EXHIBIT 10.1
RESEARCH, DEVELOPMENT AND LICENCE AGREEMENT
DATED MAY 11, 1999 BETWEEN
PRAXIS PHARMACEUTICALS, INC. AND XXXXXXXXX INTERNATIONAL INC.
RESEARCH, DEVELOPMENT AND LICENCE AGREEMENT
DATED THE 11TH DAY OF MAY, 1999
BETWEEN:
PRAXIS PHARMACEUTICALS, INC.,
a body corporate incorporated pursuant
to the laws of the State of Utah,
one of the United States of America
and having an office at
ANUTECH Court, North Road, in the
City of Canberra, ACT, Australia
("Praxis")
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XXXXXXXXX INTERNATIONAL INC., a body corporate
incorporated pursuant to the laws of
the Province of British Columbia, Canada
and having an office at
Xxxxx 000, 000 Xxxxxx Xxxxxx,
Xxxx of Vancouver, British Columbia, Canada
("XXXXXXXXX")
WHEREAS:
A. The Australian National University is the owner of certain patents related to
the invention entitled "Phosphosugar-based anti-inflammatory and/or
immunosuppressive drugs" and certain patent applications related to an invention
entitled "Novel phosphosugars and phosphosugar-containing compounds having
anti-inflammatory activity" which are described in more detail herein;
B. ANUTECH PTY Ltd. ("Anutech"), the commercialization company of
the Australian National University, has entered into an
agreement as agent for and on behalf of the Australian
National University with Praxis pursuant to which Praxis has
been granted an exclusive licence for the use of the
inventions described above in specified areas of application;
C. Praxis has and intends to continue to conduct research and development
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related to the above described inventions;
D. Praxis wishes to obtain funding from XXXXXXXXX to conduct research in the
area of arthritis and dermal wrinkles and related to the above inventions;
X. XXXXXXXXX wishes to obtain an exclusive, world-wide licence to make, use and
sell products and processes developed by Praxis relating to arthritis and dermal
wrinkles;
NOW THEREFORE, in consideration of the mutual terms and
conditions contained herein, the parties hereto agree as follows:
PART I - DEFINITIONS AND INTERPRETATION
SECTION 1 - DEFINITIONS
In this Agreement, including this Section, the following
defined terms have the meanings indicated:
(a) "Anutech Licence Agreements" means the agreement entered into
between Anutech and Praxis dated 27th October, 1997, a copy of
which is attached hereto as Schedule "D";
(b) "Closing Date" means September 30th, 1999
(c) "Confidential Information" means confidential or proprietary
information, trade secrets, know-how and technical information
related to the inventions claimed pursuant to the Patents and
any other information disclosed in confidence by Praxis to
XXXXXXXXX or by XXXXXXXXX to Praxis;
(d) "Field of Use" means arthritis and dermal wrinkles;
(e) "Intellectual Property" means any and all methods, devices,
techniques, discoveries, inventions (whether or not
patentable), know-how, ideas,
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processes, trade secrets and other proprietary information,
including any patent right, copyright, trade secret or similar
right;
(f) "Licensed Patent Applications" means:
(i) the patent applications relating to the invention
entitled "Novel phosphosugars and
phosphosugar-containing compounds having
anti-inflammatory activity", including United State
Patent Application No. 08/953305, Australian
Application No. 41866/97 and any patent applications
filed now or in the future in any country which
disclose and claim the same inventions or the
priority of Australian Provisional Application PO
3098/96, filed October 18, 1996; and
(ii) all patent applications related to the New
Intellectual Property;
(g) "Licensed Patents" means:
(i) the patents described on Schedule "A" hereto;
(ii) all patents issued out of the Patent Applications;
(iii) any patents issued in any country disclosing and
claiming the same inventions as those claimed in the
patents referred to in clauses (i) and (ii) hereof;
and
(iv) all divisions, re-issues, re-examinations,
continuations, renewals and extensions of the
foregoing;
(h) "Licensed Product" means any product the manufacture or use of
which is covered by a Valid Claim;
(i) "Licensed Technology" means:
(i) the inventions disclosed and claimed in the Licensed
Patent Applications and Licensed Patents;
(ii) any additional Intellectual Property related to the
inventions referred to in clause (i), their
description, use, or application; and
(iii) all Confidential Information in any way related to
the inventions referred to in clause (i) hereof and
the Intellectual Property referred to in clause (ii)
hereof;
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(j) "Net Revenue" means all consideration received by XXXXXXXXX:
(i) for the sale or other disposition of Licensed
Products; and
(ii) pursuant to the terms of any sublicences granted by
XXXXXXXXX in accordance with Section 11(3);
less the following:
(A) all costs incurred by XXXXXXXXX in the
development of Licensed Products, including,
without limitation, payments made by
XXXXXXXXX to Praxis pursuant to Section 8,
costs and expenses incurred by XXXXXXXXX
pursuant to Section 13 and expenses incurred
by XXXXXXXXX in connection with obtaining
Regulatory Approvals, including those
referred to in Section 17;
(B) all costs of direct materials, labour and
overhead expenses required in the
manufacture and production of Licensed
Products;
(C) costs incurred by XXXXXXXXX in connection
with the marketing, selling and distribution
of Licensed Products;
(D) any tax or government charge (other than an
income tax) levied on the sale,
transportation or delivery of Licensed
Product;
(E) trade and quantity discounts or rebates
actually allowed and taken; and
(F) credits or allowances given or made for
rejection or return of previously sold
Licensed Products;
(k) "New Intellectual Property" means Intellectual Property that
is developed by Praxis during the conduct of the Research
Projects performed by Praxis in accordance with Section 8;
(l) "Regulatory Approval" means any approvals, licenses,
registrations or authorizations of any relevant authority
having jurisdiction necessary for the development, use,
importation, packaging, marketing, distribution, sale, storage
and transportation of the Licensed Products;
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(m) "Research Projects" means the Research and Development
Projects relating to dermal wrinkles and arthritis conducted
in accordance with Section 8;
(n) "Shares" means shares in the capital stock of XXXXXXXXX
described as Class A Common and having the rights set out on
Schedule "B" hereto;
(o) "Valid Claim" means a claim of any issued and unexpired
Licensed Patent which claim has not been held unenforceable,
unpatentable or invalid by a decision of a court or government
body of competent jurisdiction, unappealable or unappealed
within the time allowed for appeal, which has not been
rendered unenforceable through disclaimer or otherwise, and
which has not been lost through an interference proceeding or
by abandonment.
SECTION 2 - GOVERNING LAW AND JURISDICTION
This Agreement shall be governed by and interpreted in
accordance with the laws in force in the Province of British Columbia. The
parties hereby submit to the jurisdiction of the Courts of British Columbia.
SECTION 3 - CURRENCY
All monetary units, except as expressly stated otherwise in
this Agreement, are in United States dollars.
SECTION 4 - AFFILIATES
For the purpose of this Agreement, a company is an Affiliate
of a party if:
(a) the party owns or controls, directly or indirectly, 50% or
more of the voting stock of that company;
(b) the party owns or controls, directly or indirectly, sufficient
voting stock in that company to elect a majority of the
directors of that company;
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(c) that company owns or controls, directly or indirectly, 50% or
more of the voting stock of the party;
(d) that company owns or controls, directly or indirectly,
sufficient voting stock in the party to elect a majority of
the directors of the party;
(e) an organization owns or controls, directly or indirectly, 50%
or more of the voting stock of the party and that company; or
(f) an organizations owns or controls, directly or indirectly,
sufficient voting stock in the party and the company to elect
a majority of the directors of the party and that company.
SECTION 5 - SCHEDULES
The following Schedules are incorporated into and form part of
this Agreement:
Schedule "A" - Patents
Schedule "B" - Share Rights
Schedule "C" - Research Projects
Schedule "D" - Anutech Licence
PART II - PURCHASE AND SALE OF SHARES
SECTION 6 - SUBSCRIPTION AND PURCHASE
(1) In consideration for the licensing rights to the Praxis Intellectual
Property, XXXXXXXXX hereby agrees to transfer, on or before the Closing Date,
260,000 pre-split shares or 2.6 million post-split shares of Xxxxxxxxx
International Inc. to Praxis, and guarantees that the Shares will be issued as
fully paid up and non-accessible Shares; that the Shares be allotted and that a
certificate for the Shares be issued to Praxis.
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(2) Praxis shall certify as at the Closing Date that the following
representations and warranties are correct:
(a) Praxis is engaged primarily in the business of developing a
unique panel of natural carbohydrate based compounds and
exploiting commercial applications of such;
(b) there are no material lawsuits against Praxis, or its
directors or officers that are related to the business of
Praxis, nor, to the best of the knowledge of Praxis and its
directors and officers are any being contemplated;
(c) Praxis is current in all taxes owed, including payroll taxes,
and on all debts, accounts payable and leases;
(d) Praxis has provided copies of its most recent financial
statements to XXXXXXXXX and the information contained in such
financial statements is complete and accurately reflects
Praxis' situation, financial and otherwise;
(e) a copy of every material executed lease, licence, partnership
or collaboration agreement (whether technical, marketing,
manufacturing or other) stockholder agreement, loan agreement,
employment agreement, purchase and sale agreement has been
provided to XXXXXXXXX;
(f) a comprehensive listing and description of all Intellectual
Property in the name of Praxis or obtained by Praxis through
licensing has been provided to XXXXXXXXX as have copies of
file wrappers for all Licensed Patent Applications and there
are no existing or potential patent disputes of which Praxis
is aware or for which Praxis has not provided full and
complete disclosure to XXXXXXXXX;
(g) a complete and current listing of Praxis' capital structure
and the terms and conditions associated therewith has been
provided to XXXXXXXXX, including a list of all shareholders,
options, Warrants, puts and other instruments that may affect
XXXXXXXXX'x equity position after shareholdings are fully
diluted;
(h) there are no material written or oral agreements with any
other person or corporation pursuant to which Praxis or it
directors or officers have agreed to do anything beyond the
requirements of the formal written contracts referred to in
clause (e);
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(i) the transfer of the Shares to Praxis contemplated by this
Agreement will not constitute a breach of any contract or
commitment to which XXXXXXXXX is a party;
(j) Praxis has filed all necessary tax returns;
(k) this Agreement has been duly authorized, executed and
delivered by Praxis and is a legal, valid and binding
obligations of Praxis enforceable by XXXXXXXXX in accordance
with its terms, except as enforcement may be limited by
bankruptcy, insolvency and other laws affecting the rights of
creditors generally;
(l) the execution and delivery of this Agreement by Praxis and the
completion of the transactions herein will not result in a
breach or violation of any of the provisions of any obligation
of Praxis under any contract to which Praxis may be a party;
any judgment, decree, order or award of any court,
governmental body or arbitrator having jurisdiction over
Praxis; or any applicable law, statute, ordinance, regulation
or rule;
(m) the issue of the Shares to Praxis is in compliance with the
constating documents of XXXXXXXXX; and
(n) Praxis is not a non-resident of Canada within the meaning of
Section 116 of the Income Tax Act (Canada).
(3) If at any time prior to the Closing Date:
(a) Praxis shall have failed to comply with any term or condition
contained herein;
(b) any representations and warranties set out in Section 6(2) is
incorrect in any material respect;
(c) there is any material default under debts owed by Praxis which
default has not been cured within any applicable grace period;
or
(d) any material final judgments are rendered against Praxis;
XXXXXXXXX may terminate this Agreement upon written notice to Praxis.
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(4) All registration and recording fees payable to third parties in connection
with the closing of the transactions outlined in this Section 6 shall be borne
by Praxis.
SECTION 7 - PURCHASE OF ADDITIONAL SHARES
Praxis shall not purchase any Shares in addition to those to
which Praxis is entitled pursuant to Section 6 unless such purchase is made in
conjunction with or pursuant to an agreement between Praxis and XXXXXXXXX for
the acquisition by Praxis of voting control of XXXXXXXXX.
PART III - RESEARCH AND DEVELOPMENT
SECTION 8 - RESEARCH PROJECTS
(1) Praxis shall conduct the Research Projects and perform all work described in
Schedule "C".
(2) Praxis shall commence work on October 1st, 1999 and shall use reasonable
efforts to complete the Research Projects in accordance with the work schedule
included as part of Schedule "C".
(3) The Research Projects shall be performed by Praxis in a thorough and
diligent manner in accordance with Good Laboratory Practices and normal
professional standards.
(4) Praxis shall report to XXXXXXXXX at the times and in the manner set forth in
Schedule "C".
