable to the conduct of studies
in the United States and the EU, including without limitation,
GMPs, GLPs and GCPs.
(viii) During the term hereof, NexMed will not take any action or
enter into any agreements that may affect Schering's rights
under this Agreement.
(c) Schering hereby represents and warrants to NexMed that Schering:
(i) As of the Effective Date, except as it may have previously
disclosed to NexMed in writing, Schering has not received any
notices of infringement or any written communications relating
in any way to a possible infringement with respect to the
Product, and that it is not aware that the manufacture, use or
sale of the Product infringes any Third Party patent rights.
(ii) During the term hereof, Schering will not take any action or
enter into any agreements that may affect NexMed's rights
under this Agreement or affect the NexMed Patents, NexMed
Trademark or NexMed Information.
22
XIV
TERM AND TERMINATION
14.1 Term. This Agreement shall commence as of the Effective Date and,
unless sooner terminated as provided herein, shall continue in effect
on a country-by-country basis until the last Patent protection of the
Product expires or ten (10) years after the First Commercial Sale of
the Product in such country, whichever is longer. Schering will notify
NexMed about the First Commercial Sale of the Product in each country.
This Agreement will automatically extend for periods of one (1) year
unless either Party give written notice to the other Party of its
intention not renew at least one (1) year prior to the expiry date. The
EU is considered to be one country for the purpose of this Section
14.1.
14.2 Termination
(a) In the event that NexMed fails to receive the acceptance of
filing of the Product for indication moderate to severe ED by
the European Health Authorities in the EU before December 31,
2006, Schering has the right to terminate this Agreement and
Schering must exercise this termination right on or before
March 31, 2007.
(b) Schering may terminate this Agreement in case that NexMed
fails to receive the unconditional Regulatory Approval of the
Product for indication moderate to severe ED by the European
Health Authorities or the Reference Member State before
December 31, 2008. Schering must exercise this termination
right on or before March 31, 2009.
(c) In the event that NexMed fails to obtain the Necessary Patents
in a Major Country and because of such failure Schering is
unable to achieve a market share in such country which is
equivalent to Schering's market share in the remainder of the
Territory for two (2) consecutive years after Mutual
Recognition has been obtained, Schering shall have the right
to terminate the contract in its entirety, upon six (6) months
prior written notice to NexMed.
In case of market changes which lead to margins which are
below a level acceptable for Schering the Parties shall meet
and negotiate in good faith in order to find a suitable
solution. In case no solution has been found, Schering is
entitled to terminate the Agreement with six (6) months
notice. All open Firm Orders have to be fulfilled by NexMed
and to be paid by Schering.
(d) Failure of Schering or NexMed to comply with any of their
respective material obligations and conditions contained in
this Agreement shall entitle the other Party to give the Party
in default notice requiring it to cure such default. If such
default is not cured within sixty (60) days after receipt of
such notice, the notifying Party shall be entitled (without
prejudice to any of its other rights conferred on it by this
Agreement) to terminate this Agreement. Notwithstanding the
foregoing, in the event of a non-monetary default, if the
default is not reasonably capable of being cured within the
sixty (60) day cure period by the defaulting Party and such
defaulting Party is making a good faith effort to cure such
default, the notifying Party may not terminate this Agreement,
provided however, that the notifying Party may terminate this
Agreement if such default is not cured within one hundred
eighty (180) days of such original notice of default. The
right of either Party to terminate this Agreement as
hereinabove provided shall not be affected in any way by its
waiver of, or failure to take action with respect to any
previous default.
(e) In the event that one of the Parties hereto shall go into
liquidation, a receiver or a trustee be appointed for the
property or estate of that Party and said receiver or trustee
is not removed within thirty (30) days, or the Party makes an
assignment for the benefit of creditors (collectively, a
"Bankruptcy Event"), and whether any of the aforesaid
Bankruptcy Events be the outcome of the voluntary act of that
Party, or otherwise, the other Party shall be entitled to
terminate this Agreement.
23
(f) In the event that this Agreement expires or is terminated by
Schering in accordance with Section 14.2 (a) or (b) above or
by either Party in its entirety in accordance with Sections
14.2 (c) or (d) hereof, Schering will, with respect to each
country for which the termination applies entirely: (i) not
use the NexMed Information or any other Confidential
Information of NexMed as long as it has to be kept
confidential pursuant to Article X hereof in such country;
(ii) not infringe any of the NexMed Patents in such country;
(iii) make all payments accrued under this Agreement with
respect to such country prior to the effective termination or
expiration date; (vi) transfer all Marketing Authorizations,
regulatory filings and approvals related to the Product in
such country to NexMed, in accordance with the following
provisions: (a) Schering or the relevant Affiliate or
sublicensee of Schering shall perform all necessary activities
to complete the transfer of all Marketing Authorizations,
regulatory filings and/or approvals as promptly as practicable
after the expiration or the termination of this Agreement to
the benefit of NexMed or NexMed's designee; (b) NexMed shall
accept or cause each NexMed designee to accept the transfer of
the corresponding Marketing Authorizations, regulatory filings
and/or approvals and shall cooperate with Schering or
Schering's Affiliate or sublicensees to effect such transfer;
and (c) the costs for the transfer of all Marketing
Authorizations, regulatory filings and/or approvals or for a
new registration shall be borne by NexMed; (vii) the licenses
granted by NexMed to Schering shall terminate; and (viii) sell
to NexMed, at any time within ninety (90) days of such
termination, at NexMed's election, all or any portion of the
inventory of the Product owned by Schering or its Affiliates
which are intended for sale in such country at a price equal
to Schering's or its Affiliate's fully burdened costs for such
inventory. Such election shall be made by NexMed in writing
and within thirty (30) days of such termination or expiration.
If NexMed elects to purchase such Schering inventory, then
Schering shall ship at NexMed's cost and direction such
inventory to NexMed. NexMed shall pay for such inventory in
advance of receipt of such inventory.
(g) Except where expressly provided for otherwise in this
Agreement, termination of this Agreement shall not relieve the
Parties hereto of any liability, including any obligation to
make payments hereunder, which accrued hereunder prior to the
effective date of such termination, nor preclude either Party
from pursuing all rights and remedies it may have hereunder or
at law or in equity with respect to any breach of this
Agreement nor prejudice any Party's right to obtain
performance of any obligation.
(h) In the event that Schering is not actively Commercializing the
Product in any three (3) of the Major Countries, by the
earlier of the dates contemplated by the launch sequence
agreed to by the Parties or three (3) years after Marketing
Authorization for the Product has been granted in the
Reference Member State, then NexMed shall have the right to
terminate this Agreement upon six (6) months prior written
notice to Schering.
(i) In the event that (A) Schering ceases to actively
Commercialize the Product in any European Union country and
(B) the Non-Commercialization Ratio for any year after the
third anniversary of the First Commercial Sale of the Product
is greater than 1.0, NexMed shall have the right to terminate
this Agreement in its entirety upon six (6) months prior
written notice to Schering. For the purpose of assessing
whether this termination right exists, the Parties shall,
beginning the earlier of (i) the third anniversary of the
First Commercial Sale of the Product, and (ii) the year
following the cessation of significant marketing activities in
any Non-Commercialized Country, and continuing for the
remainder of the term of this Agreement within 30 days of the
end of each calendar year, evaluate the Non-Commercialization
Ratio.
14.3 Termination without cause. Schering may terminate this Agreement at any
time. In case that Schering exercises this termination right within 12
months after the Effective Date Schering shall pay Euro 500.000 to
NexMed. In case that Schering exercises this termination right between
12 months after the Effective Date and the first Marketing
Authorization in the EU as defined in Section 6.1, Schering shall pay
Euro 1.000.000 to NexMed. In case that Schering exercises this
termination right after the achievement of the first Marketing
Authorization in the EU as defined in 6.1, Schering may exercise this
termination right with 180 days notice to the end of a calendar year.
24
14.4 Surviving Rights. The rights and obligations set forth in this
Agreement shall extend beyond the termination of the Agreement only to
the extent expressly provided for herein, or to the extent that the
survival of such rights or obligations are necessary to permit their
complete fulfillment or discharge.
25
ARTICLE XV
INDEMNIFICATION
15.1 Indemnification. Schering hereby agrees to save, defend and hold NexMed
and its officers, directors, consultants, agents and employees harmless
from and against any and all Third Party suits, claims, actions,
demands, liabilities, expenses or losses, including reasonable legal
expenses and attorneys' fees (collectively "Losses") resulting from or
arising out of the use, sale or Commercialization of the Product except
to the extent such Losses result from or arise out of breach by NexMed
of this Agreement, including without limitation the inaccuracy of any
representation of NexMed set forth in this Agreement or breach of any
of NexMed's warranties set forth in Article XIII, or resulting from
NexMed's manufacture of the Product not in accordance with the Quality
Specifications or the gross negligence or any negligence in connection
with a material breach of this Agreement or willful misconduct of
NexMed, in which case NexMed hereby agrees to save, defend and hold
Schering and its directors, officers, agents and employees harmless
from any and all such Third Party Losses.
