Sublicense Agreement - Innovative Biotechnologies International Inc. and LIfe Sciences Inc.
SUBLICENSE AGREEMENT
THIS SUBLICENSE AGREEMENT made and entered into as of July 29, 1999
("Effective Date") between INNOVATIVE BIOTECHNOLOGIES INTERNATIONAL, INC., a
Delaware corporation having offices at 335 Lang Boulevard, Grand Island, New
York 14072 ("INNOVATIVE") and LIFE SCIENCES, INC., a Delaware corporation with
offices at 2900 72nd Street North, St. Petersburg, FL 33710 ("LSI").
WHEREAS, INNOVATIVE is the holder of an exclusive worldwide license
from the Cornell Research Foundation, Inc. ("Foundation") under certain United
States patents and applications which are listed in attached Exhibits A and B,
respectively;
WHEREAS, the work leading to the inventions disclosed and claimed in
Exhibits A and B were supported in part by an agency of the U.S. Government,
Foundation is obligated to comply with the U.S. Office of Management & Budget's
Circular No. A-124 and 37 CFR Part 401;
WHEREAS, LSI wants to secure a non-exclusive sublicense under said
patents and patent applications under the terms and conditions herein; and
WHEREAS, INNOVATIVE is willing to grant a non-exclusive sublicense to
LSI under said patents and patent applications under the terms and conditions
herein;
NOW, THEREFORE, in consideration of the covenants and obligations
hereinafter set forth, the parties hereto hereby agree as follows:
ARTICLE 1 - DEFINITIONS
The following definitions will apply throughout this Agreement:
1.1 "Field of Use" shall mean the detection of target nucleic
acids only to the extent such nucleic acids are first amplified by Nucleic Acid
Sequence Based Amplification (NASBA Technology) as described in attached
Exhibit C.
1.2 "INNOVATIVE Technology" shall mean all inventions, designs,
know-how, and technologies developed or licensed by INNOVATIVE, whether
patented or unpatented, including without limitation inventions, designs,
know-how, and technologies relating to liposomes and their use in migration
strip assays, with or without the use of interdigitated electrode arrays.
1.3 "Licensed Application" shall mean the U.S. patent
applications listed at Exhibit A, and any continuation, continuation-in-part,
or divisional applications thereof, as well as any foreign counterparts
thereof.
1.4 "Licensed Patent" shall mean the U.S. patents listed at
Appendix B, any U.S. patents issuing from a Licensed Application, all reissues
and reexamination certificates thereof, as well as any foreign counterparts
thereof.
<PAGE> 2
1.5 "Licensed Products" shall mean products or uses claimed or
embodied in a Licensed Application or Licensed Patent or products or uses
utilizing the INNOVATIVE Technology.
1.6 "Licensed Year" shall mean each twelve (12) month period
beginning on the Effective Date of this Agreement and, thereafter, on the
anniversary date thereof.
1.7 "LSI Technology" shall mean all inventions, designs,
know-how, and technologies developed or licensed by LSI, whether patented or
unpatented.
1.8 "Net Sales Revenues" shall mean the gross amount of revenue
collected by LSI, its subsidiaries, contractors or sales agents from its
customers for the sale or use of Licensed Products starting on the Effective
Date of this Agreement, less: (1) trade and/or quantity discounts; (2) returns
and allowances; (3) retroactive price reductions; and (4) royalties paid to
others.
1.9 "Term" shall mean the period of time from the Effective Date
until the expiration date of the last to expire of the Licensed Patents. In the
event there are no Licensed Patents, the term of this Agreement shall be eight
(8) years from the Effective Date.
ARTICLE 2 - GRANT
2.1 Subject only to the rights of and obligations to the U.S.
Government as set forth in U.S. Office of Management & Budget Circular A-124 or
37 CFR Part 401, INNOVATIVE hereby grants to the LSI for the Term, under the
terms and conditions set forth below, a non-exclusive worldwide sublicense to
make, have made, use, sell, offer to sell, or distribute Licensed Products in
the Field of Use.