(5) XXXXXXXXX shall pay to Praxis the total sum of $250,000.00 USD, after
deduction for any loans to the company, payable as an initial payment of $62,500
USD
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and then in three equal quarterly instalments of $50,000 USD payable on the
first day of each month commencing on January 1st, 2000 and a single, and final,
quarterly payment of $37,500 USD on October 1st, 2000, such payments to be
exclusive of any taxes, whether municipal, provincial, federal or Goods and
Services. The funds paid by XXXXXXXXX to Praxis pursuant to this Section 8 shall
only be used by Praxis for the conduct of the Research Projects and shall only
be expended in accordance with the budget included as part of Schedule "C",
unless Praxis obtains prior written authorization from XXXXXXXXX.
(6) XXXXXXXXX and Praxis shall, not less than once every three (3) months,
review and evaluate progress on the Research Projects. Following such reviews
milestones as set out in Schedule C may be revised as and when needed by mutual
agreement between XXXXXXXXX and Praxis.
(7) Praxis shall use reasonable efforts to ensure that the technology used in
the Research Projects does not infringe on any patents or proprietary rights of
other persons.
SECTION 9 - RECORDS AND CONFIDENTIALITY
(1) Praxis shall maintain complete and accurate records of the activities
conducted and results obtained pursuant to the Research Projects, all in
accordance with good scientific practice. Upon written request from XXXXXXXXX,
Praxis shall provide copies of any such records to XXXXXXXXX.
(2) Praxis shall keep full, accurate and complete records of books of account
relating to financial aspects of the Research Projects. XXXXXXXXX, or a
designate of XXXXXXXXX, may from time to time upon reasonable prior written
notice to Praxis examine, audit or have examined or audited the records and
books of account of Praxis.
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(3) All data, reports, plans, records, logs and other information relating to
the Research Projects shall be treated by Praxis and XXXXXXXXX as the
confidential property of both parties and both parties shall use all reasonable
efforts to ensure that such information is kept strictly confidential during the
term of this Agreement and for a period of ten (10) years thereafter. Nothing
herein shall prevent Praxis from using, disclosing or authorizing disclosure of
information:
(a) which is or becomes part of the public domain through no act
or failure on the part of Praxis;
(b) which was in Praxis' possession prior to its development
pursuant to the Research Projects or prior to receipt or
acquisition from XXXXXXXXX;
(c) which is disclosed to Praxis by a third party without a
covenant of confidentiality, provided that such third party
is, to the knowledge of Praxis, under no obligation of
confidentiality with respect to the information; or
(d) with the prior written authorization of XXXXXXXXX.
SECTION 10 - OWNERSHIP OF NEW INTELLECTUAL PROPERTY
(1) New Intellectual Property shall promptly be disclosed by Praxis to XXXXXXXXX
and thereafter shall be included as part of the Licensed Technology and licensed
to XXXXXXXXX pursuant to Section 11.
(2) All expenses connected with preparing, filing, prosecuting, obtaining,
maintaining and enforcing intellectual property rights related to the New
Intellectual Property shall be borne by XXXXXXXXX.
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PART IV - LICENCE
SECTION 11 - GRANT
(1) Praxis hereby grants to XXXXXXXXX an exclusive, world-wide sublicence under
the Licensed Patent Applications and Licensed Patents, and an exclusive,
world-wide sublicence under the New Intellectual Property, to use the Licensed
Technology and to make, use and sell any products, compounds, compound uses,
processes, applications, methods or procedures within the Field of Use.
(2) XXXXXXXXX shall be entitled to grant further sublicences of the rights
granted by Praxis to XXXXXXXXX pursuant to Section 11(1) hereof. XXXXXXXXX shall
advise Praxis in writing of any and all sublicences granted by XXXXXXXXX in
accordance with this Section 11(3) and shall provide Praxis with the following
information:
(a) name of the sublicencee;
(b) the amount of any licence fee or royalties payable by the
sublicencee; and
(c) such further information as may be reasonably requested by
Praxis.
(3) XXXXXXXXX may assign this Agreement to an Affiliate of XXXXXXXXX or may
transfer or assign the rights and obligations of XXXXXXXXX pursuant to Parts
III, IV or V, or any combination thereof, to an Affiliate of XXXXXXXXX.
XXXXXXXXX shall advise Praxis in writing of any such transfer or assignment.
Notwithstanding any such transfer or assignment, XXXXXXXXX shall at all times
remain liable to Praxis for the performance of the obligations set out herein,
including the obligation to pay to Praxis a share of Net Revenue in accordance
with Section 12.
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SECTION 12 - REVENUE
(1) Net Revenue shall be apportioned between the parties and XXXXXXXXX shall pay
to Praxis an amount equal to thirty five percent (35%) of Net Revenue of Praxis
products for so long as there are Valid Claims.
(2) All payments required to be made pursuant to Section 12(1) shall be made
according to Section 8(5).
SECTION 13 - RECORDS AND REPORTS
(1) XXXXXXXXX shall keep full, accurate and complete records and books of
account relating to Net Revenue and any amounts payable by XXXXXXXXX to Praxis
pursuant to Section 12 hereof.
(2) All payments made by XXXXXXXXX to Praxis pursuant to Section 12 shall be
accompanied by a report providing such information as is reasonably required by
Praxis to determine an accurate determination of the amounts payable by
XXXXXXXXX to Praxis in accordance with Section 12.
(3) Praxis may from time to time, upon reasonable prior notice to XXXXXXXXX have
the records and books of account maintained by XXXXXXXXX in accordance with
Section 13(1) hereof audited or examined by a duly authorized independent
chartered accountant to ascertain the accuracy of the payments made. All costs
of any audit, examination or report shall be payable by Praxis, unless the
report discloses an underpayment of five (5%) percent or more, in which case the
cost of the audit, examination or report shall be payable by XXXXXXXXX.
SECTION 14 - PROTECTION, ENFORCEMENT AND INFRINGEMENTS
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(1) Praxis shall permit XXXXXXXXX to control and direct (including the selection
of patent agents or patent attorneys) the preparation, filing and prosecution of
all patent applications the subject of this Agreement included within the Field
of Use of the Licensed Technology, including the New Intellectual Property.
Without limiting the generality of the foregoing, Praxis shall, upon XXXXXXXXX'x
request and at XXXXXXXXX'x cost and expense, file and prosecute patent
applications to protect the Licensed Technology in any country that a patent
application has not been filed. XXXXXXXXX shall consult with Praxis on the
content of all patent applications and related filings. Praxis shall bear all
costs related to the preparation, filing, prosecution and maintenance with
respect to the Licensed Patents described on Schedule "A", the Licensed Patent
Applications described in Section 1(g)(i) and any other patents or Licensed
Patent Applications that disclose and claim the same inventions. XXXXXXXXX shall
pay all costs of preparing, filing, prosecuting and maintaining all Licensed
Patent Applications and Licensed Patents related to the New Intellectual
Property.
(2) If either party believes that any Licensed Patents are being infringed by
another person, that party shall promptly notify the other party and shall
provide any evidence of infringement which is reasonably available. XXXXXXXXX
shall have the first right and option, but not the obligation, to bring an
action for infringement, at XXXXXXXXX'x sole cost and expense, against the
alleged infringer. If XXXXXXXXX elects to take such action, the conduct of the
action shall be entirely under the direction and control of XXXXXXXXX. If
XXXXXXXXX exercises the rights contained herein, XXXXXXXXX may name Praxis as a
party plaintiff in such action, suit or proceeding, if reasonably necessary
under the circumstances, provided that XXXXXXXXX shall indemnify and hold Praxis
and Anutech harmless from any costs or expenses incurred in connection with such
action, suit or proceeding. Any damages or sums recovered by XXXXXXXXX in any
such action, suit or proceeding, or any settlement thereof, shall be retained by
XXXXXXXXX, but, to the extent that the recovery reflects lost sales of Licensed
Products, the net amount after deducting expenses incurred by XXXXXXXXX, shall
be included as part of Net Revenue.
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(3) If XXXXXXXXX elects not to pursue an action for infringement, whether alone
or jointly with Praxis, Praxis shall have the right and option, but not the
obligation, at Praxis's sole cost and expense, to bring the action for
infringement against the alleged infringer. Any damages or sums recovered by
Praxis in such action, suit or proceeding, or any settlement thereof, shall be
retained by Praxis, but, to the extent that the recovery reflects lost sales of
Licensed Products, Praxis shall pay to XXXXXXXXX one-half of the net amount
after deducting expenses incurred by Praxis.
(4) The parties shall cooperate in defending any impeachment, interference or
infringement action, suit or proceeding brought against either Praxis or
XXXXXXXXX related to the Licensed Technology.
(5) The parties shall not take any actions that may be reasonably known to
compromise the position of the other party with respect to legal proceedings
commenced or to be commenced or being defended by the other party.
(6) The parties shall render all reasonable assistance, including providing all
documents in their possession and any witnesses as are or may be required in the
conduct of any proceedings referred to herein. If any party renders such
assistance at the request of another party, the requesting party shall reimburse
the assisting party for expenses incurred to render such assistance.
SECTION 15 - WARRANTIES, INDEMNITIES AND INSURANCE
(1) Praxis represents and Warrants to XXXXXXXXX that, as of the Closing Date:
(a) Praxis owns or has valid and enforceable licenses of the
Licensed Technology free and clear of all liens, charges,
security interests
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and encumbrances, licences and other restrictions;
(b) the Anutech Licence Agreement is in full force and effect,
unamended and that neither Praxis nor Anutech are in default
of any of the terms and conditions contained therein;
(c) to the best of Praxis's knowledge and belief, the practising
of the Licensed Technology will not infringe the rights of any
other person; and
(d) to the best of Praxis's knowledge and belief, it is not aware
of any activities or conduct of any other person that would
constitute infringement of the Licensed Technology.
(2) The parties shall assume and be liable for their own losses, damages and
expenses of any nature whatsoever which they may suffer, sustain, pay or incur
by reason of any matter or thing arising out of, or in any way related to this
Agreement, except for such losses, costs, damages and expenses as are the result
of the wilful breach of any term herein by the other party or the wilful or
negligent acts or omissions of the other party.
(3) Each party shall indemnify and hold harmless the other party, its employees
and agents, from and against any and all claims, demands and costs whatsoever
that may arise out of, directly or indirectly, the indemnifying party's
performance of this Agreement or that of the indemnifying party's employees or
agents. Such indemnifications shall survive this Agreement.
(4) Praxis shall, at its own expense and without limiting its liabilities
herein, maintain comprehensive or commercial general liability insurance with an
insurer in an amount not less than $1,000,000.00 per occurrence (annual general
aggregate, if any, not less than $2,000,000.00), insuring against bodily injury,
personal injury and property damage, including loss of use thereof. Such
insurance shall include blanket contractual liability.
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(5) From the date that any Product arising out of the the Licenced Technology is
first applied for therapeutic human use (and for the term or foreseeable term of
the human use) XXXXXXXXX undertakes to hold product liability insurance to the
value of at least $10,000,000.00. Such policies shall name Praxis as additional
insureds and shall be purchased from a reputable insurer. Certificates
evidencing the coverage shall be provided to Praxis.
SECTION 17 - REGULATORY APPROVALS
(1) XXXXXXXXX shall use reasonable efforts to obtain Regulatory Approvals.
(2) Praxis shall assist XXXXXXXXX in obtaining Regulatory Approvals in the
various countries by providing such information and data as may be in the
possession of Praxis necessary for or of assistance in obtaining any Regulatory
Approvals. XXXXXXXXX shall be responsible for all regulatory, agency, filing,
inspection and other fees and expenses and charges incurred in connection with
obtaining any Regulatory Approvals pursuant to Section 17(1).
(3) Praxis shall ensure that all information and data generated by Praxis that
is related to the Clinical Trials or would be of any assistance to XXXXXXXXX in
obtaining Regulatory Approvals shall be maintained in a form suitable for
submission to regulatory authorities and shall at all times be kept secure and
confidential.
PART VI - GENERAL
SECTION 18 - TERM AND TERMINATION
(1) The term of this Agreement shall expire on the expiration of the last
Licensed Patent. Upon the expiration of this Agreement, XXXXXXXXX'x licence
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pursuant to Section 11 shall become a fully paid-up, perpetual licence.
(2) This Agreement may be terminated at any time upon the mutual agreement of
the parties.
(3) If:
(a) either party has breached any of its obligations pursuant to
this Agreement and fails to remedy such breach or to commence
and diligently pursue reasonable steps to remedy such breach
within sixty (60) days after notice in writing from the other
party;
(b) either party becomes bankrupt or insolvent or takes the
benefit of any statute for bankrupt or insolvent debtors or
makes any proposal, assignment or arrangement with its
creditors, or any steps are taken or proceedings commenced by
any person for the dissolution, winding up or termination of
either parties existence or the liquidation of its assets; or
(c) a trustee, receiver, receiver manager or like person is
appointed with respect to the business or assets of a party;
the party in default may terminate this Agreement by giving written notice to
the party in default.