15.2 Each indemnified Party agrees to give the indemnifying Party prompt
written notice of any Loss or discovery of fact upon which such
indemnified Party intends to base a request for indemnification under
Section 15.1. Each Party shall furnish promptly to the other copies of
all papers and official documents received in respect of any Loss. With
respect to any Loss relating solely to the payment of money damages and
which will not result in the indemnified Party becoming subject to
injunctive or other relief or otherwise adversely affecting the
business of the indemnified Party in any manner, and as to which the
indemnifying Party shall have acknowledged in writing the obligation to
indemnify the indemnified Party hereunder, the indemnifying Party shall
have the sole right to defend, settle or otherwise dispose of such
Loss, on such terms as the indemnifying Party, in its sole discretion,
shall deem appropriate. The indemnifying Party shall obtain the written
consent of the indemnified Party, which shall not be unreasonably
withheld or delayed, prior to ceasing to defend, settling or otherwise
disposing of any Loss if as a result thereof the indemnified Party
would become subject to injunctive or other equitable relief, or any
remedy other than the payment of money which is the responsibility of
the indemnifying Party. The indemnifying Party shall not be liable for
any settlement or other disposition of a Loss by the indemnified Party
which is reached without the consent of the indemnifying Party. The
reasonable costs and expenses, including reasonable fees and
disbursements of counsel incurred by any indemnified Party in
connection with any Loss, shall be reimbursed on a quarterly basis by
the indemnifying Party, without prejudice to the indemnifying Party's
right to contest the indemnified Party's right to indemnification and
subject to refund in the event the indemnifying Party is ultimately
held not to be obligated to indemnify the indemnified Party.
15.3 In the event any Party becomes liable to pay any damages to a Third
Party with respect to any matter related to the Product, the Parties
hereby agree that any such damages shall be borne by the Party in whose
sphere of responsibility lays the responsibility for the damage, and,
to that effect, the Parties further agree to define sphere of
responsibilities with respect to the manufacture and quality control as
laid out in Appendix 7 to the QAA of this Agreement. In the event
either Party fails to fulfil its obligations pursuant to this Article,
the other Party shall be entitled to notify it and such failure shall
be deemed a default as more fully described in Section 14.2 (d) of this
Agreement.
15.4 Insurance. NexMed agrees and warrants that, beginning with the First
Commercial Sale and continuing during the term of this Agreement and
for a period of five (5) years thereafter, it shall obtain and maintain
at its own expenses, product liability insurance from a recognized
insurance carrier providing liability coverage in the aggregate, per
occurrence and per year, with coverage limits of not less than fifteen
million Euro ((euro)15,000,000). NexMed will prove this insurance cover
by furnishing Schering with copies of the relevant insurance
documentation.
15.5 This Article XV shall survive the termination or expiration of this
Agreement.
26
ARTICLE XVI
MISCELLANEOUS
16.1 Assignment.
(a) Each Party may assign this Agreement or any of its rights or
obligations under this Agreement to any of its Affiliates;
provided, however, that such assignment shall not relieve the
Party of its responsibilities for performance of its
obligations under this Agreement.
(b) The Parties may not assign this Agreement to any Third Party
without the prior written consent of the other Party, such
consent not to be unreasonably withheld or unduly delayed,
except in connection with a sale of all or substantially all
of the assets to which this Agreement relates.
(c) This Agreement shall be binding upon and inure to the benefit
of the permitted assigns of the Parties. Any purported
assignment not in accordance with this Agreement shall be
void.
16.2 Force Majeure. Neither Party shall lose any rights hereunder or be
liable to the other Party for damages or losses on account of failure
of performance by the defaulting Party if the failure is occasioned by
government action, war, fire, explosion, flood, strike, lockout,
embargo, act of God or any other cause beyond the control of the
defaulting Party,.; provided that the Party claiming force majeure has
extended all reasonable efforts to avoid or remedy any such force
majeure, continues to employ such efforts and promptly notifies the
other Party of such force majeure event.
16.3 Lost Profits. Neither party shall be responsible or liable with respect
to any subject matter of this Agreement to the other Party for any
indirect, incidental, consequential, exemplary or punitive damages
including, but not limited to, loss of profits, even if such Party is
made aware of the possibility of such damages.
16.4 Further Actions. Each Party agrees to execute, acknowledge and deliver
such further instruments and to do all such other acts, as may be
necessary or appropriate in order to carry out the purposes and intent
of this Agreement.
16.5 No Trademark Rights. Except as otherwise provided herein, no right,
express or implied, is granted by this Agreement to use in any manner
the names "Schering" or "NexMed" or any other trade name or trademark
of the other Party or its Affiliates in connection with the performance
of this Agreement.
16.6 Notices. All notices hereunder shall be in writing, effective upon
receipt, and shall be delivered personally, mailed by registered or
certified mail (return receipt requested, postage prepaid), or sent by
express courier service, to the other Party at the following addresses
(or at such other address for a Party as shall be specified by like
notice):
(a) If to Schering:
00000 Xxxxxx, Xxxxxxx
(b) If to NexMed :
000 Xxxxxxxxx Xxxxxxxxx
Xxxxxxxxxxxx, XX 00000, XXX
16.7 Waiver. Except as specifically provided herein, the waiver from time to
time by either of the Parties of any of their rights or their failure
to exercise any right or remedy shall not operate or be construed as a
continuing waiver of same or of any other of such Party's rights or
remedies provided in this Agreement.
16.8 Severability. Each Party hereby agrees that it does not intend, by its
execution hereof, to violate any public policies, statutory or common
laws, rules, regulations, treaties or decisions of any government
agency or executive body thereof of any country or community or
association of countries. Should one or more provisions of this
Agreement be or become invalid, the Parties hereto shall substitute, by
mutual consent, valid provisions for such invalid provisions, which
27
valid provisions in their economic and other effects are sufficiently
similar to the invalid provisions that it can be reasonably assumed
that the Parties would have entered into this Agreement with such valid
provisions. In case such valid provisions cannot be agreed upon, the
invalidity of one or several provisions of this Agreement shall not
affect the validity of this Agreement as a whole or the validity of any
portions hereof, unless the invalid provisions are of such essential
importance to this Agreement that it is to be reasonably assumed that
the Parties would not have entered into this Agreement without the
invalid provision.
16.9 Ambiguities. The Parties acknowledge and agree that: (a) each Party and
its counsel reviewed and negotiated the terms and provisions of this
Agreement and have contributed to its revision; (b) the rule of
construction to the effect that any ambiguities are resolved against
the drafting Party shall not be employed in the interpretation of this
Agreement; and (c) the terms and provisions of this Agreement shall be
construed fairly as to the Parties hereto and not in favor of or
against any Party, regardless of which Party was generally responsible
for the preparation of this Agreement.
16.10 Governing Law and Place of Jurisdiction. This Agreement shall be
governed by and interpreted in accordance with the laws of Germany.
Place of jurisdiction shall be Frankfurt.
16.11 Headings. The section and paragraph headings contained herein are for
the purposes of convenience only and are not intended to define or
limit the contents of said sections or paragraphs.
16.12 Counterparts. This Agreement may be executed by the Parties in one or
more counterparts. Such counterparts may be exchanged by facsimile
(provided that each executed counterpart is transmitted in one complete
transmission). Where there is an exchange of executed counterparts,
each Party shall be bound by this Agreement notwithstanding that
original copies of this Agreement may not be exchanged immediately. The
Parties shall cooperate after execution of this Agreement and exchange
by facsimile to ensure that each Party obtains an original, executed
copy of this Agreement.
16.13 Entire Agreement; Amendments. This Agreement, including all Schedules
attached hereto, all documents and things incorporated herein by
reference and all of the documents delivered concurrently herewith set
forth all the covenants, promises, agreements, warranties,
representations, conditions and understandings between the Parties
hereto and supersede and terminate all prior agreements and
understandings between the Parties. No subsequent alteration,
amendment, change or addition to this Agreement shall be binding upon
the Parties hereto unless reduced to writing and signed by the
respective authorized officers of the Parties.
16.14 Expenses. Except as otherwise specified in this Agreement, all costs
and expenses, including, without limitation, fees and disbursements of
counsel, financial advisers and accountants, incurred in connection
with this Agreement and the transactions contemplated hereby shall be
paid by the Party incurring such costs and expenses.
16.15 Independent Contractors. The status of the Parties under this Agreement
shall be that of independent contractors. Neither Party shall have the
right to enter into any agreements on behalf of the other Party, nor
shall it represent to any person that it has any such right or
authority. Nothing in this Agreement shall be construed as establishing
a partnership or joint venture relationship between the Parties.
28
IN WITNESS WHEREOF, Schering and NexMed have caused this Agreement to
be executed as of the Effective Date by their respective duly authorized
representatives.
Berlin, ................... Robbinsville,...................
Schering Aktiengesellschaft NexMed, Inc.
/s/ /s/ /s/
................ ................. .............................
..................
Xxxxxx Xxxxxx Xx. Xxxxxx Xxxx Xx. X. Xxxxxx Mo
Hong Kong, ..................
NexMed International Limited
Xxxxxx Xxx
/s/
..........................
.............................
