Exhibit 10.3
Confidential Materials omitted and filed separately with the
Securities and Exchange Commission. Asterisks denote omissions.
CONFIDENTIAL
LICENSE AND SUPPLY AGREEMENT
THIS LICENSE AND SUPPLY AGREEMENT (this "AGREEMENT") is made as of May 16, 2007
(the "EFFECTIVE DATE"), by and between CYDEX, INC., a Delaware corporation with
offices at 00000 X. 00xx Xxxxxxx, Xxxxxx, Xxxxxx 00000 ("CYDEX"), and CRITICAL
THERAPEUTICS, INC., a Delaware corporation with offices at 00 Xxxxxxxx Xxxxxx,
Xxxxxxxxx, XX 00000 ("COMPANY").
RECITALS
WHEREAS, CyDex is engaged in the business of developing and commercializing
novel drug delivery technologies designed to enhance the solubility and
effectiveness of existing and development-stage drugs;
WHEREAS, CyDex is the exclusive worldwide licensee of CAPTISOL(R), a
patented drug formulation system designed to enhance the solubility and
stability of drugs;
WHEREAS, CyDex and Company are parties to a Limited Clinical Use Agreement,
effective as of May 12, 2005 ("LIMITED CLINICAL USE AGREEMENT") which governed
the terms of Company's evaluation of a drug formulation containing the Compound
(as hereinafter defined) and CAPTISOL(R), the terms of which agreement CyDex and
Company intend to replace and supersede with the terms of this Agreement;
WHEREAS, Company desires to obtain a license to use CyDex's patented drug
formulation system in connection with its development and commercialization of
the Compound and CyDex is willing to grant such license to Company under the
terms and conditions set forth herein;
WHEREAS, CyDex desires to sell CAPTISOL(R) to Company, and Company desires
to purchase CAPTISOL(R) from CyDex, in accordance with the terms and conditions
contained herein; and
NOW, THEREFORE, in consideration of the following mutual promises and other
good and valuable consideration, the receipt and sufficiency of which is
acknowledged, the parties, intending to be legally bound, agree as follows:
1. DEFINITIONS.
For the purposes of this Agreement, the terms hereunder shall have the
meanings as defined below:
1.1 "AFFILIATE" means, with respect to any party, any entity controlling,
controlled by, or under common control with such party, during and for such time
as such control exists. For these purposes, "control" shall refer to the
ownership, directly or indirectly, of at least fifty percent (50%) of the voting
securities or other ownership interest of the relevant entity.
1.2 "ALTERNATE SUPPLIER" has the meaning specified in SECTION 3.7(C).
1
1.3 "CAPTISOL" means the drug formulation technology marketed by CyDex as
CAPTISOL(R), also known scientifically as sulfobutylether (beta)(beta)
cyclodextrin, sodium salt.
1.4 "CAPTISOL DATA PACKAGE" means (a) all toxicology/safety and other
relevant scientific safety data owned, licensed or developed by CyDex and its
Affiliates; (b) all toxicology/safety and other relevant scientific data owned,
licensed or developed by the licensees or sublicensees of CyDex or its
Affiliates or other third parties (to the extent permitted in the applicable
license or other agreements between CyDex and/or its Affiliates and such
licensees, sublicensees or other third parties) on CAPTISOL alone (and not in
conjunction with a product formulation); and (c) all CMC and manufacturing
process data relating to the preparation of CAPTISOL, in each case to the extent
necessary or useful for the formulation of the Licensed Product. For purposes of
clarity, "CAPTISOL Data Package" shall include all dossier of data and
information on CAPTISOL provided by CyDex under the Limited Clinical Use
Agreement, including without limitation Material Safety Data Sheets,
certificates of analysis, information on material stability and storage
conditions, packaging, specifications, test methods, reference standards, and
re-evaluation dates for CAPTISOL as well as known or expected adverse events
related to the use of CAPTISOL.
1.5 "CAPTISOL IMPROVEMENT" means any technology or improvement related to
CAPTISOL, whether or not patentable, that is developed by Company or its
Affiliates or Sublicensees, solely or jointly with a third party, during the
Term in the course of exercising its rights or performing its obligations under
this Agreement. "CAPTISOL Improvement" shall in no event include (i) any
improvements to the composition of matter of the Licensed Product, (ii) a method
of making or using the Licensed Product that does not relate to CAPTISOL or
(iii) any improvements in the composition of matter of the Compound.
1.6 "CLAIM" has the meaning specified in SECTION 10.1.
1.7 "CLINICAL GRADE CAPTISOL" means CAPTISOL which (a) has been
manufactured under conditions of current good manufacturing practices for bulk
excipients as set forth in U.S. Pharmacopoeia (1078) as of the Effective Date or
any successor thereto, (b) is intended for use in humans, and (c) is intended
for clinical trials for the Licensed Product.