(4) If Praxis is in default of any of its obligations related to the performance
of the Research Projects, and has failed to remedy such breach within sixty (60)
days after notice in writing from XXXXXXXXX, XXXXXXXXX may terminate the
Research Projects immediately upon written notice to Praxis. If XXXXXXXXX
terminates the Research Projects in accordance with this Section 18(4):
(a) XXXXXXXXX shall reimburse Praxis for costs and expenses
incurred in accordance with the budget included as part of
Schedule "C" to the date of termination;
(b) XXXXXXXXX shall have no further obligation with respect to the
conduct of
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the Research Projects or any costs and expenses related
thereto;
(c) notwithstanding the termination of the Research Project, all
New Intellectual Property developed prior to the date of
termination shall be disclosed by Praxis to XXXXXXXXX and
shall be included as part of the Licensed Technology and
licensed to XXXXXXXXX pursuant to Section 11; and
(d) XXXXXXXXX shall have the right to complete the Research
Project, or any part thereof at its own cost and expense and
any results; improvements to Intellectual Property sublicenced
from Praxis under the terms of this Agreement; new patents and
patent applications arising from this shall be deemed to be
New Intellectual Property.
(5) The following sections shall survive termination of this Agreement: 1, 2, 3,
4, 5, 9 and 15.
SECTION 19 - PUBLICITY
(1) A copy of all public announcements and press releases which either party
intends to release or make regarding products or technology covered by the
licence shall be provided to the other party prior to being released or made.
Any public announcement or news release that names, refers to or in any way
identifies both parties shall be approved by both parties prior to being
released or made. Each party shall respond to a request for approval within five
(5) working days of receipt of the copy and the approval of each party shall not
be unreasonably withheld.
(2) If either party is prevented from complying with Section 19(1) as a result
of the requirements of a Securities Commission or other regulatory body, the
party shall not be considered to be in breach of this Agreement, but shall use
reasonable efforts to consult with and keep the other party informed.
(3) The parties shall not use each other's name in any advertising material
without the prior written consent of the other party, which consent may be
arbitrarily
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withheld.
(4) Subject to subsection (3), XXXXXXXXX shall be responsible for and have
control of labelling of Licensed Products.
SECTION 20 - COMPLIANCE WITH LAWS
The parties shall observe and comply with all applicable laws,
ordinances, codes and regulations of Government agencies, including Federal,
Provincial, Municipal and local governing bodies having jurisdiction.
SECTION 21 - RELATIONSHIP
Nothing in this Agreement shall be construed as:
(a) constituting either party as the agent, employee or
representative of the other party; or
(b) creating a partnership or as imposing upon either party any
partnership duty, obligation or liability to the other party.
SECTION 22 - NOTICES
All notices or other communications required or permitted to
be given hereunder shall be in writing and shall be sent to the following
addresses or such other addresses as the relevant party may notify from time to
time:
TO: Xxxxxxx X Xxxxxx, CEO
Praxis Pharmaceuticals Inc.
GPO Box 1978
Xxxxxxxx, XXX, Xxxxxxxxx 0000
Facsimile: 61 2 6279 9758
-21-
TO: Xxxxx Xxx
XXXXXXXXX INTERNATIONAL Inc.
#000 - 000 Xxxxxx Xxxxxx
Xxxxxxxxx, Xxxxxxx Xxxxxxxx X0X 0X0
Facsimile: (000) 000-0000
Notices sent by prepaid registered mail shall be deemed to be received by the
addressee on the 7th day (excluding Saturdays, Sundays, statutory holidays and
any period of postal disruption) following the mailing thereof. Notices
personally served or transmitted by facsimile shall be deemed received when
actually delivered or transmitted, provided such delivery shall be made during
normal business hours.
SECTION 23 - ASSIGNMENT
Except as expressly permitted pursuant to Section 11, the
parties shall not assign this Agreement or any part thereof, or any rights
hereunder without the prior written consent of the other party, such consent not
to be unreasonably withheld.
SECTION 24 - FURTHER ASSURANCES
The parties shall with reasonable diligence take all action,
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SECTION 25 - SETTLEMENT OF DISPUTES
(1) If there is any dispute or disagreement related to or arising out of this
Agreement (the "Disagreement") the parties shall refer the Disagreement for
resolution
-22-
to their respective Chief Executive Officers, or their nominees.
(2) If the Disagreement is not resolved pursuant to Section 25(1) within thirty
(30) days (or such longer period as agreed upon between the parties), a mediator
shall be appointed by the parties who shall assist the parties in resolving the
Disagreement.
(3) If the Disagreement is not resolved under Section 25(2) within thirty (30)
days (or such longer period as agreed upon between the parties) either party may
refer the Disagreement to be resolved by arbitration conducted as follows:
(a) either party may require arbitration by giving written notice
to arbitrate to the other party, which written notice shall
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(b) if the parties are able to agree upon a single arbitrator, the
arbitration shall be conducted before the single arbitrator;
(c) if the parties have been unable to agree upon the selection of
a single arbitrator within two (2) weeks after receipt of the
notice requiring arbitration, each party shall within one (1)
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nominate one neutral arbitrator. If either party fails to
nominate an arbitrator in accordance with this clause, the
arbitrator so nominated shall proceed to conduct the
arbitration alone. If both parties nominate neutral
arbitrators in accordance with this clause, the two
arbitrators so nominated shall nominate a third arbitrator
within one (1) week of their nomination;
(d) the arbitrator or arbitrators shall immediately proceed to
hear and determine the Disagreement. The parties agree that it
is important that all Disagreements be resolved promptly and
the parties therefore agree that the arbitration shall be
required to be conducted expeditiously and that the final
disposition shall be accomplished within two (2) weeks. The
parties shall ensure that the arbitrator or arbitrators upon
accepting the nomination shall agree that the arbitrator has
time available for the timely handling of the arbitration in
order to achieve final disposition within two (2) weeks;
(e) the decision of the arbitrator or arbitrators shall be
rendered in writing, without reasons and shall be promptly
served upon both parties. If the
-23-
arbitration is being conducted before a panel of three
arbitrators, the decision of any two of the three arbitrators
shall be decision of the arbitration panel. The decision of
the arbitrator or arbitrators shall be binding upon the
parties;
(f) in the event of the death, resignation, incapacity, neglect or
refusal to act of any arbitrator, and if the neglect or
refusal continues for a period of five (5) days after notice
in writing of such has been given by either party, another
arbitrator shall be nominated to replace the arbitrator by the
person who has originally nominated that arbitrator;
(g) the costs of the arbitration shall be in the discretion of the
arbitrators, and shall be borne by the parties in accordance
with the decision of the arbitrators;
SECTION 26 - ENUREMENT
This Agreement shall enure to the benefit of and be binding
upon the parties hereto and their respective successors and permitted assigns.
IN WITNESS WHEREOF the parties hereto have executed this
Agreement as of the day and year first above written.
PRAXIS PHARMACEUTICALS, INC.
Per: /S/ XXXXX XXXXXXXX (PRESIDENT)
Per:
XXXXXXXXX INTERNATIONAL INC.
Per: /S/ XXXXX XXX
Per:
SCHEDULE "A" - PATENTS
----------------------
UNITED STATES PATENT [19] [11] PATENT NUMBER: 5,506,210
Parish et al. [45] DATE OF PATENT: Apr. 9, 1996
--------------------------------------------------------------------------------
[54] PHOSPHOSUGAR-BASED 4,935,406 6/1990 Xxxxxxx et al............... 514.54
ANTI-INFLAMMATORY AND/OR
IMMUNOSUPPRESSIVE DRUGS
FOREIGN PATENT DOCUMENTS
[75] inventors: Xxxxxxxxxxx X. Xxxxxx, Xxxxxxxx;
Xxxxxxx X. Xxxxxx, Kambah; Xxxxx 596800 1/1987 Australia
X. Xxxxxxxxxx, Sterling, all of Australia 614772 4/1989 Australia
158879 10/1985 European Xxx. Off.
194710 9/1986 European Xxx. Off.
[73] Assignee: The Australian National University, 2144332 0/0000 Xxxxxx Xxxxxxx
Xxxxx, Xxxxxxxxx 2185398 7/1987 United Kingdom
[21] Appl. No.: 988,001
OTHER PUBLICATIONS
[22] Filed: Dec. 29, 1992
Patent Abstracts of Japan, vol. 7, No. 7,
Related U.S. Application Data issued 07 Oct. 1982, Murakami, "Production
of Mannose Monophosphate salt Derivative",
C144, p. 7, JP, A, 57-163491.
[63] Continuation of Ser. No. 656,082, filed as PCT/AU89/ Patent Abstracts of Japan, vol. 12, No.
00350, Aug. 18, 1989, abandoned. 482, issued 17 Aug. 1988, Murata,
"Preventive and Remedy for Hypertension",
C553, p. 48, JP.A, 63-198629.
[30] Foreign Application Priority Data Journal of Biological Chemistry, vol. 257,
No. 17, issued 10 Sep. 1982, Xxxxxxx et
al., "Binding of Phosphorylated Oli-
Aug. 19, 1988 [AU] Australia ............... P199942/88 gosaccharides to Immobilized
Phosphomannosyl Receptors", pp. 9938-9943.
Journal of Biological Chemistry, vol. 258,
[51] Int. Cl.6 .......................... A61K 31/70; C07H 11/04; Xx. 0, xxxxxx 00 Xxx. 0000, Xxxxx xx xx.,
X00X 13/00 "The Spectrum of Anionic Oligosaccharides
Released by Endo-B-N-acetylglucosainidase H
[52] U.S. Cl. .......................... 514/23; 514/825; 514/885; from Glycoproteins" pp. 2808-2814.
536/117
PRIMARY EXAMINER-Xxxxxxx X. Xxxxxxxx
ASSISTANT EXAMINER-Xxxxxxx Xxxxx
[58] Field of Search ..................... 514/23, 825, 885; ATTORNEY, AGENT, OR FIRM-Bacon & Xxxxxx
536/117
[57] ABSTRACT
The invention relates to a method of anti-
inflammatory and/or immunosuppressive
treatment of an animal or human patient
[56] References Cited comprising administering to the patient an
effective amount of at least one
U.S. PATENT DOCUMENTS phosphosugar or derivative thereof, or a
phosphosugar-containing oligosaccharide or
4,096,250 6/1978 Hill ......................... 536/117 polysaccharide or derivative thereof.
4,122,179 10/1978 Vegezzi ....................... 514/23
4,247,540 1/1981 Xxxxxxxx ..................... 424/537 17 Claims, 1 Drawing Sheet
4,448,771 5/1984 Xxxxxxx et al. ............. 514/23
4,703,040 10/1987 Markov ....................... 536/117
4,739,046 4/1988 XxXxxxx ..................... 536/117
4,745,185 5/1988 Maryanoff et al. ............ 536/117
5,506,210
1 2
PHOSPHOSUGAR-BASED and/or immunosuppressive agents. In this
ANTI-INFLAMMATORY AND/OR aspect, there is provided a method of
IMMUNOSUPPRESSIVE DRUGS anti-inflammatory and/or immunosup-
pressive treatment of an animal or human
5 patient which comprises administration to
the patient of an effective amount of at
least one phosphosugar or a derivative
This application is a continuation thereof, or a phosphosugar-containing
of U.S. application Ser. No. 07/656.082, oligosaccharide or polysac-charide or a
filed Mar. 6, 1991, now abandoned, which 10 derivative thereof.
is the U.S. national phase of In another aspect, this invention
International application serial number relates to the use of at least one
PCT/AU89/00350, filed Aug. 18, 1989. phosphosugar or phosphosugar-containing
This invention relates to oli-gosaccharide or polysaccharide in the
phosphosugars and phospho- sugar preparation or manu-facture of a
containing compounds that possess anti- 20 pharmaceutical or veterinary composition
inflammatory and/or immunosuppressive for anti-inflammatory and/or
activity, and in particular it relates immunosuppressive treatment. In this
to the use of these compounds as anti- aspect, there is provided a
inflammatory and/or immunosuppressive pharmaceutical or veterinary composition
agents in animals and man. which comprises at least one phosphosugar
25 or a derivative thereof, or a
BRIEF DESCRIPTION OF THE DRAWINGS phosphosugar-containing oligosac-charide
or polysaccharide or a derivative
thereof, together with an acceptable
FIG. 1 is a graphical representation pharmaceutical or veterinary carrier or
of the analysis of phosphosugar diluent therefor.
specificity presented in Table III. 30 Phosphosugars and phosphosugar-
containing oligosac-charide or
DETAILED DESCRIPTION polysaccharide which may be used in
accordance with the present invention
comprise both naturally occurring and
The lysosomes of cells contain a wide synthetic compounds containing or
range of degrada- tive enzymes which 35 comprising phosphosugar residues, that
play a central role in the entry of is, sugar residues bearing at least one
leukocytes into inflammatory sites. phosphate moiety. Particularly useful
Lysosomal enzymes, produced in the rough phosphosug- ars include phosphomannoses,
endoplasmic reticulum, undergo phosphofructoses, phospho-galactoses and
glycosylation followed by a number of phosphoglucoses, while particularly
'trimming' and phosphorylation reactions 40 useful oligosaccharides or
resulting in oligosaccharides rich in polysaccharides include polysaccharides
mannose-6-phosphate residues (1-3). containing phosphomannose residues.