29
List of Schedules
Schedule 1 - Countries of Territory
Schedule 2 - Existing Preclinical Development and the Existing Trials
Schedule 3 - Quality Assurance Agreement
Schedule 4 - Development plan
Schedule 5 - List of NexMed's Trademark and Domain Names
Schedule 6 - NexMed Patents
30
Schedule 1 - Countries of Territory
1. European Union
Austria Italy
Belgium Latvia
Czech Republic Lithuania
Cyprus Luxemburg
Denmark Malta
Estonia Netherlands
Finland Poland
France Portugal
Germany Slovakia
Great Britain Slovenia
Greece Spain
Hungary Sweden
Ireland
2. European Union and European Economic Area
European Union
Iceland
Liechtenstein
Norway
Switzerland
3. Eastern Europe and Middle East
Albania Afghanistan
Armenien Bahrain
Azerbaijan Bangladesh
Belarus Egypt
Bosnia-Xxxxxx. India
Bulgaria Iran
Croatia Iraq
Georgia Israel
Kazakhstan Jordan
Kirghizia Kuwait
Macedonia Lebanon
Mongolia Libya
Moldavia Oman
Montenegro Qatar
Romania Pakistan
Russia Saudi Arabia
Serbia South Africa
Tadzhikistan Sri Lanka
Turkey Syria
Turkmenistan United Arab Emirates
Ukraine Yemen
Uzbekistan
4. Region Asia/Pacific
Australia
New Zealand
31
Schedule 2 - Existing Preclinical Development and the Existing Trials
NEXMED (U.S.A.), INC.
ALPROX-TD(R) PRECLINICAL DEVELOPMENT PROGRAM
[Background information: Comprehensive preclinical development
programs have been completed on both the Alprox-TD alprostadil cream and the
NexACT-88 enhancer. Both the HCl salt and the free base forms of DDAIP have been
studied and summarized below as NexACT-88 HCl and NexACT-88 Base, respectively.
NexACT-88 HCl is currently contained in the current formulation of Alprox-TD.]
TOXICITY STUDIES WITH ALPROSTADIL CREAM
Acute Toxicity Studies
Acute Oral Toxicity Study of Alprostadil, 0.4%, w/w, Topical Cream in the Rat
(X. Xxxxxxx Study Number 483/Innapharma Study Number CNNX9702 4602, date:
7-17-1997)
Primary Penile Irritation in the Rat with Alprostadil, 0.4%, w/w, Topical Cream
(X. Xxxxxxx Study Number 494/Innapharma Study Number CNNX9702 4807, date:
7-22-1997)
Primary Skin Irritation in the Rat with Alprostadil, 0.4%, w/w, Topical Cream
(X. Xxxxxxx Study Number 484/Innapharma Study Number CNNX9702 4804, date:
7-17-1997)
Acute Intravaginal Toxicity Study of Alprostadil, 0.4%, w/w, Topical Cream in
Rabbits (X. Xxxxxxx Study Number 486/Innapharma Study Number CNNX9702 4803,
date: 7-22-1997)
Acute Intravaginal Tolerance Study of Alprostadil, 0.4%, w/w, Topical Cream in
Rabbits (X. Xxxxxxx Study Number 493/Innapharma Study Number CNNX9702 4808,
date: 7-22-1997)
Primary Eye Irritation Study in the Rabbit with Alprostadil, 0.4%, w/w, Topical
Cream (X. Xxxxxxx Study Number 488/Innapharma Study Number CNNX9702 4802, date:
7-22-1997)
Repeated Dose Toxicity Studies
Four Day Skin Irritation in the Rat with Alprostadil, 0.4 w/w, Topical Cream (X.
Xxxxxxx Study Number 485/Innapharma Study Number CNNX9702 4806, date: 7-22-1997)
Final Report Enhancer Histopathology Evaluation (KUPM 21-Day Study, date:
5-19-97)
28-Day Penile Toxicity Study in the Male Rabbit (MPI Study Number 818-003, date:
10-12-1999)
28-Day Vaginal Toxicity Study in the Female Rabbit (MPI Study Number 818-004,
date: 10-13-1999)
Topical Application of DDAIP and Prostaglandin to the Canine Penis (KUPM Letter
Report, date: 8-12-1995)
28-Day Topical Penile Toxicity Study in the Dog (MPI Study Number 818-009, date:
10-13-1999)
32
28-Day Vaginal Toxicity Study in the Female Rabbit (MPI Study Number 818-011,
date: 3-14-2001)
28-Day Intrameatal Irritation Study in Male Dogs (MPI Study Number 818-010,
date: 3-2-2001)
28-Day Intrameatal Irritation Study in Male Dogs (MPI Study Number 818-012,
date: 3-2-2001)
Addendum to the Final Report, Toxicokinetic Analysis For The 28-Day Penile
Toxicity Study in the Male Dog, (MPI Study Number 818-009, date: 2-25-2002)
Mutagenicity Studies
Mutagenicity Test with Alprostadil, 0.4% w/w, Topical Cream In the
Salmonella/Mammalian-Microsome Reverse Mutation With a Confirmatory Assay
(Covance Study Number 19025-0-409R/ Innapharma Study Number CNNX9705 5001, date:
2-26-1998)
In Vivo Mouse Micronucleus Assay with Alprox-TD(R) (Covance Study Number
22071-0-455OEC, date: 4-10-2001)
In Vitro Studies
Compatibility of Latex Condoms with Alprox-TD(R) (Alprostadil) Cream (SGS U.S.
Testing Company Inc., Report Number 150496, date: 5-16-2001)
Cytotoxicity Agar Diffusion Test of Alprox-TD(R) Placebo Cream Without DDAIP
HCl, pH 5.5, Lot Number 219I0698 (Consumer Product Testing Company V00-0069-2,
date: 7-26-2000)
Cytotoxicity Agar Diffusion Test of Alprox-TD(R) Cream, Alprostadil 0.4% with 5%
DDAIP HCl, pH 5.5, Lot Number NKF018 (Consumer Product Testing Company
V00-0069-1, date: 7-26-2000)
Assessment of Spermicidal Activity of Alprox-TD(R) Cream (Alprostadil 0.4% w/w
and 5% w/w DDAIP HCl); Alprox-TD(R) Placebo Cream (without DDAIP HCl) and DDAIP
HCl 5% w/w in Phosphate Buffer pH 5.5 In Comparison To a Positive Control (CPTC
Number M00-1655, date: 10-25-2000)
Evaluation of the Permeability of Lubricated and Nonlubricated Latex Condoms
Treated with Alprox-TD(R) (alprostadil) Cream: Permeability of Alprostadil and
Dodecyl-2-N,N-dimethylaminopropionate (DDAIP) (Protocol/Study Number:
NEXM-030508, Technical Report Number: TR-029, Revised July 31, 2003)
TOXICITY STUDIES WITH NEXACT(R)-88 Base
Acute Toxicity Studies
Acute Oral Toxicity of NexACT(R)-88 in Rat (X. Xxxxxxx Study Number
482/Innapharma Study Number CNNX9702 4601, date: 7-17-1997)
33
Acute Oral Toxicity of NexACT(R)-88 in Rat (X. Xxxxxxx Study Number
524/Innapharma Study Number CNNX9703 4601, date: 3-9-1998)
Acute Intravaginal Tolerance Study of NexACT(R)-88 in Rabbits (X. Xxxxxxx Study
Number 508/Innapharma Study Number CNNX9703 4804, date: 2-27-1998)
Percutaneous Toxicity Study in the Rabbit with NexACT(R)-88 (X. Xxxxxxx Study
Number 523/Innapharma Study Number CNNX9703 4602, date: 5-15-1988)
Primary Skin Irritation in the Rabbit with NexACT(R)-88 (X. Xxxxxxx Study Number
504/Innapharma Study Number CNNX9703 4802, date: 2-17-1998)
Dermal Irritation in Rabbits (KUPM Summary, date: 9-2-1994)
Primary Eye Irritation Study in Rabbits with NexACT(R)-88 (X. Xxxxxxx Study
Number 516/Innapharma Study Number CNNX9703 4801, date: 2-17-1998)
Dermal Sensitization Study in Guinea Pigs with NexACT(R)-88 Modified Xxxxxxx
Design (X. Xxxxxxx Study Number 487/Innapharma Study Number CNNX9703 4803, date:
5-15-1998)
Acute Oral Toxicity Limit Test of NexACT(R)-88 Base in The Rat (Celsis Study
Number SA 837201, date: 3-29-2000)
Acute Oral Toxicity Limit Test of NexACT(R)-88 Base in The Mouse (Celsis Study
Number SA 837202, date: 3-29-2000)
Primary Dermal Irritation Test of NexACT(R)-88 Base in The Rabbit (Celsis Study
Number SA 837203, date: 3-9-2000)
A Comparative Acute Oral Toxicity Study of Dodecyl-2-N,N-dimethylaminopropionate
(DDAIP) in CD-1 Mice (MPI Study Number 818-024, date: 6-27-2001)
Repeated Dose Toxicity Studies
Dermal Irritation in Rats (KUPM Summary, date: 7-26-1995)
Effect Upon the Rat of Intraperitoneal Injection of Enhancer (KUPM 111, date:
4-20-1995)
Effect Upon the Rat of Intraperitoneal Injection of Enhancer (KUPM 112, date:
5-11-1995)
28-Day Subcutaneous Toxicity Study in the Rat (MPI Study Number 818-001, date:
10-11-1999)
Dermal Irritation in Rabbits (KUPM Summary, date: 11-26-1994)
28-Day Subcutaneous Toxicity Study in the Rabbit (MPI Study Number 818-002,
date: 10-11-1999)
Dermal Irritation in Guinea Pigs (University of Utah Summary, date: 3-1-1995)
34
Effect of Topical Application of Enhancer Formulation upon Canine Penis (KUPM
Protocol 131 and Summary, date: 5-31-1995)
5-Day Mouse Dose Screening Study to Determine Maximum Tolerated Local and
Systemic Dose of Dodecyl-2-N,N-dimethylaminopropionate (DDAIP) (BioReliance