2.2 The sublicense granted to LSI in Section 2.1 includes the
right to have the Licensed Products in the Field of Use made by third parties
under contract, provided such contract manufacturing is subject to and
conditioned upon appropriate supervision and quality assurance and control by
LSI. The contract manufacturer shall be bound in writing to respect all rights
of INNOVATIVE set forth in this Agreement and to supply all Licensed Products
it produces exclusively to LSI.
2.3 LSI shall not sublicense its rights and obligations under
this Agreement unless such sublicense is approved in writing by both the
Foundation and INNOVATIVE.
2.4 The rights granted to LSI pursuant to Sections 2.1, 2.2, and
2.3 do not include any right for LSI to sell to any other entity, including
Organon Teknica B.V., a Boxtel Netherlands company, a product line that will
combine NASBA Technology with INNOVATIVE Technology. ARTICLE 3-TECHNICAL
SUPPORT TO LSI
3.1 Provided that LSI is meeting its obligations under this
Agreement, INNOVATIVE shall provide LSI with technical support regarding the
INNOVATIVE Technology. Such technical support shall be in the form of phone and
email consultation or onsite visits, as described in Sections 3.2 and 3.3.
3.2 Technical support in the form of phone and email consultation
shall be provided by INNOVATIVE to LSI free of charge in an amount not to
exceed ten (10) hours per month.
<PAGE> 3
Any technical support requested by LSI in excess of ten (10) hours per month
shall be charged to LSI at a rate of $ 175 per hour. Such amounts shall be
invoiced by INNOVATIVE to LSI on a monthly basis and shall be payable by LSI
within thirty (30) days of invoicing.
3.3 Technical support in the form of onsite visits shall be
provided by INNOVATIVE to LSI for a period of eighteen (18) months from the
Effective Date. During this period, LSI shall be entitled to no more than four
(4) onsite visits, of duration not longer than three (3) consecutive days,
exclusive of travel time, by INNOVATIVE personnel or its consultants.
Alternatively, LSI may visit INNOVATIVE or one of its consultants, at its
expense for one or more of these onsite visits. LSI shall be fully responsible
for all travel, car rental, food and lodging, and all other reasonable travel
expenses incurred by INNOVATIVE personnel or its consultants in connection with
such onsite visits, provided they are approved in advance by LSI. LSI shall
reimburse INNOVATIVE within ten (10) days of incurring such costs.
ARTICLE 4 - REPRESENTATIONS AND WARRANTIES
4.1 Mutual Representations. The parties each represent and
warrant:
4.1.1 Such party is duly organized and validly existing
under the laws of the state of its incorporation and has full corporate power
and authority to enter into this Agreement and carry out the provisions hereof.
4.1.2 Such party is duly authorized to execute and deliver
this Agreement and to perform its obligations hereunder.
4.1.3 This Agreement is a legal and valid obligation
binding upon it and enforceable in accordance with its terms. The execution,
delivery, and performance of this Agreement by such party does not conflict
with any agreement, instrument, or understanding, oral or written, to which it
is a party or by which it may be bound, nor violate any law or regulation of
any court, governmental body or administrative or other agency having
jurisdiction over it.
4.2 Representations by INNOVATIVE
4.2.1 INNOVATIVE represents that, subject only to the
rights of and obligations to the U.S. Government as set forth in U.S. Office of
Management Budget Circular A-124 or 37 CFR, INNOVATIVE has the right to grant
the above sublicense.
4.2.2 INNOVATIVE, to the best of its knowledge, represents
that Foundation is the sole owner of the Licensed Applications and Licensed
Patents, subject to the exclusive license to INNOVATIVE and the rights of the
U.S. Government as set forth in U.S. Office of Management Budget Circular A-124
or 37 CFR.
4.2.3 INNOVATIVE MAKES NO WARRANTY OF MERCHANTABILITY OR
FITNESS FOR A PARTICULAR PURPOSE OR ANY OTHER WARRANTY, EXPRESS OR IMPLIED.
INNOVATIVE MAKES NO WARRANTY THAT USE OF THE INNOVATIVE TECHNOLOGY WILL NOT
INFRINGE ON PATENT RIGHTS OR OTHER PROPRIETARY RIGHTS OWNED BY OTHERS.