These mannose-6- phosphate residues are Presently preferred phosphosugars include
specific recognition markers of lyso- mannose-6-phosphate and fructose-1-
somal enzymes (3). It is this marker on phosphate. Preferred phosphosugar
the enzymes that is recognized by a 45 derivatives are the esters including
mannose phosphate receptor (MPR) which acetate esters, particularly the 1,2, 3,
mediates transport of lysomsomal enzymes 4-tetraacetate of mannose-6-phosphate.
to lysosomes. This receptor functions Whilst it is not intended that the
not only in internal transport of present invention should be restricted in
lysosomal enzymes but is also important 50 any way by a theoretical explanation of the
in their secretory pathway and their mode of action of the phosphosugars in accordance
expression on cell surfaces (1). Receptor- with the invention, it is presently believed that
lysosomal enzyme interactions have been these active compounds may exert their own anti-
extensively studied (4-6) and shown to be inflammatory effect, by acting as antagonists or
inhibited by exogenous mannose-6-phosphate. competitive inhibitors of the natural ligand of
Work leading to the present invention has 55 mannose phosphate receptors (MPR) on cells.
been based on the hypothesis that Accordingly, the active phosphosugars or
mannose-6-phosphate and related phosphosugar phosphosugar-containing oligosaccharides or
structures might act as anti-inflammatory polysaccharides may include any such compounds
agents in vivo, possibly by depleting which are effective antagonists or competitive
leukocytes of their lysosomal enzymes 60 inhibitors of the natural ligand of the MPR.
although this has not been shown previously. The active anti-inflammatory and/or immuno-
As a result of these investigations, it suppressive agents in accordance with the present
has now been discovered that certain phospho- invention may be used to treat inflammatory
sugars, notably mannose-6-phosphate and diseases or conditions such as multiple sclerosis
fructose-1-phosphate, are in fact effective 65 and rheumatoid arthritis, as well as in the
anti-inflammatory agents, continuous treatment of the inflammatory process associated
infusion of the sugars inhibiting experimental with the rejection of organ transplants (since
allergic encephalomyellits (EAE), an animal massive mononuclear cell infiltrates are usually
inflammatory disease of the central nervous associated with acute graft rejection). These
system resembling multiple sclerosis in humans. active agents may be used alone, in combination
Polysaccharides containing D-mannose with with one or more other phosphosugars, or in
phosphate residues have also been found to combination with other known anti-inflammatory or
inhibit EAE. immunosuppressive agents. In particular,
Phosphosugars, particularly mannose-6- compositions of phosphosugars and sulphated
phosphate, have also been found to exhibit polysaccharides with heparanase-inhibitory activity
an anti-inflammatory effect on passively may act synergistically and represent a formulation
induced adjuvant arthritis. Adjuvant-induced with potent anti-inflammatory activity. The anti-
arthritis in the rat shares a number of inflammatory activity of these sulphated poly-
features with arthritis in humans, viz. saccharides is disclosed in detail in International
the presence of a proliferative synovitis Patent Application No. PCT/AU88/00017.
and subcurtaneous nodules, swelling of The anti-inflammatory and/or immunosuppressive
extremities, and ultimately cartilage activity and use of the phosphosugars in accordance
and bone errosion. This animal model has with the present invention is demonstrated in the
been extensively used for detection of following Example.
anti-inflammatory and immunosuppressive drugs.
Finally, phosphosugars have been
found to be effective as an
immunosuppresant in preliminary
experiments, particularly in controlling
the delayed hypersensitivy reaction.
In a first aspect, therefore, the
present invention relates to the use of
phosphosugars and phosphosugar-
containing oligosaccharides and
polysaccharides as anti-inflammatory
3 4
The first data column in the Tables
EXAMPLE 1 refers to the number of animals in each
group which showed any clinical signs of
Inhibition of EAE. EAE during the entire course of the
In this Example, a number of experiment. Thus, although 7/10 animals
phosphosugars and one phospho- 5 treated with mannose-6-phosphate
polysaccharide were tested for their developed some clinical signs of disease
ability to inhibit development of EAE in (Table III) the severity of these disease
rats. (All phosphosugars tested are symptoms was extremely mild compared with
commercially available and were obtained untreated animals, i.e. <10% disease
from Sigma Chemical Co., St. Louis, Mo., 10 severity of controls when clinical scores
U.S.A.). Experimental details are and duration of disease are examined. In
included in the footnotes to the Tables this sense, the mannose-6-phosphate data
setting out the test results. in Tables I and III are almost identical.
Table I presents data from an EAE Similarly, the estimation of disease
experiment in rats where mannose-6- severity can be used to rank the anti-
phosphate, administered to animals via 15 inflammatory activity of phosphosugars
osmotic pumps, totally inhibited which only partially inhibit disease,
development of disease. The data e.g., glucose-6-phosphate and fructose-
presented in Table II demonstrates that 1,6-diphosphate.
a four fold reduction in the mannose-6-
phosphate dose (40 mg/rat/week to 10 20 TABLE I
mg/rat/week) still resulted in a -----------------------------------------------------------
substantial reduction in disease
severity, i.e. the lowest dose of Effect of Mannose-6-Phosphate on Adoptively
phosphosugar reduced disease severity to Transferred EAE
37.7% that of control animals. -------------------------------------------
Analysis of phosphosugar specificity 25 Mean Mean Mean Length
revealed (Table III) that fructose-1- No. With Day Clinical Disease
phosphate was as effective as mannose-6- Treatment EAE/Total Onset Score (days)
phosphate at inhibiting disease. -----------------------------------------------------------
Fructose-6-phosphate was also a
compartively effective inhibitor of EAE, Control 8/8 5.2 3.0 3.5
whereas galactose-6-phosphate, glucose- Mannose-6- 0/8 0 0 0
6-phosphate and fructose-1-6-diphosphate 30 phosphate
were partially inhibitory. Glucose-1- -----------------------------------------------------------
phosphate and D-mannose apparently had
little or no effect on disease Legend to Table 1:
progression. These results are EAE induced in Xxxxx rats with 30 + 106 ConA activated
displayed graphically in FIG. 1. Such EAE effector cells. Miniosomotic pumps containing
phosphosugar specificity closely 35 phosphosugar were implanted subcultaneously on day 3
rsembles the monosaccharide specificity after cell transfer. Dose was 40 mg/rat delivered over
of the mannose-6-phosphate receptors on a 7 day period by 2.0 ml pumps. Clinical EAE was
cells (1). graded according to the following scheme: 0 asymptomanic;
In two separate experiments (Table 1, flaccid distal half of tail; 2, entire tail flaccid;
IV) administration of the D-mannose 3, ataxia, difficulty in righting; 4, hind limb weakness;
polysaccharide (mannan) from SACCHAROMY- 40 and 5, hind limb paralysis.
CES CEREVISIAE, which contains phosphate
moieties, totally inhibited EAE,
indicating that phosphomannans can
inhibit disease.
Histological examination of central
nervous system (CNS) tissue from
untreated animals with EAE and EAE
animals which had been treated with
either mannose-6-phosphate or mannan
containing phosphate moieties, (Table V)
revealed that both treatments
dramatically inhibited development of CNS
lesions. No lesions were detected in
mannose-6-phosphate treated animals and a
small number of lesions, compared with
controls, in mannan treated rats. Such data
are consistent with the view that the
sugars are inhibiting entry of leukocytes into
the CNS.
TABLE II
---------------------------------------------------------------------------------------------------------------------------
Effect of Mannose-6-Phosphate Dose on Adoptively Transferred EAE
----------------------------------------------------------------
No. with Mean Mean Mean Length Disease Severity
Treatment Dose (mg) EAE/total Day Onset Clinical Score Disease ( %Control)
---------------------------------------------------------------------------------------------------------------------------
Control ---- 4/4 4.5 3.5 4.5 100%
Mannose-6-Phosphate 40 1/3 5.0 0.3 0.7 1.7%
Mannose-6-Phosphate 20 4/4 5.0 1.5 3.0 28.6%
Mannose-6-Phosphate 10 4/4 5.0 1.8 3.3 37.7%
---------------------------------------------------------------------------------------------------------------------------
Legend to Table II:
Experimental details as in Table I. Mannose-6-phosphate dose represents amount
of phosphosugar delivered to rats over a 7 day period via mino-osmotic pumps.
"Disease Severity" represents product of mean clinical score and mean length
disease.
5,506,210
5 6
TABLE III
---------------------------------------------------------------------------------------------------------------------------
Phosphosugar Specificity of EAE Inhibition
------------------------------------------
No. with Mean Mean Mean Length Disease Severity
Treatment EAE/Total Day Onset Clinical Score Disease(days) (% Control)
---------------------------------------------------------------------------------------------------------------------------
Control 9/9 5.0 3.6 4.2 100%
Mannose-6-phosphate 7/10 6.0 0.9 1.5 8.9%
Fructose-1-phosphate 3/5 5.5 1.2 1.6 12.6%
Fructose-6-phosphate 4/5 6.0 1.6 2.4 25.4%
Galactose-6-phosphate 5/5 5.2 2.0 3.0 40.5%
Glucose-6-phosphate 5/5 5.4 2.0 3.8 50.3%
Fructose-1,6-diphosphate 5/5 5.4 2.4 3.4 54.0%
Glucose-1-phosphate 5/5 5.2 3.0 3.8 75.5%
D-mannose 5/5 5.2 2.9 4.4 84.5%
---------------------------------------------------------------------------------------------------------------------------
Legend to Table III:
Experimental details as in Table I. "Disease Severity" represents product of
mean clinical score and mean length of disease.
(HANSENULA HOLSTII) as described by
TABLE IV 20 Xxxxxxxxxx et al. (7), that contains
---------------------------------------------------- mannose phosphate residues.
Inhibition of Adoptively Transferred EAE by Yeast The pentasaccharide is an isolated
Mannan monophosphomanno-pentaose fragment, 6-
---------------------------------------------------- phospho-mannose-a(1-3)-{mannose-a-(1-
Mean Mean Mean Length 3)}2-mannose-a-(1-2)-mannose, of the
No. with Day Clinical Disease 25 exocellular phosphomannan produced by
Treatment EAE/Total Onset Score (days) PICHIA HOLSTII (HANSENULA HOLSTII)
---------------------------------------------------- described by Xxxxxxxxxx et al. (7).
Expt. 1 In these experiments, details of which
------- were as in Table I, the number of cells
Control 5/5 4.8 3.5 4.0 transferred was 25x106 /rat, while the
Yeast mannan 0/6 0 0 0 30 dose of compound administered was 10
Expt. 2 mg/rat delivered over a 7 day period by
------- mini-osmotic pumps, commencing on day 3
Control 4/4 5.0 3.1 3.7 after cell transfer. The results are set
Yeast mannan 0/4 0 0 0 out in Table VI.
----------------------------------------------------
Legend to Table IV: 35 TABLE VI
Yeast mannan from SACCHAROMYCES CEREVISIAE (Xxxxx'x --------------------------------------------------
yeast). Experimental details as in Table I. Control PPME Pentasaccharide
--------------------------------------------------
EAE/Total 5/5 3/5 1/5
--------------------------------------------------
40
EXAMPLE 3
Suppression of Passive Adjuvant Arthritis
(DA x Lew)F rats were immunized with
45 M.BUTYRICUM in light mineral oil given in
TABLE V each foot. Ten days later spleens were
--------------------------------------------------- removed and incubated as single cell
Histological analysis of EAE Inhibition in Rats suspension tissue culture medium in +5
Receiving Mannose-6-Phosphate and Mannan ug/xx XxxX for 75 hrs. Cells were
----------------------------------------------- harvested, washed and transferred i.v. at
No. Sections No. Lesions/ 50 65 x 10 6 cells/rat into (DA x Lew)F
Treatment scanned Lesions section recipients.
--------------------------------------------------- Treated rats were implanted on the day
Expt. 1 they received cells with miniosmotic
------- pumps which delivered 6 mg/rat/day of
Control 1 10 110 11.0 mannose-6-phosphate for 14 days. Control
Control 2 8 206 25.7 55 rats were sham operated. The results are
Mannose-6-phosphate 1 18 0 0 shown in Table VII as % of pre-cell
Mannose-6-phosphate 2 15 0 0 injection foot size. {Average for group;
Expt. 2 n=4 (mannose-6-phosphate); n=6
------- (control)}.