Study Number AA33KP.1D12.01.BTL, Report Number 18.1D12.01, date: 2-14-2001)
Comparative Toxicity of Five Lots of Dodecyl-2-N,N-dimethyl aminopropionate in
Mice (BioReliance Study Number AA33KP.1D12.02.BTL, Report Number 18.1D12.02,
date: 8-1-2001)
28-Day Repeated Dermal Toxicity Study in Mice: Test Article:
Dodecyl-2-N,N-dimethylaminopropionate (DDAIP) (BioReliance Study Number
AA33KP.2D32.08.BTL, date: 11-15-2001)
28-Day Repeated Dermal Toxicity Study of Dodecyl-2-N,N-dimethylaminopropionate
(DDAIP) in Mice (BioReliance Study Number AA33KP.2D32.10.BTL, date: 1-17-2002)
6-Month Subcutaneous Toxicity Study in the Rat (MPI Study Number 818-015, dated:
2-21-2002)
11-Month Subcutaneous Toxicity Study in the Dogs (MPI Study Number 818-018,
dated: 3-6-2003)
Mutagenicity Studies
Xxxx Test (KUPM Letter, date: 9-21-1995)
Mutagenicity Test with NexACT(R)-88 in the Salmonella/ Mammalian-Microsome
Reverse Mutation Assay with a Confirmatory Assay (Covance Study Number
19026-0-409R/Innapharma Study Number CNNX9703 5001, date: 2-26-1998
Mutagenicity Test on NexACT(R)-88 Measuring Chromosomal Aberrations in Chinese
Hamster Ovary (CHO) Cells (Covance Study Number 19026-0-437OECD; Date:
4-27-1998)
Developmental Preclinical Toxicity Studies with NexACT(R)-88 Base
A Range-Finding Subcutaneous Developmental Toxicity Study in Rabbits (MPI Number
818-017, date: 12-20-2000)
A Range-Finding Embryo-Fetal Developmental Toxicity Study in Rats (MPI Number
818-016, date: 12-20-2000)
A Subcutaneous Developmental Toxicity Study in Rabbits With NexACT(R)-88 (MPI
Study Number 818-020, date: 9-6-2002)
Study of Fertility and Early Embryonic Development to Implantation in Rats with
NexACT(R)-88 (MPI Study Number 818-021, date: 8-6-2001)
A Subcutaneous Developmental Toxicity Study in Rats With NexACT(R)-88 (MPI
Research Study Number 818-019, date: 7-13-2001)
Carcinogenicity Studies with NexACT(R)-88 Base
26-Week Dermal Carcinogenicity Study in Mice (BioReliance Study Number
AA33KP.7D82.04.BTL, Addendum, date: 8-5-2002)
Interim Results: 2-Year Rat Subcutaneous Carcinogenicity Study (MPI Research
Study Number: 818-022, date: 1-6-2003)
Safety Pharmacology Studies with NexACT(R)-88 Base
Dodecyl-2-N,N-dimethylaminopropionate (DDAIP) Cardiovascular and Respiratory
Evaluation in the Anesthetized Dog Following Subcutaneous Administration.
(Huntingdon Life Science Study NXM 001/032342,date: 10-21-2003)
CNS Safety Pharmacology Evaluation of Dodecyl-2-N,N-dimethylaminopropionate
(DDAIP) in the Rat Using the Xxxxx Multidimensional Observational Assessment
(Huntingdon Life Sciences Study 02-6555, date: 5-15-2003)
TOXICITY STUDIES WITH NEXACT(R)-88 HCl
Acute Toxicity Studies
Acute Oral Toxicity Limit Test of NexACT(R)-88 HCl in the Rat (Celsis Study
Number SA 838165, date: 4-4-2000)
Acute Oral Toxicity Limit Test of NexACT(R)-88 HCl in the Mouse (Celsis Study
Number SA 838164, date: 4-13-2000)
Primary Dermal Irritation Test of NexACT(R)-88 HCl in the Rabbit (Celsis Study
Number SA 838166, date: 4-19-2000)
Intravenous Toxicity Study of NexACT(R)-88 HCl in the Mouse (Celsis Study Number
SA 838040, date: 6-22-2000)
Mutagenicity Studies
In Vivo Mouse Micronucleus Assay with Dodecyl-2-N,N-dimethyl aminopropionate
(DDAIP) HCl Salt, Lot Number NXD-M0001-SD-1-7-39 (Covance 21354-0-455OECD, date:
7-28-2000)
35
Salmonella-Escherichia Coli/ Mammalian-Microsome Reverse Mutation Assay with a
Confirmatory Assay With Dodecyl-2-N,N-dimethylaminopropionate Hydrochloride
(DDAIP HCl) (Covance Study Number 21354-0-409OECD, date: 10-12-2000)
L5178 TK +/- Mouse Lymphoma Forward Mutation Assay with a Confirmatory Assay
with Dodecyl-2-N,N-dimethylamino propionate HCl (DDAIP HCl) (Covance Study
Number 22071-0-455OEC, date: 4-10-2001)
In Vitro Studies
Cytotoxicity Agar Diffusion Test of DDAIP HCl 5% w/w in Phosphate Buffer, pH
5.5, Lot Number 3-101-A (Consumer Product Testing Company Number V00-0069-3,
date: 7-26-2000)
Absorption, Distribution, Metabolism and Excretion Studies
Partition Coefficient, Plasma Stability, Protein Binding and Microsomal
Metabolism of Dodecyl-2-N,N-dimethylamino propionate Hydrochloride (DDAIP HCl)
(Absorption Systems Number 00-NEXM.PO1R1, date: 8-24-2000)
In Vitro Metabolism of Dodecyl-2-N,N-dimethylaminopropionate Hydrochloride
(DDAIP HCl) in Liver Microsomes and Skin Homogenates, (Absorption Systems Report
Number 01-NEXM.PO1R2, date: 10-25-2001)
Effect of Esterase Inhibitors on Dodecyl-2-N,N-dimethylamino propionate
Hydrochloride (DDAIP HCl) Metabolism In Vitro Using Liver Microsomes, Skin
Homogenates and Plasma (Absorption Systems Report Number 01-NEXM.PO4R1, Revised,
date:
3-11-2002)
The Determination of DDAIP in Dog Plasma Using a Liquid Chromatography Method
with MS-MS Detection (Draft Report Huntingdon Report Number 01-8729, 01-8797,
date: 2-20-2002)
Pharmacokinetics, Subcutaneous and Topical Absorption, Mass Balance and Tissue
Distribution of Total Radioactivity in Rats Administered a Single Intravenous,
Subcutaneous, or Topical Dose of Dual-Radiolabeled
Dodecyl-2-N,N-Dimethylaminopropionate (DDAIP) (Xxxxxxx Study Number
0830RN19.001, date: 02-25, 2003)
Literature Review and Prediction of Putative Metabolites and Elimination
Pathways of Dodecyl-2-N,N-dimethylamino propionate (DDAIP) (Xxxxxxxx Report
Number NEXMED: 111401, date: 7-30-2002)
Mass Spectrometric Investigation of a Metabolite/Degradant of
Dodecyl-2-N,N-dimethylaminopropionate (DDAIP) in Samples of Dog Plasma (From
Protocol 818-023, HLS Study # 01-8729) and Rat Plasma (Protocol 818-015, HLS
Study #00-8670A), (Huntingdon Life Sciences Report Number HUD 022/014234, date:
8-3-2002)
Pharmacokinetic Study of NexACT(R)-88 in Dogs (MPI Report Number: 818-023, date:
10-31- 2002)
Assessment of Lauric Acid Formation Following Incubation of Dodecanol and DDAIP
in Human Microsomes (Absorption Systems Report 02-NEXM.PO4R4-Report 1, Revision
2, date: 11-14-2003)
36
Human Topical Safety Studies with Alprox-TD(R), NexACT(R)-88 Base and
NexACT(R)-88 HCl
Evaluation of Primary Irritation Potential of
Dodecyl-2-N,N-dimethylaminopropionate (DDAIP) Base in Humans (Single 24-Hour
Application) (HTR Project Number 00-000000-00, date: 10-24-2000)
Evaluation of Primary Irritation Potential of
Dodecyl-2-N,N-dimethylaminopropionate HCl (DDAIP HCl) in Humans (Single 24-Hour
Applications) (HTR Project Number 00-000000-00, date: 10-24-2000)
Evaluation of Primary Irritation Potential of
Dodecyl-2-N,N-dimethylaminopropionate (DDAIP), HCl and Base and Alprostadil,
0.4% w/w Cream with DDAIP HCl and DDAIP Base in Humans (Single 24-Hour
Applications) (HTR Project Number 00-000000-00, date: 10-24-2000)
Evaluation of Primary Irritation Potential of Alprostadil Topical Cream
Formulations After a Single 24-Hour Application in Humans (HTR Project Number
00-000000-00, date: 12-12-2000)
Evaluation of Phototoxicity and Photoallergy of
Dodecyl-2-N,N-dimethylaminopropionate (DDAIP) Base and HCl Salt in Humans (HTR
Project Number 00-000000-00, date: 9-29-2000)
Repeated Insult Patch Test of Dodecyl-2-N,N-dimethyl aminopropionate Base
(DDAIP) and Hydrochloride Salt (DDAIP HCl) in Male and Female Volunteers
(Consumer Product Testing Company Number C00-0649.01-.05, date: 1-9-2001)
Pharmacokinetic Study of Alprox-TD(R) and NexACT(R)-88 Base
An Evaluation of the Pharmacokinetic Profile of Alprox-TD Alprostadil Cream
After Administration of a Single Dose to Patients with Erectile Dysfunction
(Symbiance, Inc. Report MED 2000-003, date: 12-23-2002)
Human Risk Assessment of NexACT(R)-88 Base
Risk Assessment of the Permeation Enhancement Excipient
Dodecyl-2-N,N-dimethyaminopropionate in Alprox-TD(R) (alprostadil) Topical Cream
(Federal Research Consultants, Report Number FRC-NEXM.RPT121902, dated 1-6-2003)
37
Schedule 2
NEXMED (U.S.A.), INC.