<PAGE> 4
4.2.4 INNOVATIVE MAKES NO REPRESENTATIONS REGARDING THE
SCOPE OF THE LICENSED PATENTS AND THE LICENSED APPLICATIONS.
4.3 Representations by LSI
4.3.1 LSI represents that it has certain worldwide rights
together with other geographically limited rights to make, have made, use,
sell, offer to sell, or distribute products utilizing NASBA Technology.
4.3.2 Except as to INNOVATIVE, LSI represents and warrants
that no individual or entity has asserted to LSI that LSI would be infringing
any foreign or domestic patent or would be misappropriating or improperly using
or disclosing any trade secret, confidential information, or know-how (and LSI
is unaware of any basis for such claim) which relates in any manner to the
subject matter of this Agreement.
ARTICLE 5 - LICENSING FEES
5.1 In consideration of the non-exclusive worldwide sublicense
granted hereunder, LSI agrees to pay INNOVATIVE a sublicensing fee of
$150,000 payable as follows:
5.1.1 A non-refundable payment of $ 25,000 upon execution
of this Agreement;
5.1.2 An additional non-refundable payment of $ 25,000 on
the six (6) month anniversary of the Effective Date of this Agreement;
5.1.3 An additional non-refundable payment of $100,000 on
the eighteen (18) months anniversary of the Effective Date of this Agreement or
upon the first sale of Licensed Product in the Field of Use, whichever shall
occur first.
ARTICLE 6 - ROYALTY PAYMENTS
6.1 LSI shall pay to INNOVATIVE a running earned royalty of ten
(10) percent of Net Sales Revenue for sales or uses in all regions of the
world, except that a reduced royalty rate of four (4) percent of Net Sales
Revenue shall apply to sales or uses in the following countries:
6.1.1 People's Republic of China.
6.1.2 Taiwan.
6.1.3 Nations of sub-Sahara Africa (See Exhibit D)
6.2 Minimum Royalty Payments.
<PAGE> 5
6.2.1 In order to maintain its non-exclusive rights,
pursuant to this Agreement, LSI shall pay INNOVATIVE a Minimum Royalty on an
annual basis, according to the following schedule:
Licensed Year Minimum Royalty
------------- ---------------
Licensed Year 1 - 1.5 $ 0
Licensed Year 1.5 - 2.0 $ 10,000 (for 6 month period)
Licensed Year 3 $ 50,000
Licensed Year 4 $ 75,000
Licensed Year 5 $ 135,000
Licensed Year 6 $ 200,000
Licensed Year 7 and thereafter $ 250,000
6.2.2 Minimum Royalty payments, pursuant to Section 6.2.1,
shall be made in quarterly installments in advance of each calendar quarter for
the Licensed Year in which they are due. Such Minimum Royalty payments are not
refundable nor applicable to succeeding Licensed Years.
ARTICLE 7 - ACCOUNTING AND PAYMENT SCHEDULE
7.1 Royalties, pursuant to Section 6.1, shall be paid by LSI to
INNOVATIVE on a quarterly basis for each Licensed Year within sixty (60) days
following the end of that quarter, to the extent such royalties exceed the
Minimum Royalty payments for that quarter of the Licensed Year made in advance
under Section 6.2.
7.2 Within sixty (60) days following the end of each quarter of
the Licensed Year, LSI shall deliver to INNOVATIVE a report ("Royalty Report")
in writing setting forth sales of Licensed Products (including a negative
report, if appropriate). LSI shall keep accurate records, certified by it,
showing the information by which LSI arrived at a royalty determination and
will permit a person appointed by INNOVATIVE or Foundation to make such
inspection of said records as may be necessary to verify Royalty Reports made
by LSI.
7.3 In making the royalty payments pursuant to Section 7.1,
conversion from foreign currencies, if any, shall be based upon the conversion
rate on the last day of the month in which the Net Sales Revenues were
collected.
7.4 Royalty payments which are delayed beyond the sixty (60) days
after the end of the quarter in which they become due, pursuant to Section 7.1,
shall be subject to a ten percent (10%) per annum charge for the first thirty
(30) days and an eighteen percent (18%) per annum thereafter.