Control 1 15 284 19.0 60
Control 2 12 303 25.0 TABLE VII
Yeast mannan 1 18 30 1.1 ------------------------------------------------------
Yeast mannan 2 15 92 6.7
--------------------------------------------------- Day Mannose-6-Phosphate Control
65 ------------------------------------------------------
Legend to Table V: 4 97.3% 106.4%
Rats were killed 9 days after cell transfer and 6 105.8% 129.7%
sections of the lower thoracic-upper lumbar spinal 7 102.8% 149.7%
cord examined for inflammatory lesions. 9 108.4% 148.5%
Animals treated as in Table I. 11 107.6% 184.2%
14 117.4% 220.1%
------------------------------------------------------
EXAMPLE 2 EXAMPLE 4
Inhibition of EAE
In further experiments using the EAE model of Effect on Delayed-Type Hypersensitivity (DTH)
Example 1, other mannose phosphate-containing C57B1 mice were sensitised by i.v. injection 105
compounds were used, including PPME and a pentasac- of washed sheep red blood cells. 5 days later they
charide. were
PPME is the purified high molecular weight,
acid-resistant fragment, (polysaccharide core
fraction) of the isolated exocellular phosphomannan
produced by PICHIA HOLSTII
5,506,210
7 8
challenged in the right hind footpad 3. A method according to claim 2,
with SRBC. Each mouse was given a 0.25 wherein said active agent is mannose-6-
ml injection i/p at the same time of phosphate.
either saline, mannose-6-phosphate or 4. A method according to claim 2,
the 1,2,3,4-tetraacetate of mannose-6- 5 wherein said active agent is fructose-1-
phosphate and all injections were phosphate.
repeated a further 6 times at approx. 5. A method according to claim 2,
31/2 hour intervals. The dose in each wherein said active agent is fructose-6-
injection of mannose-6-phosphate was phosphate.
0.15 mg and of 1,2,3,4-tetraacetate of 10 6. A method according to claim 1,
mannose-6-phosphate was also 0.15 mg. wherein said organic ester is an acetate.
At 24 hours after challenge the DTH 7. A method according to claim 6,
swelling was measured. Mannose-6- wherein said organic ester is the
phosphate reduced the swelling by 52.5%, 1,2,3,4-tetracetate of mannose-6-
and the 1,2,3,4-tetraacetate of mannose- 15 phosphate.
6-phosphate by 91.5%, as compared with 8. A method according to claim 1,
the saline controls. wherein said oligosac-charide or
polysaccharide is the D-mannose
polysaccharide (mannan) from
REFERENCES 20 SACCHAROMYCES CEREVISIAE.
9. A method according to claim 1,
1. vonFigura, K. and Hasilik, A. (1986), wherein said oligosac-charide or
XXX, REV. BIOCHEM. 55; 167. polysaccharide is the purified high
2. West, C.M. (1986). MOL. CELL,BIOCHEM. molecular weight, acid-resistant fragment
72; 3. 25 (polysaccharide core fraction) of the
3. Xxxxxxx, S. and Xxxxxxx, X.X. (1972). exocellular phosphomannan produced by
BIOCHEM. BIOPHYS. RES. COMM. 49: PICHIA HOLSTII (HANSENULA HOLSTII), or an
992. oligosaccharide fragment derived
4. Xxxxx, A. and Xxxxxxxx, S. (1983). therefrom.
J.BIOL. CHEM. 258: 2808. 30 10. A method according to claim 9,
5. Xxxxxxx, H.D., Creek, K. E. and Sly, wherein said oligosac-charide fragment is
W. S. (1982). J. BIOL. CHEM. 257: the monophosphomannopentaose fragment, 6-
9938. phospho-mannose-a(1-3)-{mannose-a(1-3)}2.
6. Xxxxxxx, X. X. and Rome, L. H. mannose-a-(1-2)-mannose.
(1982). ARCH, BIOCHEM. BIOPHYS. 35 11. A method according to claim 1,
214: 681. wherein said treatment comprises
7. Brettbauer, X. X. Xxxxxxxxxxx, X. X. treatment of inflammatory disease of the
and Xxxxx, X. X., central nervous system.
(1973), BIOCHEMISTRY 12(7): 1251. 12. A method according to claim 1,
We claim: 40 wherein said treatment comprises
1. A method of treatment of treatment of arthritis.
arthritis, of inflammatory disease of 13. A method according to claim 1,
the central nervous system, to control wherein said treatment comprises
the delayed type hypersensitivity treatment to control the delayed-type
reaction, or of the inflammatory process 45 hypersensitivity reaction.
associated with rejection of organ 14. A method according to claim 1,
transplants in a warm-blooded animal, wherein said treatment comprises
which comprises administering to the treatment of rheumatoid arthritis.
warm-blooded animal in need thereof a 15. A method according to claim 1,
therapeutically effective amount of at wherein the treatment is of the
least one active agent selected from the inflammatory process associated with the
group consisting of phosphomannoses, rejection of organ transplants.
phosphofructoses and pharmaceutically 16. A method of treating arthritis in
acceptable salts and organic esters an animal subject, which comprises
thereof, oligosaccharides containing administering to the subject a
phosphomannose residues, polysaccharides therapeutically effective amount of
containing phosphomannose residues, and mannose-6-phosphate or a pharmaceutically
pharmaceutically acceptable salts and organic acceptable salt or organic ester thereof.
esters thereof, oligosaccharides containing 17. A method of treating inflammatory
phosphomannose residues, polysaccharides disease of the central nervous system in an
containing phosphomannose residues, and animal subject, which comprises administering
pharmaceutically acceptable salts and to the subject a therapeutically effective
organic esters thereof, said active agent amount of mannose-6-phosphate, fructose-1-
being an antagonist or competitive phosphate, or a pharmaceutically acceptable
inhibitor of the natural ligand of a salt or organic ester thereof.
mannose phosphate receptor.
2. A method according to claim 1,
wherein said active agent is selected from * * * * *
the group consisting of xxxxxxx-0-
xxxxxxxxx, xxxxxxxx-0-xxxxxxxxx, fructose-
6-phosphate, and fructose-1,6-diphosphate.
SCHEDULE "C" - RESEARCH PROJECTS
--------------------------------
APPENDIX C
DEVELOPMENT PROGRAM FOR NEUTRICEUTICAL AND COSMETIC AGENTS.
MAJOR ITEMS
-----------
SCALE-UP
Bulk isolation and purification for "batch" preparations
Time 2 months (+ 2 weeks)
-
a) Along the way to full scale production pilot batches will be QA'd
and combined for immediate use in all tests
b) Target is for 250 g batch sizes
ARTHRITIS TRIALS
Time 6 months
This includes: 1) Ethics Committee approval (application in by 29/1/99)
2) Re-establishing model (active and passive)
3) Delivery and dose-finding studies including
i) Gavage
ii) Drinking water
iii) Food
iv) confirmation by mini-osmotic pump delivery
SKIN TRIALS
Time 6 - 8 months
This includes: 1) Formulation preparations (negotiations now going)
2) Evaluate dermal delivery formulations
3) Establishing a model for quick delivery assessment
4) Establish a wrinkle model and test materials
MILESTONES SCHEDULE
-------------------
0-3 MONTHS
Preparation of batch material for all subsequent testing.
Produce formulations for skin testing
Commence trials in animal models of rheumatoid arthritis
3-6 MONTHS
Test skin formulations for penetration and effect
Complete rheumatoid arthritis animal studies
6-9 MONTHS
Begin skin toxicity studies
File skin cosmetic patent (material and formulation coverage)
9-12 MONTHS
Complete skin toxicity studies
Commence animal wrinkle model studies
12 MONTHS-
Complete wrinkle model studies
BASIS OF PROCEDURES
-------------------
PREPARATION OF BULK MATERIAL
We will require bulk preparations of PM5 for all of our studies, including
formulation for skin delivery and dose-finding studies in both models. We
haven't done bulk preparations. We anticipate some minor teething problems but
nothing insurmountable in the immediate term. We will get some idea of batch to
batch variability as we scale up. Because of equipment limitations we plan to
standardise on 250 g preps. The biggest batch we have ever prepared is 5 g.
Meanwhile we are running several smaller scale preps per week. We will have this
sorted within 6 to 8 weeks.
ARTHRITIS
We have run the arthritis model previously, indeed this earlier work forms a
crucial part of the original patent. We can run both the active and passive
forms of the disease. The advantages of the passively-transferred arthritis
include consistency of disease between individual animals (and between groups)
and the ability to control the severity of the disease (through the number of
cells transferred). The disadvantages include the additional work load and time
involved and the increased numbers of animals required. So, obviously, the
advantages of the active form are the reverse and include reduced effort and
time, as well as fewer animal numbers required. The attendant disadvantages of
active arthritis are having very little control over the disease severity and
therefore variations both within and between groups. The other major advantage
from the therapeutic point is that the passive form of the disease is more like
the real clinical situation, ie the only time patients present is when they have
symptoms (in other words after the disease is established). So, the human
clinical situation is that only the efferent (clinical disease) is treated, not
the afferent or induction phase of arthritis. The bottom line is that we will
run both to start with and make an early decision regarding dose-finding studies
etc. We will know whether or not this is going to be a "goer" within 6 months.
SKIN TRIALS
In the first instance we need to have a delivery method. We have started
negotiations with Soltec Ltd. for preparing various formulations. We also have a
verbal agreement with Lipoderm in Canada to do formulations for us. We intend to
do some very preliminary studies with these formulations (such as dose it go in
and come out of the vehicle intact etc) and as quickly as possible put labelled
material into those showing promise in order to measure skin penetration.
Preliminary tolerance and dose-finding studies will be carried out as soon as we
have the material formulated. It will most likely xxxx 0 months to get to this
stage.
Further testing will require animal models and (believe it or not) there is a
"wrinkly mouse" model available. This, of course, is a bit further down the road
but we will be planning to set this up while the other work is going. In the
mean time we will also try a few other simple approaches by looking at a simple
model of fibroblast migration in skin, probably by direct injection in the
immediate term but topical as soon as we have formulated material. This work
will be running in parallel with the kinetic topical formulation work.
SCHEDULE "D" - ANUTECH LICENCE AND
----------------------------------
RESEARCH & DEVELOPMENT AGREEMENT
--------------------------------
PRAXIS Pharmaceuticals Inc.
and
ANUTECH Pty. Ltd.
----------------------------------
LICENCE
and
RESEARCH & DEVELOPMENT
AGREEMENT
----------------------------------
Corporate Centre
ANUTECH Pty. Ltd.
ANUTECH Court
Xxx Xxxxx Xxxxx xxx Xxxxx Xxxx
Xxxxx, XXX 0000
Xxxxxxxxx
Tel: (00) 0000 0000
Fax: (00) 0000 0000
THIS AGREEMENT is made on the 27th day of October 1997
BETWEEN:
ANUTECH PTY LTD, ACN 008 548 650 with its registered office at
ANUTECH Court, Cnr Xxxxx Drive and Xxxxx Road, Acton, Australian
Xxxxxxx Xxxxxxxxx, Xxxxxxxxx 0000 ("ANUTECH").
And: Praxis Pharmaceuticals Inc., a company incorporated in Nevada with
its registered office at 1 East First Street, Reno, Nevada, USA
("Praxis").
RECITALS:
A. Praxis was incorporated on 20 June 1997 with the intention that it
raise capital, acquire intellectual property and research, develop and
commercialise pharmaceuticals.
B. ANUTECH is the commercial agent of the Australian National University
("ANU"), and enters into this Agreement as agent for and on behalf of
ANU.
C. ANU possesses intellectual property in the area of phosphosugars and
their analogues as anti-inflammatory agents.
D. Praxis wishes to license the ANU intellectual property in order to
undertake further research and development and commercialisation of the
intellectual property.
E. In accordance with the terms and conditions set forth in this
agreement, ANUTECH is willing to grant such a licence to Praxis with
its term dependant on Praxis achieving certain capital raising,
research and commercialisation milestones. ANUTECH will also undertake
a program of research and development on behalf of Praxis.
IT IS AGREED AS FOLLOWS:
1. DEFINITIONS AND INTERPRETATION
---------------------------------------
1.1 In this Agreement, unless there is something inconsistent with the
context, the following terms and expressions shall have the following
meanings:
"Agreement" means this agreement.
"ANU Intellectual Property" means the following intellectual property
owned by the ANU:
(a) Know-how and expertise in relation to phosphosugars and their
anti-inflammatory activity; and
(b) the patents and patent applications set out in Schedule 1,
including all divisions, continuations, continuations-in-part,
renewals, extensions and additions thereof.