ALPROX-TD(R) CLINICAL DEVELOPMENT PROGRAM
Summary of U.S. Clinical Studies Completed on Alprox-TD(R) (alprostadil) Cream
--------------------- ----------- ------------------------------ --------- -------------------------------------
Protocol Primary Treatment Groups N Status and Results
End Points (mg PGE1) / Dosage/
patients/subjects
--------------------- ----------- ------------------------------ --------- -------------------------------------
Phase 1 Studies
----------------------------------------------------------------------------------------------------------------
NM-AP-001 Safety 400 mcg, 800 mcg, 1600 mcg/ 60 COMPLETED
single dose/ male and female ---------
subjects Submitted in original IND.
--------------------- ----------- ------------------------------ --------- -------------------------------------
MED 2000-003 Safety 0, 100 mcg, 200 mcg, 300mcg/ 20 COMPLETED
single dose/ male patients ----------
Study
report submitted S/N 117.
--------------------- ----------- ------------------------------ --------- -------------------------------------
NEXSCIN 2001-001 Safety 100 mg 99mTc sulfur colloid 6 COMPLETED
cream, 100 mg 99mTc-HMPAO ---------
cream/2 doses/ male subjects Study report in-progress.
--------------------- ----------- ------------------------------ --------- -------------------------------------
Phase 2 Studies
----------------------------------------------------------------------------------------------------------------
MED 99-001 Efficacy 0, 500 mcg, 1000 mcg, 1500 29 COMPLETED
and mcg/ male patients ----------
Safety
--------------------- ----------- ------------------------------ --------- -------------------------------------
MED 99-002A Efficacy 0, 50 mcg, 100 mcg, or 161 COMPLETED
and 200mcg/11doses/ male patients -----------
Safety Integrated report (with 2000-002A)
submitted S/N 101.
--------------------- ----------- ------------------------------ --------- -------------------------------------
MED 2000-002A Efficacy 0, 100 mcg, 200 mcg, 300 142 COMPLETED
and mcg/ 11 doses/ male patients -------------
Safety Integrated report (with 99-002A)
submitted S/N 101.
--------------------- ----------- ------------------------------ --------- -------------------------------------
MED 2000-007 Efficacy 0, 100 mcg, 200 mcg, 300 24 COMPLETED
and mcg- four way cross-over/ -------------
Safety male patients Study report in-progress.
--------------------- ----------- ------------------------------ --------- -------------------------------------
Phase 3 Studies
----------------------------------------------------------------------------------------------------------------
MED 2000-004 Efficacy 0, 100 mcg, 200 mcg., 300 740 COMPLETED
and Safety mcg/ 25 doses/ male patients ------------
Study report in-progress.
--------------------- ----------- ------------------------------ --------- -------------------------------------
MED 2000-005 Efficacy 0, 100 mcg, 200 mcg, 300 740 COMPLETED
and Safety mcg/ 25 doses/ male patients -------------
Study report in-progress.
--------------------- ----------- ------------------------------ --------- -------------------------------------
MED 2000-006 Safety Open label 100 mcg, 200 mcg, 1000 INCOMPLETE
300 mcg/ 97 doses/ male -------------
patients
--------------------- ----------- ------------------------------ --------- -------------------------------------
38
Schedule 2
NEXMED (USA), INC.
ALPROSTADIL CREAM OVERSEAS CLINICAL DEVELOPMENT PROGRAM
Summary of Overseas Clinical Studies Completed on Alprostadil Cream
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
Protocol Primary Treatment Groups (mcg N Status and
End PGE1)/Dosage/ Results
Points Patients/Subjects
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-28-OL Safety 300 mcg/single 79 COMPLETED
(Clinical Study to Investigate the Safety and Efficacy and dose/male patients -----------
of Alprostadil Cream in an Open Label Trial) Efficacy Submitted in
China NDA
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-28-DB Safety COMPLETED
(Clinical Study to Investigate the Safety and Efficacy and 300 mcg/single 64 ---------
of Alprostadil Cream in Double-blind Trial) Efficacy dose/male patients Submitted in
China NDA
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-36 Safety COMPLETED
(Clinical Study to Investigate the Safety and Efficacy and 300 mcg/10 doses/male 56 ------------
of Alprostadil Cream in a Multiple Use Open Label Efficacy patients Submitted in
Trial) China NDA
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-38
(A Multi-center, Randomized, Double-blind, Placebo COMPLETED
Controlled Clinical Study to Assess the At-home, Efficacy ------------
Efficacy and Safety of Alprostadil Cream for the and 300 mcg/10 doses/male 157 Submitted in
Treatment of Erectile Dysfunction) Safety patients China NDA
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-38A COMPLETED
(An Open-label Clinical Study to Assess the At-home, -----------
Efficacy and Safety of Alprostadil Cream for the 300 mcg/16 doses/male Submitted in
treatment of Erectile Dysfunction) Efficacy patients 40 China NDA
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-HK COMPLETED
(An Open-label Study of the Efficacy and Safety of Efficacy 300 mcg/15 doses/male --------------
Alprostadil Cream in Male Erectile Dysfunction and patients 40 Submitted in
Patients) Safety Hong Kong NDA
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
300 mcg with various COMPLETED
NM-AP-39B-SALT Safety NEXACT-88 60 ----------
(Clinical Safety Study of Alprostadil Cream with concentrations/Single Study report
Various NEXACT-88 Concentration) dose/Male patients in file
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
300 mcg with various
NM-AP-40A Efficacy NEXACT-88 COMPLETED
(Clinical Double-blind Efficacy and Safety Study of and concentrations/Single 91 ----------
Alprostadil Cream in Mild to Moderate ED Patients by Safety dose/Male patients Study report
Using XXXX) in file
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-40C
(A Randomized, Double-Blind, Placebo-Control, Parallel 300 mcg with various COMPLETED
Design Study to Assess Clinical Efficacy and Safety of Efficacy NEXACT-88 105 -------------
alprostadil Cream with Various NEXACT-88 and concentrations/8 Study report
Concentrations) Safety doses/Male patients in file
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-42A 100 mcg, 200 mcg, 300
(Comparison Study of Clinical Objective Criteria of Efficacy mcg and MUSE 500 mcg, COMPLETED
Intrameatal Administration of Alprostadil Cream and and 1000 mcg/ Single 97 -----------
Intrameatal or Intraurethral Administration of MUSE Safety dose/Male patients Study report
Suppository with AVS in Mild to Moderate ED Patients in file
Using XXXX)
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-42C 100 mcg, 200 mcg, 300 COMPLETED
(Comparison of Clinical Objective Criteria of Efficacy mcg and MUSE 500 mcg, -----------
Alprostadil Cream and MUSE in Mild to Moderate ED and 1000 mcg/ Single 70 Study report
Patients Using Doppler (Duplex Ultrasound) Safety dose/Male patients in file
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
NM-AP-40F 300 mcg with various 280 COMPLETED
(A Randomized, Placebo Controlled, Double-blind, Efficacy NEXACT-88 ------------
Parallel Design Efficacy and Safety Study of and concentrations/8 Study report
Alprostadil Cream with Various NEXACT-88) Safety doses/Male patients in file
-------------------------------------------------------- ---------- ------------------------- ----- ----------------
39
Schedule 3 - Quality Assurance Agreement
Preamble
This Quality Assurance Agreement (hereinafter "QAA") defines the conditions to
be fulfilled by NexMed and Schering in order to ensure that all manufacturing
operations subject to an authorization for marketing are carried out in
accordance with the information given in the Marketing Authorization Application
as accepted by the competent authorities.