SECTION 8 - LSI DUTY OF DILIGENCE
8.1 LSI shall exercise due diligence to effect the introduction
of Licensed Products into the commercial market as soon as practical. LSI
agrees to develop and exploit Licensed
<PAGE> 6
Products with diligence by manufacture and/or sale of Licensed Products for the
duration of the term of this Agreement. In any event, within thirty six (36)
months from the Effective Date, LSI shall have commenced sales of Licensed
Products and have achieved Net Sales Revenues of at least one and one-half
million dollars (U.S.).
8.2 Within thirty (30) days after the end of each Licensed Year,
LSI shall provide an annual progress report to INNOVATIVE which describes the
progress that LSI is making toward product introduction.
8.3 LSI further agrees to maintain quality control over Licensed
Products and generally attend to proper, safe, fair, lawful, and reasonable
development and exploitation of the market for Licensed Products made and/or
sold by it.
ARTICLE 9 -INFRINGEMENT OF LICENSED PATENT RIGHTS BY THIRD PARTIES
9.1 In the event that any infringement of a Licensed Patent shall
come to the attention of INNOVATIVE or LSI, then that party shall duly inform
the other party, and INNOVATIVE shall inform Foundation. Foundation shall, in
its sole discretion, determine whether or not to prosecute a patent
infringement action. If Foundation elects not to prosecute a patent
infringement action, then INNOVATIVE may cause legal proceedings against the
alleged infringer at its own expense.
9.2 In any proceedings initiated by Foundation or INNOVATIVE,
Foundation or INNOVATIVE, as the case may be, shall be entitled to employ
counsel and control the course of litigation. LSI, at the expense of Foundation
or INNOVATIVE, shall cooperate with and assist Foundation or INNOVATIVE in any
proceedings initiated or defended by Foundation or INNOVATIVE.
ARTICLE 10 - DEFENSE OF THIRD PARTY INFRINGEMENT CLAIMS
10.1 In the event, INNOVATIVE or LSI becomes aware that LSI's
activities pursuant to Article 2 is the subject of a claim for patent
infringement, that party shall promptly notify the other and the parties shall
consider the claim and the most appropriate action to take. LSI shall have the
right to control the defense of any such suit brought against LSI and shall do
so at its own expense. The parties shall have the right to require each other's
reasonable cooperation in any such suit, upon written notice, and INNOVATIVE
shall have the obligation to participate and LSI shall bear the costs of its
participation. LSI shall have the right to enter into any settlement upon
INNOVATIVE's written consent, which consent shall not be unreasonably withheld.
10.2 In the event LSI's activities pursuant to Article 2 are
enjoined as a result of a patent infringement claim based solely on the
INNOVATIVE Technology, Licensed Patents, or Licensed Applications, the Minimum
Royalty payments under Section 6.2 shall be suspended for the duration of the
injunction. Should the Minimum Royalty payments be suspended due to an
injunction and the injunction is subsequently terminated, LSI shall resume
Minimum Royalty payments starting at the Licensed Year, pursuant to Section
6.2.1, at which the injunction was first imposed.
<PAGE> 7
ARTICLE 11 - INDEMNIFICATION AND HOLD HARMLESS OBLIGATIONS OF LSI
11.1 In no event shall INNOVATIVE be liable for any loss, claim,
damage, or liability, of any kind or nature, which may arise from or in
connection with the acts of LSI under this Agreement.
11.2 LSI agrees, at its sole expense, to indemnify or hold
harmless INNOVATIVE and Foundation, their trustees, officers, directors,
employees, agents, and consultants, including those at Cornell University,
against any and all claims, suits, losses, damages, costs, fees, and expenses
(including attorney fees and litigation costs), resulting from or arising out
of acts by LSI under this Agreement. LSI shall reimburse INNOVATIVE for all of
INNOVATIVE's expenses, including attorney fees and disbursements, arising out
of or relating to a claim by INNOVATIVE to enforce Article 11.