"Commencement Date" means the 27th day of October 1997.
"Confidential Information" means any information whether written, oral,
electronic or in any other form which is disclosed by a party or its
representatives, is claimed as confidential to itself and which relates
to the ANU Intellectual Property, Research, Results, Products,
Agreement and business of the parties. It includes all copies and notes
generated from the disclosure but does not include information which:
(a) is in the public domain at the time of disclosure;
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
(b) becomes a part of the public domain after disclosure, otherwise
than as a result of any unauthorised activity and/or omission on
the part of the recipient;
(c) the recipient can prove is already in its own possession at the
time of disclosure and which was not acquired from the other party
directly or indirectly;
(d) is rightfully acquired from a third party who did not obtain it
under an obligation of confidentiality; or
(e) is legally required to be disclosed - the party required to make
disclosure shall notify the other to allow that party to assert
whatever exclusions available to it under such law.
"DOLLAR", "DOLLAR" or "$" means Australian dollars unless otherwise
indicated.
"FIELD" means the use of phosphosugars for treatment of:
(a) inflammatory skin conditions;
(b) inflammation resulting from abdominal/pelvic surgery; and
(c) ocular inflammation;
and expressly excludes:
(d) topical application for wound care; and
(e) use of fructose-1,6-diphosphate, administered non-topically, for
the treatment or prophylaxis of ischaemic disorders in humans,
which includes transplantation and immunosuppression.
"INTELLECTUAL PROPERTY" shall mean all or any of the following:
(a) Trade Marks: means any trade xxxx or trade name whether registered
or not under, or by reference to which, a Product or service is
known;
(b) Patents: meaning any patents or patent applications including all
divisions, continuations, renewals, extensions and patents of
addition thereof which have been or are in the future filed and
granted as a patent;
(c) Copyright subsisting in any form or manner whether written or
stored in any form (whether visible or not) including without
limitation brochures, design logos, insignia, computer programs,
software, firmware and hardware;
(d) Designs (whether or not registered);
(e) Know-How: meaning the unpatented, technical information,
processes, formulae, technical and technological documentation,
reports, computer programs, biological materials, procedures or
methods, all current and accumulated knowledge, skills and
experience;
"NET SALES" means:
(a) for an arms length sale of any Product means the gross amount
invoiced by Praxis, its subsidiaries, joint venturers, licensees
or agents less the following:
(i) transport and insurance related charges actually allowed and
taken;
(ii) trade, quantity or cash discounts or rebates actually
allowed and taken;
(iii)credits or allowances given or made on account of price
adjustments, recalls or destruction requested or made by an
appropriate government agency; and
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
(iv) any tax (excluding income tax), excise or other government
charge upon or measured by the sale, transportation, delivery
or use of the Product included in such amount which is
actually incurred.
(b) for a non-arms length sale, means the most recent Net Sales at
which Praxis, its subsidiaries, joint venturers licensees or
agents has sold similar quantities of Products in an arms length
sale.
"PRODUCTS" means any matter, article or thing which incorporates or
arises from the whole or partial use of ANU Intellectual Property or
Results.
"QUARTER" means each consecutive 3 month period that ends on 31 March,
30 June, 30 September and 31 December each year.
"RESEARCH BUDGET" means the budget as set out in Schedule 2 and amended
by the Research Management Committee from time to time pursuant to
clause 9 (Research Management Committee).
"RESEARCH LEADER" means Xx. Xxxxxxx X. Xxxxxx or such other person or
persons as may be nominated by ANUTECH and agreed by Praxis .
"RESEARCH" means the objectives and program of research described in
Schedule 3 and undertaken on behalf Praxis by ANUTECH or ANU pursuant
to clause 7 (The Research).
"RESULTS" means all Intellectual Property, materials (including
substances, compounds, biological material, products, samples and
devices) and information (including trade secrets, processes,
techniques, designs, plans, data, test results, findings, evaluations
and reports) generated as a result of or in connection with the
Research
"SUBLICENSE FEES" means all payments to Praxis in consideration for
rights to the ANU Intellectual Property, Results and Products pursuant
to a sublicence, assignment, joint venture, strategic alliance or other
arrangement.
Sublicence Fees shall not include:
(a) fees for research and development undertaken by ANU including for
example preclinical research and clinical studies; nor
(b) the royalty percentage above that is required to be paid by Praxis
pursuant to clause 3 (License Consideration).
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
1.2 In this Agreement unless the contrary intention appears:
(a) a reference to a clause, schedule, attachment, annexure or
appendix is a reference to a clause of or schedule, attachment,
annexure or appendix to this Agreement and references to this
Agreement include any recital, schedule annexure, attachment, or
appendix;
(b) a reference to this Agreement or another instrument includes any
variation or replacement of either of them;
(c) a reference to a statute, ordinance, code or other law includes
regulations and other instruments under it and consolidations,
amendments, re-enactments or replacements of any of them;
(d) the singular includes the plural and vice versa;
(e) if a period of time is specified and dates from a given day or the
day of an act or event, it is to be calculated exclusive of that
day;
(f) if an event must occur on a stipulated day which is not a business
day, then the stipulated day will be taken to be the next business
day;
(g) headings are inserted for convenience and do not affect the
interpretation of this Agreement;
(h) words importing any one gender shall mean and include masculine,
feminine and/or neuter where appropriate;
(i) words importing natural persons shall (where appropriate) mean and
include corporations and unincorporated associations and vice
versa;
(j) schedules and attachments form part of and are incorporated in
this Agreement.
1.3 For the avoidance of doubt the recitals to this Agreement shall form
part of this Agreement and in the event of any inconsistency between
the recitals and the other provisions of this Agreement the other
provisions of this Agreement shall prevail.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
2. GRANT OF LICENCE
-------------------------
2.1 ANUTECH grants to Praxis an exclusive, worldwide licence to use and
exploit ANU Intellectual Property and Results within the Field,
including the right to sublicense pursuant to clause 6 (Right to
Sublicense).
3. LICENCE CONSIDERATION
------------------------------
3.1 In consideration for the grant of the licence Praxis will pay to
ANUTECH:
(i) a 10% royalty on Net Sales of Products by Praxis;
(ii) 50% of all royalty income on Net Sales of Products received from
sublicensees;
(iii) 15% of all Sublicence Fees.
4. LICENCE TERM
---------------------
4.1 The term of the Licence commences upon the Commencement Date until the
expiration of the last to expire of the patents covered by this
agreement, unless otherwise earlier terminated pursuant to clause 5
(Performance of Praxis) or clause 20 (Termination) or extended by the
written agreement of the parties.
5. PERFORMANCE OF PRAXIS
------------------------------
5.1 If Praxis fails to comply with the following performance milestones,
ANUTECH has at its election the right to terminate this Agreement in
accordance with clause 20 (Termination).
5.2 Capital raising milestones:
(a) On or before 31 July 1998, Praxis shall raise capital of at least
$700,000 for use under this Agreement.
(b) On or before 31 July 1999, Praxis shall raise capital of at least
an additional $1,000,000 for use under this Agreement.
5.3 Research milestones
Pursuant to the Research Milestones as set out in Schedule 3 Praxis
shall:
(a) achieve the Aims within the Start and Finish dates; and
(b) ensure that sufficient research funds are made available to
undertake the Research.
5.4 Commercialisation milestones
Praxis shall use best efforts to commercialise the ANU Intellectual
Property and Results by undertaking an ongoing and active research,
developmental, manufacturing, marketing, licensing or capital raising
program, as appropriate, directed toward the exploitation of the ANU
Intellectual Property and Results within the Field.
Part of these best efforts includes Praxis providing to ANUTECH as soon
as practicable a business plan (and any updates thereafter) which
addresses Praxis's capacities, objectives and strategies for such a
commercialisation program.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
Praxis shall also provide ANUTECH with an annual written report (on the
anniversary of the Commencement Date) on its progress towards achieving
these commercialisation milestones.
6. RIGHT TO SUBLICENSE
----------------------------
ANUTECH grants to Praxis the right to sublicence ANU Intellectual
Property and Results within the Field, subject to:
(a) the prior written approval of ANUTECH which shall not be
unreasonably withheld;
(b) the sublicensee being bound to similar terms as contained in this
Agreement; and
(c) the royalty and Sublicence Fee stream provided for in clause 3
(Licence Consideration) are reserved.
7. THE RESEARCH
---------------------
7.1 ANUTECH shall procure that researchers from the ANU or where else
required, shall carry out Research on behalf of Praxis in accordance
with the terms of this Agreement and pursuant to the general outline of
the Research Milestones.
7.2 Praxis and ANUTECH wish to retain flexibility in relation to the
Research. The scope, priority and emphasis of the Research may be
changed, altered or added to from time to time by written agreement of
the Research Management Committee.
7.3 Research shall commence on 1 November 1997 and continue until at least
December 2000, whereupon the parties will negotiate in good faith for
its continuation or completion.
7.4 Throughout the Research, the Research Leader, will be responsible for
the conduct, general management, and supervision of the Research.
Through the Research Leader, ANUTECH will ensure there is a high and
consistent level of communication and cooperation between and among all
personnel engaged in the Research, and that the Research is conducted
in a diligent professional manner commensurate with high scientific
standards and practices and in accordance with all applicable statutory
and other legal requirements as well as all relevant good laboratory
practices.
7.5 ANUTECH shall ensure that the Research Leader and any personnel engaged
in the Research enter into appropriate confidentiality agreements in a
form consistent with the confidentiality obligations under this
Agreement.
7.7 ANUTECH shall prepare and submit to the Research Management Committee
written reports at quarterly intervals throughout the Research, or at
such other intervals as may be agreed. The reports shall set out in
reasonable and informative detail, particulars of the research
undertaken during the period, accomplishments and inventions (if any),
difficulties encountered (if any) and possible future directions for
the Research. ANUTECH and the Research Project Leader may provide
informal reports of any progress, difficulties encountered or
inventions to Praxis as they occur during the term of the Agreement.
7.6 ANUTECH and the research team are independent contractors and are not
employees, agents, officers or partners of Praxis. The parties
acknowledge that Xx Xxxx Xxxxxx and Xx Xxxxx Xxxxxxxx are part of the
research team as well as shareholders and officers of Praxis therefore
the parties will ensure that any conflicts of interest are managed
appropriately.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
8. PAYMENT OF RESEARCH FUNDS
----------------------------------
8.1 In consideration of ANUTECH's conduct of the Research, Praxis will pay
ANUTECH quarterly in advance and in accordance with the initial
Research Budget in Schedule 2.
8.2 Subsequent Research Budgets shall be determined on an annual basis by
the Research Management Committee. Such budgets shall include funds for
at least the following:
(a) salaries and salary related expenses for research team and
consultants;
(b) salary increments;
(c) consumables, equipment, sundry items and animals; and
(d) administrative and overhead costs for the ANU and ANUTECH.
8.3 ANUTECH shall ensure that funds paid by Praxis pursuant to this
Agreement are only used and applied in accordance with that which is
contemplated by this Agreement.
8.4 ANUTECH shall maintain accounts of all income and expenditure in
relation to the Research according to standard accounting principles.
ANUTECH shall provide to Praxis on a quarterly basis, financial
statements on income, commitments and expenditure.
9. RESEARCH MANAGEMENT COMMITTEE
--------------------------------------
9.1 A Research Management Committee shall be established:
(a) it shall comprise one representative nominated by each party and
such other persons as may be nominated and agreed to by the
parties from time to time for the purpose of providing expertise
to the committee;
(b) be chaired by the person nominated by ANUTECH; and
(c) meet quarterly or at such other intervals as agreed by all members
of the committee, either in person at such location(s) as are
agreed and/or via telephone conference;
9.2 The functions of the Research Management Committee will be to:
(a) monitor and discuss the progress of the Research and if necessary,
to determine amendments to the Research direction;
(b) review and determine the annual Research Budgets;
(c) review any issues of disclosure of Confidential Information and
publications;
(d) discuss generally any patent applications, patents and new
inventions; and
(e) consider and manage any conflicts of interest.
9.3 The decisions of the Research Management Committee shall be binding on
the parties.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
10. OWNERSHIP
------------------
10.1 The following shall be owned by the ANU and licensed to Praxis pursuant
to the terms of this Agreement:
(a) Results;
(b) improvements to ANU Intellectual Property ; and
(c) new patents and patent applications arising from the Research,
Results and use of ANU Intellectual Property.
10.2 ANU shall have a non-determinable right to use the Results but only for
its own on-going internal research.