The QAA is added to the Licence, Supply and Distribution Agreement between the
parties. In case of ambiguities between this QAA and the Licence, Supply and
Distribution Agreement, the latter shall prevail.
ss. 1 Definitions
"Final Release" shall mean release of Finished Product(s) to the market
"Finished Product" shall mean the Bulk Product in its final packaged
and labeled form
"Manufacturing Documentation" consists of the description of
manufacturing of Bulk Product(s) including the in-process controls and
processing instructions including the xxxx of materials
"Packaging Instructions" describe the procedure of packaging and
include the xxxx of materials for the packaging of the Bulk Product(s);
"Testing Standards" shall mean the written description of the sum of
testing methods
ss. 2 Subject-matter of the QAA
The subject-matter of this QAA is to ensure that the manufacturing
operations during the manufacture of the Bulk Product / Finished
Product are carried out in accordance with the recognized
pharmaceutical regulations and other regulations as well as
requirements of the authorities, the requirements of the EC Directive
2003/94/EC effective as of Nov. 2003, the requirements of the GMP
guidelines, the EC GMP Guide and the GMP requirements of the US Food
and Drug Administration (FDA) each in its current version in so far as
these affect quality of the Bulk Product(s) / Finished Product.
This QAA governs the rights, duties and responsibilities of NexMed and
Schering regarding the manufacture of Bulk Product / Finished Product.
The appendices mentioned in this QAA, and all documents to which
reference is made in the appendices shall become an integral part of
this QAA.
ss. 3 Quality Assurance System
NexMed will ensure to maintain an effective pharmaceutical quality
assurance system according to the requirements of the EC Directive
2003/94/EC at every site at which manufacture (or any part thereof) of
Bulk Product shall occur, involving the active participation of the
management and personnel of the different services involved.
NexMed will ensure to obtain and maintain a manufacturing authorisation
and any other approvals for the purposes of manufacturing the Bulk
Product in relation to each and every site at which manufacture (or any
part thereof) of Bulk Product shall occur, to provide Schering with a
copy of such manufacturing authorisation(s) and to provide Schering
with written notice of any proposed change to such manufacturing
authorisation(s), including all necessary regulatory documentation, in
order that Schering may make any relevant variations to the Regulatory
Approval, if necessary.
NexMed declares to be in compliance with the applicable TSE
requirements as outlined in EMEA/410/01 revised 1 May 2001 and any
subsequently revised versions as well as guides from other important
countries. Also an assessment of any delivered Product regarding
residual solvents as outlined in ICH/3QC (CPMP/ICH/283/95) and
belonging regulatory requirements is performed.
40
ss. 4 Documents provided for the manufacture of the Bulk Product
NexMed will provide Schering with all neccesary documents required for
Regulatory Approval of the Product in the Territory as defined in the
Licence, Supply and Distribution Agreement. NexMed will ensure that the
Bulk Product(s) will be manufactured in accordance with the Marketing
Authorization Application. NexMed will strictly adhere to this
documentation during manufacture and will only deviate from it after
prior written approval given by Schering. Schering and NexMed will
ensure that the documentation always corresponds to the approval
granted for the Bulk Product.
The following documents are a constituent part for the manufacture of
the Bulk Product:
Quality Specification(s) and Testing Standard(s) for the Bulk Product
as laid out in Appendix 1.
Manufacturing Description for the Bulk Product as laid out in Appendix
2.
Quality Specification(s) and Testing Standard(s) for starting and
packaging materials as laid out in Appendix 3.
Packaging and batch labeling instructions as laid out in Appendix 4
Other instructions and information (inc. warning information, details
of storage, shipment instructions, SOPs etc.) as laid out in
Appendix 5.
ss. 5 Introduction of new procedures / Bulk Product(s)
In the case that the Bulk Product is to be made for the first time at
one site, the site which will manufacture the Bulk Product will conduct
process validation by using the first three consecutive batches of the
Bulk Product manufactured according to this QAA.
Validation protocols and reports to be compiled by NexMed will be
stored by NexMed at least for one year after the expiration date of the
batches covered in such protocols and reports and will be handed over
to Schering upon request. NexMed will be exclusively responsible for
the manufacture of the three validation batches.
In the case of new test procedures of the Testing Standards or a
transfer of validated test procedures a (lab-to-lab) validation for
analytical methods will be conducted, involving that/those function(s)
or department(s) of NexMed and/or Schering that are responsible for
quality testing.
NexMed and/or Schering must confirm the successful completion of the
(lab-to-Iab) validation in writing. Without this confirmation the use
of the testing methods for quality testing and the release of Bulk
Product(s) is not authorized.
In the case of unforeseen difficulties arising during the manufacture
of validation batches or during the conduct of lab-to-Iab validation,
the parties to the QAA will discuss the difficulties in good faith to
find a mutually agreeable solution.
ss. 6 Manufacture of Bulk Product / Finished Product(s)
Those employees of the parties named as responsible persons for
manufacture, quality control and release as well as employees named as
contact partners in the logistics function are specified in Appendix 6.
Schering must be informed immediately in writing of any changes in the
fields of responsibility of NexMed's responsible persons and/or contact
partner, should these occur.
41
Responsibilities of each party regarding the manufacture and quality
control are defined in Appendix 7 to this QAA.
6.1. Starting and packaging materials
The supplier of starting and packaging materials must be qualified in a
way to ensure that only properly suitable suppliers are considered.
NexMed has to ensure to test the quality of starting and packaging
materials as per Testing Standards / Quality Specifications including
in-process controls before releasing them for further manufacture.
Note: Schering shall be responsible for the final packaging material
6.2. Quality control and sampling
During manufacture of the Bulk Product NexMed will ensure to perform
the tests according to the Testing Standards and Quality Specifications
and will draw samples for testing and reserve samples. Reserve samples
consists of at least twice the quantity necessary to perfom all the
requiered tests.
The reserve samples of starting and packaging materials will be stored
until at least one year after the expiration date of the last batch of
the Bulk Product produced of them. The samples of every batch of a Bulk
Product shall be kept for one year after the expiration date of the
respective batch. The reserve samples will be transferred to Schering
on request. NexMed may draw additional reserve samples for his own use.
All these samples shall be maintained at the disposal of the competent
authorities.
6.3. Batch documentation
NexMed will document all the procedural steps stipulated in the
Manufacturing Documentation as well as all in-process controls in
batch-specific records as customarily kept by NexMed and will provide
Schering with a complete copy of the batch record of the first 3
(three) batches. The records need to be accompanied by a certificate
from NexMed stating that the Bulk Product was manufactured as per
Manufacturing Documentation, that the quality was tested according to
the Testing Standards and Quality Specifications (giving reference to
the number and edition of the relevant documents), as well as that the
results meet the contractually agreed quality (certificate of
compliance). The records must be accompanied by a certificate of
analysis and a deviation report, if applicable.
Any additional batch will be accompanied only by batch record in a
short form mutually agreed between the parties (unless Schering
requires a complete batch documentation), a certificate of compliance,
a certificate of analysis and a deviation report, if applicable.
NexMed will retain the complete batch documentation for 10 (ten) years
according to Bulk Product for the market and 30 (thirty) years
according to Bulk Product for clinical studies.
NexMed will present copies of the original manufacturing and testing
documentation to Schering and/or the relevant authorities upon request.
6.4. Batch labeling
The batches will be labeled in accordance with the packaging and batch
labeling instructions as laid out in Appendix 4.
6.5. Manufacturing problems and deviations
NexMed will without any undue delay communicate to Schering (its
responsible persons in the quality control and named contact partner in
the logistics function) details in writing of problems and deviations
within the manufacturing process, especially deviations from the
specifications in the in-process control results and in the testing
results. This duty to provide information will not limit NexMeds
contractual obligations.
42
6.6. Final release of Finished Product
The Final Release of the Finished Product in the Territory is conducted
by Schering in accordance with applicable laws.
6.7 Deficient Product(s)
A Bulk Product is deficient, if it does not comply with the quality as
described in this QAA, for example but not limited to, the acceptance
criteria of the in-process-controls and/or the Quality Specifications
and/or the Bulk Product is not fit for its purpose as intended by this
QAA.
If an Intermediate product or a Bulk Product can not be released both
parties will decide in good faith whether a rework, reprocessing or
improvement is possible and necessary.
Should the parties decide that the Intermediate product/ Bulk
Product(s) is to be destroyed, NexMed will ensure the correct disposal
of the Intermediate product/ Bulk Product(s). Upon Schering's request
NexMed will provide a proof of correct disposal according to the
applicable laws and regulations.
If the parties can not agree whether a Bulk Product is deficient,
either party may request that an independent laboratory, determined by
mutual consent of the parties, be consulted and asked to perform the
necessary investigations. The parties will accept the results of such
investigation as binding upon them.
Representations, warranties and reimbursements are dealt with in the
Licence, Supply and Distribution Agreement.
6.9 Stability Studies
NexMed will conduct all necessary stability studies on the Bulk Product
at its own cost and expense in accordance to apllicable laws. The raw
data, protocols and reports will be handed over to Schering upon
request.
ss. 7 Change Management
NexMed agrees not to use any subcontractor, or change Bulk Product(s)
composition and characteristics or not to make any other change in
manufacture, which might have an influence on the quality of Bulk
Products or regulatory aspects in the Territory (for example but not
limited to change of the manufacturing site, of the process, of process
parameters, of in process controls, of Quality Specifications, of
Testing Standards) without the prior written approval by Schering.