11.3 LSI will maintain general liability insurance in the amount
of at least $1,000,000 per occurrence with a deductible of not more than
$10,000 per occurrence with reasonable nationally recognized insurers for
property damage and destruction and injury to or death of individuals. LSI will
furnish INNOVATIVE upon request, and in any event on execution of this
Agreement and on each anniversary of the Effective Date of this Agreement,
written confirmation issued by the insurer or an independent insurance agent
confirming that insurance is maintained in accordance with the above
requirements.
ARTICLE 12 - ASSIGNMENT
12.1 The rights and obligations of LSI are not assignable except
either (1) to a successor in its business or (2) to an entity under common
ownership or control with LSI, provided such assignment is approved it writing
by both INNOVATIVE and Foundation, which authorization will not be unreasonably
withheld.
ARTICLE 13 - TERMINATION
13.1 This Agreement shall terminate at the end of the Term.
However, the provisions of Article 14, 15, and 16 shall survive.
13.2 INNOVATIVE and LSI may terminate this Agreement, in addition
to pursuing any remedies available under law or in equity, for noncompliance by
the other with any of the provisions herein by giving the noncomplying party
written notice of such noncompliance and the opportunity to cure the same. If
the non-complying party does not cure such noncompliance to the reasonable
satisfaction of the party issuing the notice of noncompliance (the "Notifying
Party") within sixty (60) days after giving the notice, the Notifying Party may
terminate this Agreement.
13.3 LSI may terminate this Agreement, without cause, by giving
INNOVATIVE written notice one-year notice prior to such termination.
ARTICLE 14 - ARBITRATION AND JURISDICTION
14.1 Resolution of all disputes over the meaning and
interpretation of this Agreement shall be attempted by conciliation and
mediation, and, if such conciliation and mediation is
<PAGE> 8
unsuccessful, then disputes shall be finally settled by an Arbitrator selected
by INNOVATIVE and LSI. If INNOVATIVE and LSI cannot agree on an Arbitrator,
then disputes shall be resolved by an Arbitration Panel comprising one
arbitrator appointed by INNOVATIVE, one arbitrator appointed by LSI, and a
Chairman of the Arbitration Panel appointed by the first two arbitrators. Any
such arbitration proceedings shall be adopted in accordance with generally
accepted arbitration rules; shall be held in the State of New York, unless
otherwise agreed by the parties; and judgment upon the arbitration award may be
entered in any court having jurisdiction.
14.2 In order to initiate procedures for dispute resolution by
conciliation, mediation, and arbitration, either party shall give written
notice to the other of its intention to resolve a dispute and, absent
satisfactory resolution, then to arbitrate. Such notice shall contain a
statement setting forth the nature of the dispute and the resolution sought.
If, within thirty (30) days of such notice, a resolution by conciliation
between the parties themselves or by mediation has not been achieved to the
satisfaction of both parties, and, if within sixty (60) days from said written
notice, an Arbitrator or Arbitration Panel has not been appointed with an
arbitration schedule satisfactory to both parties, then either party may
proceed with judicial remedies.
14.3 The parties reserve the right and power to proceed with
direct judicial remedies against the other without conciliation, mediation, or
arbitration for claims relating to breach of the royalty payment and sales
reporting provisions of this Agreement after giving written notice of such
breach to LSI followed by an opportunity period of thirty (30) days in which to
cure such breach. In collecting overdue royalty payments and securing
compliance with reporting obligations, INNOVATIVE may use all judicial remedies
available.
ARTICLE 15 - CONFIDENTIAL INFORMATION
15.1 In the course of carrying out their obligations under this
Agreement, the parties may need to disclose to one another Confidential
Information, including scientific information, business information, patent
information, and legal information. All Confidential Information shall be
provided in writing marked "CONFIDENTIAL" and, if initially disclosed verbally,
shall be confirmed in writing within thirty (30) days disclosure and marked
"CONFIDENTIAL." The obligation of confidentiality under this Agreement shall
continue for the Term. The parties shall preserve any and all Confidential
Information as confidential and shall not use any such Confidential Information
except as necessary to carry out their rights and obligations under this
Agreement. The party receiving Confidential Information shall have no liability
to the party disclosing Confidential Information with respect to the use or
disclosure to others not party to this Agreement, of Confidential Information
which the receiving party can establish to,
(a) have been known by receiving party prior to
communication by disclosing party to the receiving
party;
(b) have been a matter of public knowledge at the time
of such disclosure by the disclosing party;
(c) have become a matter of public knowledge, without
fault on the part of the receiving party, subsequent
to disclosure by the disclosing party to the
receiving party; or
<PAGE> 9
(d) have been disclosed to the receiving party from a
third party lawfully having possession of such
information without an obligation of confidentiality
to the disclosing party.