11. PROTECTION OF PATENTS
------------------------------
11.1 With respect to the existing ANU Intellectual Property patents and
patent applications:
(a) the parties shall cooperate in the prosecution and maintenance of
the patents and patent applications with the relevant patent
offices;
(b) from the Commencement Date, one third of any past and future costs
and expenses incurred in their filing, maintenance and renewal
shall be borne by Praxis;
(c) Praxis may select the countries in which patent applications are
to be filed in the name of the ANU; and
(d) if Praxis decides not to request patent protection for an
invention in any country, ANU may file or maintain at its own cost
patent applications which Praxis has declined to file or maintain,
and such patent applications or granted patents shall lie outside
the provision of this Agreement.
11.2 With respect to any new patentable inventions arising from the Research
and use of ANU Intellectual Property:
(a) Praxis may request ANUTECH to file and prosecute a patent
application, in ANU's name, for the invention or agree to treat
the invention as a trade secret;
(b) the parties shall cooperate in the prosecution and maintenance of
the patents and patent applications with the relevant patent
offices;
(c) all costs and expenses incurred in filing, maintaining and
renewing the patents and patent applications shall be borne by
Praxis;
(d) Praxis may select the countries in which patent applications are
to be filed in the name of the ANU; and
(e) if Praxis decides not to request patent protection for an
invention in any country, ANU may file or maintain at its own cost
patent applications which Praxis has declined to file or maintain,
and such patent applications or granted patents shall lie outside
the provision of this Agreement.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
12. INFRINGEMENT AND ENFORCEMENT OF PATENTS
----------------------------------------------
12.1 Infringement
In the event of any patent, the subject of this Agreement, being
infringed Praxis may at its own cost and in its own name litigate such
infringement and may settle or compromise such litigation in such a
manner as Praxis shall determine provided that Praxis shall consult
with ANUTECH in good faith in relation to those proceedings.
12.2 Enforcement
In the event that litigation is taken or threatened by a third party
against any rights associated with any patents the subject of this
Agreement, the parties shall consult in good faith and use their best
endeavours mutually to determine the manner in which these proceedings
are to be defended or resisted and to act accordingly provided always
that the parties shall first seek the opinion of counsel experienced in
such matters.
12.3 Praxis shall be entitled to retain any recovery from the litigation or
settlement. Praxis shall pay to ANUTECH a royalty pursuant to clause
3.1 (iii) to the extent that such recovery by Praxis exceeds its
expenses.
12.4 In any litigation, ANUTECH shall cooperate with Praxis in making
available all relevant records, papers, information and the like which
may be relevant and in its possession.
12.5 Nothing herein shall preclude ANUTECH from defending or pursuing any
such actions.
13. REPORTS, PAYMENTS AND ACCOUNTING
-----------------------------------------
13.1 Within 30 days after the first day of January, April, July and October
of each year, Praxis shall provide to ANUTECH a true and accurate
royalty report. This royalty report will cover payments due under
clause 3 (Licence Consideration) and specify:
(a) the total quantity of Products sold or provided by it and by its
sublicensees;
(b) the Net Sales price at which the Products were sold or provided;
(c) the calculation of the royalty due;
(d) the total royalties so calculated and due to ANUTECH; and
(e) the amount of Sublicence Fees and the royalty due.
13.2 For the term of this Agreement and simultaneous with the delivery of
each such royalty report, Praxis shall pay to ANUTECH the royalty and
any other payments due under this Agreement for the period covered by
such report.
Praxis shall be responsible for all payments that are due to ANUTECH
but have not been paid by Praxis's sublicensees to Praxis.
13.3 All payments hereunder by Praxis shall be payable in Australian
Dollars.
13.4 During the term of this Agreement, Praxis shall keep complete and
accurate records of its and its sublicensees sales of Products and
Sublicence Fees in sufficient detail to enable compliance with its
obligations under this Agreement to be verified.
13.5 Praxis shall permit ANUTECH or its representatives, at ANUTECH's
expense, to periodically examine its books, ledgers and records during
business hours and with
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
48 hours notice for the purpose of and to the extent necessary to
ensure that Praxis has complied, and is complying, with its obligations
under this Agreement.
13.6 In the event that the difference between the amount of royalty due and
the amount of royalty actually paid exceeds 5% then Praxis shall pay
the amount of the underpayment plus the cost of such examination.
13.7 If Praxis fails to pay ANUTECH an amount due under this Agreement,
Praxis shall upon notification pay to ANUTECH the amount owing together
with interest, such interest to be at the rate applicable to overdrafts
charged by the Commonwealth Bank of Australia at the date of payment,
calculated daily from the due date or the date the shortfall in payment
was effective, as the case may be. The payment of such interest shall
not preclude ANUTECH from exercising any other rights it may have
because any payment is overdue.
14. CONFIDENTIALITY
14.1 The parties acknowledge that the Confidential Information is valuable
to the party in question and each party undertakes to keep the
Confidential Information secret and to protect and preserve the
confidential nature and secrecy of the Confidential Information.
14.2. The recipient of Confidential Information must:
(a) keep it confidential;
(b) use it only for the purposes of the Agreement;
(c) not disclose it to any person other than:
(i) to those of the recipient's employees or legal advisers who
have a need to know and who have first been directed and
have undertaken orally or in writing to keep it
confidential; or
(ii) to other people, such as contractors, visitors and agents
who have a need to know and who have agreed in writing to
keep it confidential in accordance with this Agreement
(d) not copy it or any part of it other than as strictly necessary for
the purposes of this Agreement and must xxxx any such copy
"Confidential";
(e) promptly comply with any request by the discloser to return or
destroy any or all copies of Confidential Information; and
(f) implement security practices against any unauthorised copying, use
or disclosure of the Confidential Information.
14.3 Each party shall take:
(a) reasonable efforts to ensure that any person who has access to
Confidential Information does not make any unauthorised use,
reproduction or disclosure of that information; and
(b) reasonable steps to enforce the confidentiality obligations
imposed or required to be imposed by this agreement, including
diligently prosecuting at its cost any breach or threatened breach
of such confidentiality obligations by a person to whom it has
disclosed Confidential Information and, where appropriate, making
applications for interim or interlocutory relief.
14.4 The provisions of this clause 14 shall continue to have effect for a
period of four (4) years after termination or expiry of this Agreement.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
14.5. Upon the termination or expiry of this agreement the recipient of
Confidential Information shall deliver (or with the discloser's prior
consent, destroy or erase) to the discloser all material forms of
Confidential Information in its or its representatives possession,
power or control. The return of Confidential Information under this
clause does not release either party or their representatives from
their confidentiality obligations under this clause.
15. PUBLICATION
--------------------
15.1 If ANUTECH or its employees or agents wish to publish or otherwise
disclose any information contained in the ANU Intellectual Property or
Results, other than in accordance with clause 14 (Confidentiality),
including by way of written disclosure or any oral disclosure at any
seminar, lecture or other meeting ("Publication"), the following
procedures shall be observed:
(a) ANUTECH shall submit the Publication to Praxis 30 days prior to
disclosure;
(b) within the 30 day period Praxis will consider whether to agree to
the Publication and shall advise ANUTECH what part (if any) of the
information it does not wish published;
(c) if Praxis does not advise ANUTECH within the 30 day period that it
objects to the Publication it shall be deemed to have consented to
the Publication;
(d) if Praxis does advise ANUTECH of its objection then the
information in question will not be published:
(i) until the date upon which the complete Australian
specification in relation thereto becomes open to public
inspection at the Australian Patents Office; and
(ii)inthe case of information which is not patentable or which
it is not proposed to patent, for so long as further
confidential research or development work or potential or
actual commercial exploitation is being actively pursued
in relation thereto but in any case not to exceed 2 years;
(e) where appropriate, ANUTECH will make proper acknowledgment of
Praxis.
16. USE OF NAME
--------------------
16.1 Any proposed use of a party's name by the other in any published
material (including prospectus information) must be approved by the
other party in writing prior to release of that published material.
17. INDEMNITY AND INSURANCE
--------------------------------
17.1 Praxis hereby agrees to defend, indemnify and hold harmless ANUTECH,
ANU and their employees from and against any and all demands, claims,
liabilities, damages, costs and expenses which may be brought against
or incurred by ANUTECH, ANU and their employees as a result of the use
to which Praxis or its sublicensees make of the ANU Intellectual
Property, Results and Products the subject of the licence granted in
this Agreement, other than to the extent (if any) that the same are
caused solely by the gross negligence of ANUTECH, ANU or of any of
their employees.
The indemnity above shall also apply to actions that may arise out of
the capital raising that Praxis undertakes for the purposes of this
Agreement.
17.2 From the date that any Product arising out of the ANU Intellectual
Property is first applied for therapeutic human use (and for the term
or foreseeable term of the human
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
use) Praxis undertakes to hold product liability insurance to the value
of at least $100,000,000.00
17.3 Praxis shall at all times maintain in full force and effect general
liability insurance with limits of not less than $10,000,000.00.
17.4 Such policies shall name ANUTECH and the ANU as additional insureds and
shall be purchased from a reputable insurer. Certificates evidencing
the coverage shall be provided to ANUTECH.
18. WARRANTIES
18.1 Right to enter Agreement
Each Party hereby warrants to the other that it has the full right,
power, authority and liberty to enter into this Agreement and to
perform all of its respective duties and obligations hereunder. Each
party warrants to the other that it is not under any other duty or
obligation which is contrary to or inconsistent with any of its duties
and obligations hereunder.
18.2 No contrary agreements
Each party hereby warrants to the other that it will not enter into any
agreement, arrangement or understanding with any third party which is
contrary to or inconsistent with any of that party's rights, duties and
obligations under this Agreement.
18.3 Status of ANUTECH
ANUTECH warrants and covenants that it enters into this Agreement as
agent for and on behalf of ANU having full power and authority so to
do, and with the express consent of ANU, to the intent that each and
every of the warranties, covenants, terms and conditions of this
Agreement are given by and bind both ANUTECH in its own right and ANU.
18.4 Due diligence
Praxis warrants that it has undertaken a due diligence examination of
the ANU Intellectual Property licensed in this agreement and warrants
that it satisfied itself as to ANU's rights to and the validity of the
ANU Intellectual Ptoperty, in particular the patents and patent
applications set out in Schedule 1.
18.5 ANU Intellectual Property
To the best of its knowledge ANUTECH warrants and covenants that in
respect of ANU Intellectual Property either:
(a) ANU is the sole legal and beneficial owner; or
(b) ANU has such rights to the ANU Intellectual Property, as will
enable ANUTECH to perform its obligations under this Agreement.
ANUTECH makes no warranty as to whether the US Patent 5520926 (and
corresponding international patents or applications) in the name of
British Technology Group Limited infringes the ANU Intellectual
Property.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
18.5 Results achieving purpose
ANUTECH makes no representations or warranties as to the accuracy or
completeness of the Results generated by ANUTECH, or their capability
to achieve a particular purpose.
18.5 Fundamental Terms
Each party acknowledges that the warranties contained in this clause 18
(Warranties) are fundamental terms of this Agreement.
19. ASSIGNMENT, TRANSFER
19.1 This Agreement may not be assigned or otherwise transferred by Praxis
without the prior written consent of ANUTECH. An assignment is deemed
to include a change in greater than 50% beneficial ownership of shares
in Praxis with the exception of such a change in share holding in
Praxis through capital raising.
19.2 Any permitted assignee shall assume all obligations of its assignor
under this Agreement.
19.3 No assignment shall relieve Praxis of responsibility for the
performance of any accrued obligation(s) which Praxis then has
hereunder.
20. TERMINATION
20.1 A party may terminate this Agreement upon 30 days written notice to the
other party on the occurrence of any of the following by the other
party:
(a) upon or after the bankruptcy, insolvency, dissolution or winding
up of such party (other than dissolution or winding up for the
purposes of reconstruction or amalgamation); or
(b) the failure of such party to comply with its obligations under
this agreement, if such default is not cured (if capable of being
cured) within 30 days of the party not in default giving notice of
the default; or
(c) if the representations and warranties made under this Agreement
prove inaccurate or false in any material respect.
20.2 Without limiting clause 20.1 (b), ANUTECH may terminate this Agreement
upon 30 days written notice to Praxis in the event Praxis:
(a) fails to make any payment which is due and payable pursuant to
this Agreement and such payment remains unpaid for more than
30 days; or
(b) fails to achieve any of the performance milestones in accordance
with clause 5 and such default is not cured (if capable of being
cured) within 30 days of ANUTECH giving notice of the default.
20.3 The provisions of this clause 20 and clauses 14 (Confidentiality), 17
(Indemnity and Insurance), 13 (Reports, Payments and Accounting) 21.12
(Governing Law), and 21.9 (Dispute Resolution) shall continue in full
force and effect notwithstanding the termination, any alterations or
additions to the other provisions of this Agreement.