Each planned change must be submitted to the Schering responsible
persons in quality management for prior written approval, before being
put into effect by NexMed.
Schering agrees that any changes in the manufacture of the Product
affecting the Marketing Authorization must be previously authorized in
writing by NexMed within thirty days (30) from receipt hereof, even if
imposed by the local Health Regulatory Authority.
43
ss. 8 Complaints from the market
Scheirng will forward Bulk Product complaints about the quality of the
Bulk Product after detection. NexMed shall review without undue delay
the respective batch documentation, carry out tests to clarify the
cause of such a complaint, its alleged technical defect and present
Schering with a response summarizing the results of such investigation.
The final response has to be sent to Schering within twenty-one (21)
calendar days of receipt of the Bulk Product complaint of risk class
III. In case of complaints pertaining to risk class I or II preliminary
investigation statements must be available within three (3) working
days of receipt, a final statement must be written without any undue
delay, within thirty (30) calendar days at the latest. (Risk classes
according to EC Guideline 3351). The final response must also include
details on the confirmed or assumed causes of technical defect(s).
NexMed shall be responsible for the appropriate measures to prevent the
re-occurrence of any such defects and report such measures in the final
response.
If for any reasons items remain outstanding, Schering requests a
written, periodic progress update forwarded by a pre-designated company
representative of NexMed.
ss. 9 Recall
NexMed and Schering shall notify each other within twenty-four (24)
hours if any batch of Product is, or is likely to be, subject to
actions such as recalls by a Regulatory Authority. Schering shall be
responsible for notifying the proper authorities in the Territory
according to the Licence, Supply and Distribution Agreement of
information that make affect the marketability, safety, and
effectiveness of the product. Schering and NexMed shall consult with
each other regarding notification of product failure but Schering shall
make final decision regarding withdrawals or recall from the market.
ss. 10 Inspections and Quality Audits
Schering is entitled to conduct inspections and audits of the
facilities in which starting materials, packaging materials and Bulk
Product are being (or are due to be) manufactured at normal business
hours upon prior announcement.
NexMed will permit audits and/or inspections by the relevant national
or international authorities or official institutions to take place.
ss. 11 Annual Product Review
The total number of batches produced and/or tested during the past
calendar year will be evaluated and summarized in a written report to
Schering concerning the main production and quality characteristics
such as in-process control results, deviations, changes in production
and testing, out of specification results, results of release and
stability testing as well as concerning reserve samples, complaints and
recalls. If necessary, corrective measures have to be presented in a
conclusion.
44
================================================================================
Berlin, ............ Robbinsville,............
================================================================================
Schering Aktiengesellschaft NexMed, Inc.
================================================================================
45
Xx. Xxxxxx Xxxxx Xx. Xxxxxx Xxxx Xx. X. Xxxxxx Mo
Schedule 4 - Development plan
Final clinical development plan will be determined after meetings are held with
European Regulatory Groups.
46
Schedule 5 - List of NexMed Trademarks and Domain Names
1. Alprox-TD Trademark names
Alprox-TD Trademark registered in Class 5 (pharmaceutical preparations for
the treatment of sexual dysfunction):
Community Trademark Reg. No: 585,711, registered on February 1, 0000
Xxxxxxxxx No: 876155, registered on May 9, 2003
New Zealand No: 637729, registered on August 7, 2003 with effect from May 14,
2001
2. Alprox-TD Domain Names
Registered:
Xxxxxx-XX.xxx
XxxxxxXX.xxx
Xxxxxx-XX.xxx
XxxxxxXX.xxx
Domain Names Not Available:
XxxxxxXX.xxx
XxxxxxXX.xxxx
Xxxxxx-XX.xxx
Xxxxxx-XX.xxxx
47
Schedule 6 - NexMed Patents
=================== ================== ============== ========== =============
DOCKET NO. COUNTRY SERIAL/ FILED PATENT/ PUB.
========== ======= ======= ===== =============
APP. NO. NO.
------------------- ------------------ -------------- ---------- -------------
301888.3001-100 PCT PCT/US99/ 05/13/99 PUB # WO
=============== === ========= ======== =========
(NMD-102-CIP) 10596 00/69469
------------------- ------------------ -------------- ---------- -------------
301888.3001-101 AUSTRALIA 39891/99 05/13/99 757086
=============== ========= ======== ======== ======
------------------- ------------------ -------------- ---------- -------------
301888.3001-105 EPC 99 923 024.6 05/13/99
=============== === ============ ========
------------------- ------------------ -------------- ---------- -------------
301888.3001-106 HUNGARY P0201145 05/13/99
=============== ======= ======== ========
------------------- ------------------ -------------- ---------- -------------
000000.0000-000 XXXXXX 146470 05/13/99
=============== ====== ====== ========
------------------- ------------------ -------------- ---------- -------------
000000.0000-000 XXXXXX 2002/00146 05/13/99 *TR 2002
=============== ====== ========== ======== =========
00146B
======
------------------- ------------------ -------------- ---------- -------------
301888.3002-101 PCT PCT/US01/ 01/10/01 PUB # WO
=============== === ========= ======== =========
(NMD-118) 00852 01/51053A1
==========
------------------- ------------------ -------------- ---------- -------------
301888.3002-104 AUSTRALIA 29349/01 01/10/01 760576
=============== ========= ======== ======== ======
------------------- ------------------ -------------- ---------- -------------
301888.3002-108 EPC 01 942 300.3 01/10/01 PUB #
=============== === ============ ======== ======
1 255 552
=========
------------------- ------------------ -------------- ---------- -------------
= ============= ================ ========================== ==============
GRANTED INVENTORS TITLE STATUS
======= ========= ===== ======
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Topical Composition for
========= ========================
X. Xxxxxxxxxxx Prostaglandin E1 Delivery
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
10/12/02 X. Xxxxxx Topical Composition for Granted
======== ========= ======================== =======
X. Xxxxxxxxxxx Prostaglandin E1 Delivery Annuity due
X. Xxxxxxxxxxx 5/24/04
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Topical Composition for Print &
========= ======================== =======
X. Xxxxxxxxxxx Prostaglandin E1 Delivery Grant fees
X. Xxxxxxxxxxx due 4/9/04
Annuity due
5/13/04
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Topical Composition for Pending
========= ======================== =======
X. Xxxxxxxxxxx Prostaglandin E1 Delivery Annuity due
X. Xxxxxxxxxxx 5/13/04
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Topical Composition for Pending
========= ======================== =======
X. Xxxxxxxxxxx Prostaglandin E1 Delivery
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
09/23/02 X. Xxxxxx Topical Composition for Granted
======== ========= ======================== =======
X. Xxxxxxxxxxx Prostaglandin E1 Delivery Annuity due
X. Xxxxxxxxxxx ========================= 5/13/04
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin National
========= ============== =========
X. Xxxxxxxxxxx Compositions and Methods Phase; see
X. Xxxxxxxxxxx ========================= ==========
of Treatment for Male below
Erectile Dysfunction
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Accepted
========= ============== ========
X. Xxxxxxxxxxx Compositions and Methods
X. Xxxxxxxxxxx of Treatment for Male
Erectile Dysfunction
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Pending
========= ============== =======
X. Xxxxxxxxxxx Compositions and Methods
============== of Treatment for Male
X. Xxxxxxxxxxx Erectile Dysfunction
====================
- ------------- ---------------- -------------------------- --------------
48
=================== ================== ============== ========== =============
DOCKET NO. COUNTRY SERIAL/ FILED PATENT/ PUB.
========== ======= ======= ===== =============
APP. NO. NO.
------------------- ------------------ -------------- ---------- -------------
301888.3002-109 HUNGARY P0204159 01/10/01
=============== ======= ======== ========
------------------- ------------------ -------------- ---------- -------------
000000.0000-000 XXXXXX 150306 01/10/01
=============== ====== ====== ========
------------------- ------------------ -------------- ---------- -------------
301888.3002-115 SOUTH AFRICA 2002/5433 01/10/01
=============== ============ ========= ========
------------------- ------------------ -------------- ---------- -------------
000000.0000-000 XXXXXX 2002/01769 01/10/01
=============== ====== ========== ========
------------------- ------------------ -------------- ---------- -------------
301888.3002-118 PCT PCT/US02/ 09/06/02 PUB # WO
=============== === ========= ======== =========
28507 03/022310
===== =========
------------------- ------------------ -------------- ---------- -------------
301888.3002-121 PCT PCT/US03/27885 09/05/03
=============== === ============== ========
------------------- ------------------ -------------- ---------- -------------
301888.3002-124 EUROPE 02757647.9
=============== ====== ==========
------------------- ------------------ -------------- ---------- -------------
301888.3002-128 AUSTRALIA 2002323650 2/10/04
=============== ========= ========== =======
------------------- ------------------ -------------- ---------- -------------
= ============= ================ ========================== ==============
GRANTED INVENTORS TITLE STATUS
======= ========= ===== ======
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Pending
========= ============== =======
Compositions and Methods
of Treatment for Male
X. Xxxxxxxxxxx Erectile Dysfunction
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Pending
========= ============== =======
Compositions and Methods
of Treatment for Male
X. Xxxxxxxxxxx Erectile Dysfunction
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Pending
========= ============== =======
Compositions and Methods
of Treatment for Male
X. Xxxxxxxxxxx Erectile Dysfunction
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Pending
========= ============== =======
Compositions and Methods
of Treatment for Male
X. Xxxxxxxxxxx Erectile Dysfunction
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Pending:
========= ============== ========
X. Xxxxxxxxxxx Compositions and Methods Entered
============== ======================== =======
X. Xxxxxxxxxxx of Treatment for Male National
Erectile Dysfunction Reg. Phase
====================
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Methods of Treatment of Pending:
========= ======================== ========
X. Xxxxxxxxxxx Male Erectile Dysfunction Still
waiting for
X.Xxxxxxxxxxx
POA from Drs. B
Demand due
4/6/04
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin National
========= ============== ========
Compositions And Methods Stage filing
Of Treatment For Male 2/10/04.