In the event that either party is required by a judicial or
administrative process to disclose Confidential Information, it shall promptly
notify the other party and allow that party a reasonable time to oppose such
process.
In no event shall the receiving party disclose any of the Confidential
Information until it provides notice and reasonable proof to the disclosing
party as required herein. 15.2 Upon termination of this Agreement, each party
will return, without retention of any copies, all Confidential Information
received from the other party.
ARTICLE 16 - OWNERSHIP OF INVENTIONS
16.1 INNOVATIVE shall have sole rights in all INNOVATIVE
Technology as a result of either or both INNOVATIVE's ownership of INNOVATIVE
Technology and/or Foundation's exclusive license to INNOVATIVE of the
INNOVATIVE Technology.
16.2 LSI shall have sole ownership of all LSI Technology.
16.3 In the event, LSI makes any inventions relating to INNOVATIVE
Technology or the use of INNOVATIVE Technology in accordance with Article 2 of
this Agreement, LSI shall grant INNOVATIVE a royalty-free, worldwide,
non-exclusive commercial license to make, have made, use, sell, offer to sell,
or distribute products utilizing such inventions.
ARTICLE 17 - MISCELLANEOUS
17.1 Invalidity or enforceability of any provision of this
Agreement in any particular respect shall not effect the validity and
enforceability of any of the other provisions of this Agreement or of the same
provision in any other respect.
17.2 This Agreement contains the entire understanding between and
among the parties hereto and supersedes any prior understandings and agreements
between or among them respecting the subject matter of this Agreement.
17.3 No amendment, modification, or supplement of any provision of
the Agreement will be valid or effective unless made in writing and signed by a
duly authorized officer of each party. The officers signing this Agreement
shall be "duly authorized officers" for all purposes of this Agreement, unless
notice is given to the contrary.
17.4 No provision of this Agreement shall be waived by any act,
omission, or knowledge of a party or its agents or employees except by an
instrument in writing expressly waiving such provision and signed by a duly
authorized officer of the waiving party.
<PAGE> 10
17.5 This Agreement and the rights of the parties hereto shall be
interpreted in accordance with the laws of the State of New York.
17.6 This Agreement may be executed in several counterparts, each
of which shall be deemed an original copy and all of which shall constitute one
agreement binding on all parties hereto notwithstanding that all parties shall
not have signed the same counterparts.
17.7 LSI agrees that it will not use the indicia or name
INNOVATIVE or any of INNOVATIVE's personnel in advertising, promotion, labeling
of Licensed Products or in fund raising without prior written approval of
INNOVATIVE.
17.8 LSI agrees that it will not use the indicia or names of
Foundation, Cornell University or of any of their personnel in advertising,
promotion, labeling of Licensed Products or in fund raising without prior
written approval of Foundation or Cornell University or any of their personnel.
17.9 Reports, notices, and other communications to INNOVATIVE
shall be addressed to:
President
INNOVATIVE Biotechnologies International, Inc.
335 Lang Boulevard
Grand Island, New York 14072
and notices and communications to LSI shall be addressable to:
Alex Burns
Life Sciences, Inc.
2900 72nd Street North, St.
Petersburg, FL 33710
IN WITNESS WHEREOF, the parties have caused this instrument to be executed in
duplicate as of the day and year first above written.
ATTEST: INNOVATIVE BIOTECHNOLOGIES
INTERNATIONAL , INC.
By: /s/ Richard A. Montagna
----------------------------------
Richard A. Montagna
Title: President
Date:
--------------------------------
ATTEST: LIFE SCIENCES, INC.