20.4 Upon termination of this Agreement and except as otherwise expressly
provided:
(a) any rights or obligations of a party which may have arisen or
accrued prior to termination shall not be affected;
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
(b) all licences granted to Praxis under the terms of this Agreement
shall terminate and Praxis shall cease its exploitation of the
relevant intellectual property other than provided for in clause
20.4 (e);
(c) ANUTECH's Research on behalf of Praxis shall terminate;
(d) Praxis shall promptly pay to ANUTECH any amounts due under the
terms of this Agreement including royalties and Sublicence Fees
which have accrued as of the date of termination;
(e) Praxis may sell all inventory of the Product that it may have on
hand at the date of termination provided that it pays royalties as
provided in this Agreement.
20.5 If any party terminates the Agreement and sublicensees are not then in
default under the terms of their sublicence agreements hereunder,
ANUTECH shall have the right (but not the obligation) to assume and
continue sublicence agreements with payments thereunder being made by
the sublicensees directly to ANUTECH without any further obligations on
the part of Praxis with respect thereto.
20.6 Waiver by either party of any breach (or a succession of breaches) of
any one or more of the provisions of this Agreement shall not deprive
such party of any right to terminate this Agreement pursuant to the
terms of this clause 20 upon the occasion of any subsequent breach.
21. MISCELLANEOUS PROVISIONS
21.1 Binding obligations
The duties and obligations imposed and the benefits conferred by this
Agreement are to be binding upon and to enure to the parties and to
their respective successors and permitted assigns.
21.2 Other instruments
Each party shall prepare and execute such other instruments and
documents and do such other acts and things as may be necessary or
desirable to ensure each party has such rights and interest as are
contemplated for it by this Agreement or as may be necessary or
desirable to give full effect to the provisions of this Agreement.
21.3 Whole Agreement
This Agreement combines the whole understanding of the Parties relating
to its subject matter and it supersedes and cancels any and all
agreements, understandings or commitments made by the same Parties with
respect to the same subject matter. Any purported representations,
warranties or other promises of the Parties not recorded in it are of
no effect.
21.4 Amendment
The variation or waiver of a provision of this Agreement or a Party's
consent to a departure from a provision by another Party, will be
ineffective unless in writing executed by the Parties. The requirements
concerning variation or waiver apply to this clause itself.
21.5 No waiver
No waiver by either party of any breach (or a succession of breaches)
of any one or more of the provisions of this Agreement by the other
party shall be deemed to be a waiver of any subsequent breach of the
same or any other provision.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
21.6 Illegality
If any provision of this Agreement shall be construed so as to be
illegal or invalid the legality or the validity of any other provision
shall not be affected thereby. Any legal or invalid provisions shall be
severable and all other provisions shall remain in full force and
effect.
21.7 Notices
A party notifying or giving notice under this Agreement must notify
(a) in writing;
(b) addressed to the address of the recipients specified below or as
altered by notice given in accordance with this clause; and
(c) delivered by hand, facsimile, registered mail or post.
A notice shall be deemed received:
(a) if hand delivered on the date of delivery
(b) if sent by facsimile on generation of an acknowledgment that the
transmission has been successfully completed,
(c) if sent by registered mail on acknowledgment of receipt by or on
behalf of the recipient
(d) if dispatched by post, after 5 days including day of posting.
If a notice is received on a day other than a business day or after
4.30 pm on a business day, then it is deemed received on the next
business day.
Notice addresses
ANUTECH Pty Ltd Praxis Pharmaceuticals Inc.
GPO Xxx 0 00 Xxxxxx Xxxxxxx
XXXXXXXX XXX 0000 Xxxxxxxx XXX 0000
or and
ANUTECH Court c/o Corporate Trust Company of
Cnr. Xxxxx Drive and Xxxxx Road Nevada
ACTON nACT 2601 0 Xxxx Xxxxx Xxxxxx, Xxxx, Xxxxxx
00000, XXX
Facsimile: 02 6257 1433
21.8 Force Majeure
No party shall be responsible or liable to any other party for, nor
shall this Agreement be terminated as a result of any party's failure
to perform any of its obligations hereunder, with the exception of
payment of monies due and owing, if such failure results from
circumstances beyond the control of such party, including, without
limitation, requisition by any government authority or the effect of
any statute, ordinance or governmental order or regulations, wars,
strikes, lockouts, riots, epidemic disease, act of god, civil
commotion, fire, earthquake, storm, failure of public utilities, common
carriers or suppliers, or any other circumstances, whether or not
similar to the above causes. The parties shall use reasonable efforts
to avoid or remove any such causes and shall resume performance under
this Agreement as soon as feasible whenever such cause is removed;
provided however that the foregoing shall not be construed to require a
party to settle any labour dispute or to commence, continue or settle
any litigation.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
If after six months the force majeure continues, the Parties must meet
in good faith to discuss the situation and endeavour to achieve a
mutually satisfactory resolution of the problem.
21.9 Dispute resolution
If a dispute arises between the Parties out of or relating to this
Agreement (the "Dispute"), any Party seeking to resolve the Dispute
must do so strictly in accordance with the provisions of this clause.
Compliance with this clause is a condition precedent to seeking relief
in any court or tribunal in respect of the Dispute.
A Party seeking to resolve the Dispute must notify the existence and
nature of the Dispute to the other Party ("the Notification"). Upon
receipt of a Notification the Parties must refer resolution of the
Dispute to their respective chief executive officers or their nominees.
If the Dispute has not been resolved within thirty (30) days of receipt
of the Notification then any Party may refer the Dispute to the
Australian Commercial Dispute Centre Limited ("ACDC") for mediation.
The parties must negotiate in good faith, and in accordance with the
Conciliation Rules of ACDC, to resolve the Dispute.
If the Dispute has not been resolved within sixty (60) days of referral
to ACDC either Party is free to initiate proceedings in a court.
21.10 Stamp Duty
All stamp duty levied upon this agreement shall be paid by Praxis.
21.11 Costs
Each Party agrees to bear its own legal and other costs and expenses in
connection with the preparation and execution of this Agreement and of
other related documentation.
21.12 Governing law
This Agreement shall be construed in accordance with and governed by
the laws of the Australian Capital Territory, Australia, and the
parties hereby submit themselves to the jurisdiction of the courts in
and of that Territory.
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
IN WITNESS: this Agreement shall be duly executed and shall commence
from the Commencement Date:-
The COMMON SEAL of )
PRAXIS PHARMACEUTICALS INC. )
was hereunto affixed in accordance )
with its Articles of Association ) /s/ Xxxxx Xxxxxxxx
--------------------------
(Name) - (Position)
In the presence of :
/s/ X.X. Xxxxxx
---------------------------------
Signature
X.X. Xxxxxx
---------------------------------
Name
The COMMON SEAL of )
ANUTECH PTY LLD )
was hereunto affixed in accordance )
with its Articles of Association ) /s/ Xxxx Xxxx
----------------------------
Xxxx Xxxx - Managing Director
In the presence of :
/s/ X. X. Xxxx
---------------------------------
Signature
X.X. Xxxx, Secretary, Anutach Pty. Ltd.
---------------------------------------
Name
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
SCHEDULE 1
ANU INTELLECTUAL PROPERTY
PHOSPHOSUGAR-BASED ANTI-INFLAMMATORY AND/OR IMMUNOSUPPRESSIVE DRUGS
o International Application No. PCT/AU89/00350
o Inventors - Xxxxxxx Xxxxxx, Xxxxxxxxxxx Xxxxxx, Xxxxx Xxxxxxxxxx
o Priority date - 18 August 1988
o International filing date - 18 August 1989
o ANUTECH reference 140
COUNTRY APPLICATION NO. PATENT NO. STATUS
Australia 41875/89 627500 granted
Europe 89909685.3 0429522 granted
Japan 509079/89 request examination
USA 988001 5506210* granted
USA-continuation discontinued
* date of grant = 9 April 1996
NOVEL PHOSPHOSUGARS AND PHOSPHOSUGAR-CONTAINING COMPOUNDS HAVING
ANTIINFLAMMATORY ACTIVITY
o Inventors - Xxxxxxx Xxxxxx, Xxxxxxxxxxx Xxxxxx, Xxxxx Xxxxxxxxxx
o Priority date - 18 October 1996
o ANUTECH reference 278
COUNTRY APPLICATION NO. PATENT NO. STATUS
Australia PO3098/96
INT on 18 October 1997
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
SCHEDULE 2
RESEARCH BUDGET
FIRST YEAR BUDGET: NOVEMBER 1997 - NOVEMBER 1998
------------------------------------------------
SALARIES SALARY TOTAL
--------
Chemist $43,000 $54,825
OVERHEADS/CONSUMABLES
---------------------
JCSMR overheads (26% on ANU staff) $14,255
ERM $15,000
APL fee (15%) $12,612
GRAND TOTAL $96,691
SECOND YEAR BUDGET: NOVEMBER 1998 - NOVEMBER 1999
-------------------------------------------------
SALARIES SALARY TOTAL
--------
Lab Technician $35,000 $44,625
Animal Technician $36,000 $45,900
Researcher $42,000 $53,550
Chemist $43,000 $54,825
TOTAL SALARIES $338,900
CONSULTANCY
-----------
Clinical Trial Coordinator $50,000
Research Leader Consultancy $90,000
TOTAL CONSULTANCY $140,000
OVERHEADS/CONSUMABLES
---------------------
JCSMR overheads (26% on ANU staff) $51,714
ERM (@$15K/person) $90,000
Equipment $50,000
Animals $20,000
Sundry (1) $5,000
APL Fee (15%) $83,342
TOTAL OVERHEADS $300,056
GRAND TOTAL $638,956
(1) Includes: printing, advertising, postage, courier, books/subscriptions,
contingency and other miscellaneous items etc
Payment details are provided below:
Electronic Transfer: Postal Address:
Bank: National Australia Bank ANUTECH Pty Ltd
Address: 00 Xxxxxx Xxxxxxx XXX Xxx 0
Xxxxxxxx XXX 0000 Xxxxxxxx XXX 0000
Xxxxxxxxx Xxxxxxxxx
Account Name: ANUTECH Pty Ltd
Account No.: 60584 3086
Branch No.: 082 962
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
SCHEDULE 3
RESEARCH AND RESEARCH MILESTONES
THE RESEARCH -
The research program encompasses both basic and clinical research
projects in the area of inflammation treatment. The overall aims of
the program are to develop compounds with greater efficacy than those
covered currently under the ANU Intellectual Property and to
demonstrate the efficacy, in animal models (ophthalmic and abdominal
inflammation), of the drug candidates, and to prove safety and
efficacy of these agents in human skin inflammatory conditions
(psoriasis).
THE RESEARCH MILESTONES:
In broad terms the Research Milestones can be summarised as follows:
1. BASIC RESEARCH
AIMS: To develop:
(i) 3 agents which are representative of 3 new classes of compounds
with improved binding constants to the M6P/IGF II receptor and to
assess these in vitro and in vivo.
(ii) to develop or identify formulations for optimal delivery in at
least one required application, eg for use in intra-abdominal or
intra-ocular applications
Start: November 1997
Produce agents: November 1998
In vitro analysis: March 1999
In vivo analysis: November 1999
Identify and test formulation: March 1999
Assess final formulation in vivo: November 1999
Finish: November 1999
2. PRE-CLINICAL
i) Post surgical/infection adhesions
------------------------------------
AIMS: To demonstrate efficacy of lead compounds in animal models of intra-
abdominal adhesions
Start: November 1997
Develop animal models: May 1998
Safety studies: September 1998
Efficacy studies: May 1999
Finish: June 1999
ii) Ocular inflammation
-----------------------
AIMS: To demonstrate efficacy of lead compound in animal models of ocular
inflammatory conditions
Start: November 1998
Develop model: May 1999
Safety assessment: September 1999
Efficacy studies: September 2000
Finish: September 2000
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
3. CLINICAL
i) Psoriasis
------------
AIMS: To demonstrate safety and efficacy of lead compounds in the treatment
of psoriasis
Phase I/IIa:
Start: January 1998
Protocol: March 1998
Ethics: June 1998
Recruitment : October 1998
Analysis: February 1999
Finish: February 1999
Phase IIb:
Start: May 1999
Ethics: June 1999
Recruitment : January 2000
Analysis: August 2000
Finish: September 2000
Phase III
Start: September 2000
Finish: September 2003
ii) Intra-abdominal adhesions
-----------------------------
Phase I April 1999 - July 2000
Phase II October 2000 - March 2002
Phase III July 2002 - July 2005
iii) Ocular Inflammation
------------------------
Phase I September 2000 - September 2001
Phase II January 2002 - June 2003
Phase III December 2003 - December 2006
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ANUTECH Pty Ltd Praxis Pharmaceuticals, Inc.