X. Xxxxxxxxxxx Erectile Dysfunction
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Appn. Mailed
========= ============== ============
Compositions And Methods 2/10/04
Of Treatment For Male
X. Xxxxxxxxxxx Erectile Dysfunction
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
49
=================== ================== ============== ========== =============
DOCKET NO. COUNTRY SERIAL/ FILED PATENT/ PUB.
========== ======= ======= ===== =============
APP. NO. NO.
------------------- ------------------ -------------- ---------- -------------
301888.3002-129 SOUTH AFRICA 2/10/04
=============== ============ =======
------------------- ------------------ -------------- ---------- -------------
301888.3002-134 ISRAEL 2/10/04
=============== ====== =======
------------------- ------------------ -------------- ---------- -------------
301888.3006-102 PCT PCT/US03/04560 02/14/03
=============== === ============== ========
(NMD-120)
------------------- ------------------ -------------- ---------- -------------
301888.3014-102 PCT
=============== ===
------------------- ------------------ -------------- ---------- -------------
NMD-100 Europe (EPO) 94930744.1 10/07/94
======= ============ ========== ========
------------------- ------------------ -------------- ---------- -------------
NMD-100 Russian 96113047 10/07/94 2165265
======= ======== ======== ======== =======
Federation
==========
------------------- ------------------ -------------- ---------- -------------
NMD-102 Europe (EPO) 98957603.8 11/05/98
======= ============ ========== ========
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxx 000000 11/05/98
======= ====== ====== ========
------------------- ------------------ -------------- ---------- -------------
NMD-102 Turkey 2000/02158 11/05/98
======= ====== ========== ========
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxxxxx 50232/00 05/18/00
======= ========= ======== ========
------------------- ------------------ -------------- ---------- -------------
NMD-107 Europe 00932524.2 05/18/00 (1097126)
======= ====== ========== ======== =========
------------------- ------------------ -------------- ---------- -------------
NMD-107 Europe (Div. 1)
======= ===============
------------------- ------------------ -------------- ---------- -------------
= ============= ================ ========================== ==============
GRANTED INVENTORS TITLE STATUS
======= ========= ===== ======
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Appn. Mailed
========= ============== ============
Compositions And Methods 2/10/04
Of Treatment For Male
X. Xxxxxxxxxxx Erectile Dysfunction
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Prostaglandin Appn. Mailed
========= ============== ============
Compositions And Methods 2/11/04
Of Treatment For Male
X. Xxxxxxxxxxx Erectile Dysfunction
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxx Treatment of Erectile Pending
======== ====================== =======
X. Xxxxxxxxxxx Dysfunction
X. Xxxxxxxxxxx X.Xxxxxx
CH.II
DOR'S
due
8/15/04.
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Treatment of Erectile PCT Filing
========= ====================== ==========
Dysfunction due 6/27/04
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Absorption Enhancers for Pending
============== ========================= =======
Topical Pharmaceutical
Formulations
X. Xxxxxxxxxxx
X. Xxxxxxx
- ------------- ---------------- -------------------------- --------------
04/20/01 X. Xxxxxxxxxxx Absorption Enhancers for Granted
======== ============== ========================= =======
Topical Pharmaceutical
======================
Formulations
X. Xxxxxxxxxxx
X. Xxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions for Pending
============== ========================= =======
Prostaglandin E1 Delivery
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions for Pending
============== ========================= =======
Prostaglandin E1 Delivery
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions for Pending
============== ========================= =======
Prostaglandin E1 Delivery
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Crystalline Salts of Pending
============== ===================== =======
Dodecyl
2-(N,N-Dimethylamino)-Propionate
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Crystalline Salts of Allowed
============== ===================== =======
Dodecyl
2-(N,N-Dimethylamino)-Propionate
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Crystalline Salts of Authorized
============== ===================== ==========
Dodecyl
2-(N,N-Dimethylamino)-Propionate
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
50
=================== ================== ============== ========== =============
DOCKET NO. COUNTRY SERIAL/ FILED PATENT/ PUB.
========== ======= ======= ===== =============
APP. NO. NO.
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxxx X 00 00000 05/18/00
======= ======= ========== ========
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxx 000000 05/18/00
======= ====== ====== ========
------------------- ------------------ -------------- ---------- -------------
NMD-107 South Africa 2001/0142 05/18/00 2001/0142
======= ============ ========= ======== =========
------------------- ------------------ -------------- ---------- -------------
NMD-110 Europe 00903301.0 01/14/00
======= ====== ========== ========
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxxx X 00 00000 01/14/00
======= ======= ========== ========
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxx 000000 01/14/00
======= ====== ====== ========
------------------- ------------------ -------------- ---------- -------------
NMD-110 South Africa 2001/5220 01/14/00 2001/5220
======= ============ ========= ======== =========
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxx 00000 01/14/00
======= ====== ===== ========
------------------- ------------------ -------------- ---------- -------------
NMD-110 Yugoslavia P-508/2001 01/14/00
======= ========== ========== ========
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxxxxx 2001249792 04/04/01
======= ========= ========== ========
------------------- ------------------ -------------- ---------- -------------
NMD-113 Europe 01923062.2 04/04/01
======= ====== ========== ========
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxxx X 00 00000 04/04/01
======= ======= ========== ========
------------------- ------------------ -------------- ---------- -------------
= ============= ================ ========================== ==============
GRANTED INVENTORS TITLE STATUS
======= ========= ===== ======
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Crystalline Salts of Pending
============== ===================== =======
Dodecyl
2-(N,N-Dimethylamino)-Propionate
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Crystalline Salts of Pending
============== ===================== =======
Dodecyl
2-(N,N-Dimethylamino)-Propionate
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
03/27/02 X. Xxxxxxxxxxx Crystalline Salts of Granted
======== ============== ===================== =======
Dodecyl
2-(N,N-Dimethylamino)-Propionate
X. Xxxxxxxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Medicament Dispenser Pending
========= ==================== =======
Y. Mo
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Medicament Dispenser Pending
========= ==================== =======
Y. Mo
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Medicament Dispenser Pending
========= ==================== =======
Y. Mo
- ------------- ---------------- -------------------------- --------------
06/25/03 X. Xxxxxx Medicament Dispenser Granted
======== ========= ==================== =======
Y. Mo
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Medicament Dispenser Pending
========= ==================== =======
Y. Mo
- ------------- ---------------- -------------------------- --------------
X. Xxxxxx Medicament Dispenser Pending
========= ==================== =======
Y. Mo
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions Pending
============== ===================== =======
Containing
Prostaglandin E1
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions Pending
============== ===================== =======
Containing
Prostaglandin E1
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions Pending
============== ===================== =======
Containing
Prostaglandin E1
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
51
=================== ================== ============== ========== =============
DOCKET NO. COUNTRY SERIAL/ FILED PATENT/ PUB.
========== ======= ======= ===== =============
APP. NO. NO.
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxxxxx 000000 04/04/01
======= ====== ====== ========
------------------- ------------------ -------------- ---------- -------------
XXX-000 Xxx Xxxxxxx 000000 04/04/01
======= =========== ====== ========
------------------- ------------------ -------------- ---------- -------------
NMD-113 South Africa 2002/8803 04/04/01
======= ============ ========= ========
------------------- ------------------ -------------- ---------- -------------
NMD-113 Turkey 108965 04/04/01
======= ====== ====== ========
------------------- ------------------ -------------- ---------- -------------
NMD-125 PCT PCT/US03/ 12/31/03
======= === ========= ========
41658
=================== ================== ============== ========== =============
= ============= ================ ========================== ==============
GRANTED INVENTORS TITLE STATUS
======= ========= ===== ======
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions Pending
============== ===================== =======
Containing
Prostaglandin E1
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions Pending
============== ===================== =======
Containing
Prostaglandin E1
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions Pending
============== ===================== =======
Containing
Prostaglandin E1
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
X. Xxxxxxxxxxx Topical Compositions Pending
============== ===================== =======
Containing
Prostaglandin E1
X. Xxxxxxxxxxx
X. Xxxxxx
- ------------- ---------------- -------------------------- --------------
Y. Mo Topical Stabilized Pending
===== =================== =======
Prostaglandin E Compound
Dosage Forms
X. Xxxxx
= ============= ================ ========================== ==============
52