By: /s/ Alex A. Burns
----------------------------------
Alex A. Burns
Title: Vice President
-------------------------------
Date:
--------------------------------
<PAGE> 11
EXHIBIT A
U. S. PATENT APPLICATIONS
U.S. PATENT APPLICATION SERIAL NO. 09/027,324
"Liposome-Enhanced Immunoaggregation Assay & Test Device."
U.S. PATENT APPLICATION SERIAL NO. 09/034,086
"Liposome-Enhanced Immunoassay & Test Device."
U.S. PATENT APPLICATION SERIAL NO. 08/722,901
"Interdigitated Arrays for Liposome-Enhanced Immunoassay & Test Device."
U.S. PROVISIONAL PATENT APPLICATION NO. 60/086,190
"Liposome-Enhanced Nucleic Acid Detection Assay."
U.S. PROVISIONAL PATENT APPLICATION NO. 60/106,122
"Liposome-Based Analytical Test Device & Method."
<PAGE> 12
EXHIBIT B
ISSUED U.S. PATENTS
U.S. PATENT NO. 5,789,154
"Liposome-Enhanced Immunoassay & Test Device."
U.S. PATENT NO. 5,756,362
"Liposome-Enhanced Immunoaggregation Assay & Test Device."
U.S. PATENT NO. 5,753,519
"Liposome-Enhanced Immunoassay & Test Device."
<PAGE> 13
EXHIBIT C
DEFINITION OF NASBA TECHNOLOGY
The term "NASBA" refers to Nucleic Acid Sequence Based Amplification, an
isothermal, transcription-based enzymatic nucleic acid amplification procedure
that can be applied to both RNA and DNA targets. The reaction process for RNA
analytes is depicted in Figure 1. The process is initiated by the annealing of
an oligonucleotide primer (designated P1) to the RNA target present in the
nucleic acid extract obtained from the test sample. The 3' end of the P1 primer
is complementary to the target analyte; the 5' end encodes the T7 RNA polymerase
promoter. After annealing, the reverse transcriptase activity of AMV-RT is
engaged and a cDNA copy of the RNA target is produced. The RNA portion of the
resulting hybrid molecule is hydrolyzed through the action of RNase H. This
permits the second primer (P2; sense), which is complementary to an upstream
portion of the RNA target, to anneal to the cDNA strand. This permits the
DNA-dependent DNA polymerase activity of AMV-RT to be engaged, producing a
double stranded cDNA copy of the original RNA analyte with a functional T7 RNA
polymerase promoter at one end. This promoter is then recognized by the T7 RNA
polymerase, which produces a large amount of anti-sense, single stranded RNA
transcripts corresponding to the original RNA target. These anti-sense RNA
transcripts can then serve as templates for the amplification process, however
the primers anneal in the reverse order. The entire NASBA process is isothermal
and is generally conducted at 41oC. For the amplification of DNA, the process is
the same as described in Figure 1, except that an initial heat denaturing step
(e.g., 100oC, 5 minutes) is required before the addition of the enzymes to the
reaction mix.
Both INNOVATIVE and LSI understand and agree that a NASBA reaction may be
performed in one or more other manners similar to, but different from, that
depicted in Figure 1. Where LSI can demonstrate by documentary evidence that it
has obtained license rights from Organon Teknika to employ such other methods
for performance of NASBA, then INNOVATIVE and LSI hereby agree that such other
methods of performing NASBA shall be included in the definition of NASBA.
<PAGE> 14
EXHIBIT C (CONTINUED)
[GRAPHIC OF NASBA AMPLIFICATION REACTION]
<PAGE> 15
EXHIBIT D
NATIONS OF SUB-SAHARA AFRICA
Angola Mali
Botswana Mauritania
Burkina Faso Mozambique
Burundi Namibia
Cameroon Niger
Central Africa Nigeria
Chad Rwanda
Djibouti Senegal
Equatorial Guinea Sierra Leone
Eritrea South Africa
Ethiopia Sudan
Gambia Somalia
Ghana Tanzania
Ivory Coast Togo
Kenya Uganda
Lesotho Zaire
Liberia Zambia
Madagascar Zimbabwe
Malawi