1.8 "PHASE II CLINICAL TRIAL" means a human clinical trial that is intended
to initially evaluate the effectiveness of a Licensed Product in the targeted
patient population for a particular indication or indications in human subjects
with the disease or indication under study, as more fully defined in 21 C.F.R.
312.21(b).
1.9 "PHASE III CLINICAL TRIAL" means a pivotal efficacy trial whose primary
objective is to obtain a definitive evaluation of the therapeutic efficacy and
safety of a Licensed Product in patients for the particular indication in
question that is needed to evaluate the overall risk-benefit profile of a
Licensed Product and to provide adequate basis for obtaining requisite Marketing
Approval(s) and product labeling, as more fully defined in 21 C.F.R. 312.21(c).
1.10 "COMMERCIAL GRADE CAPTISOL" means CAPTISOL which (a) has been
manufactured under conditions of current good manufacturing practices for bulk
excipients as set
2
forth in U.S. Pharmacopoeia (1078) as of the Effective Date or any successor
thereto, (b) is intended for use in humans, and (c) is intended for commercial
sale of the Licensed Product.
1.11 "COMMERCIAL LAUNCH DATE" means, in any particular country, the first
sale of Licensed Product for commercial purposes for value by Company, its
Affiliates or Sublicensees to a third party, but excluding the sale, transfer or
disposition of any Licensed Product for (a) pre-clinical or animal studies
and/or (b) for clinical use or for non-clinical testing required for clinical
trials in preparation for submission or approval of a regulatory filing.
1.12 "COMPOUND" means that certain pharmaceutical compound known as
Zileuton, owned by or licensed to Company and developed and manufactured by or
on behalf of Company.
1.13 "CONFIDENTIAL INFORMATION" has the meaning specified in SECTION 8.1.
1.14 "DETAILED FORECAST" has the meaning specified in SECTION 3.2(B).
1.15 "DISCLOSING PARTY" has the meaning specified in SECTION 8.1 hereof.
1.16 "DMF" means a Drug Master File for CAPTISOL, as currently filed, or as
hereafter updated from time to time, by CyDex with the FDA.
1.17 "FDA" means the United States Food and Drug Administration, or any
successor thereto.
1.18 "GENERIC COMPETITION" has the meaning specified in SECTION 4.1(D)(II).
1.19 "IND" means an Investigational New Drug application, as defined in the
United States Federal Food, Drug and Cosmetics Act and the regulations
promulgated thereunder, or similar application filed with an equivalent
regulatory body in another country.
1.20 "INDEMNITEE" has the meaning specified in SECTION 10.4.
1.21 "INDEMNITOR" has the meaning specified in SECTION 10.4.
1.22 "LICENSED PATENTS" means all patents and patent applications in the
Territory which claim CAPTISOL and which now or at any time during the Term are
owned by or licensed to CyDex or any CyDex Affiliate with the right to
sublicense, including any and all extensions, renewals, continuations,
substitutions, continuations-in-part, divisions, patents-of-addition, reissues,
reexaminations and/or supplementary protection certificates to any such patents.
Set forth in EXHIBIT A attached hereto is a list of the Licensed Patents as of
the Effective Date. Such Exhibit shall be updated by CyDex from time to time.
Notwithstanding the foregoing, Licensed Patents expressly exclude patents and
patent applications not applicable to the Licensed Product or the particular
indication(s) for which the Licensed Product is being developed.
1.23 "LICENSED PRODUCT" means the Compound combined with or formulated
using CAPTISOL in an injectable dosage form/formulation for ultimate use in
humans.
1.24 "LOSSES" has the meaning set forth in SECTION 10.1.
3
1.25 "MARKETING APPROVAL" means final approval of an NDA by the FDA, or
final approval of a comparable document filed with an equivalent health
regulatory authority in any other country or in the European Union (using the
centralized process or mutual recognition), including all required marketing,
pricing or reimbursement approvals.
1.26 "NDA" means a New Drug Application, as defined in the United States
Federal Food, Drug and Cosmetics Act and the regulations promulgated thereunder,
or similar application filed with an equivalent regulatory body in another
country.
1.27 "NET SALES" means gross amounts invoiced by Company, its Affiliates
and Sublicensees for sales of the Licensed Product(s), less the following: (a)
normal and customary trade, quantity and/or cash discounts, allowances and
rebates actually allowed or given; (b) returns and credits actually allowed for
rejections, defects or recalls of Licensed Product, outdated or returned
Licensed Product, or because of rebates or retroactive price reductions; (c)
freight, postage, shipping insurance and other transportation expenses (if
separately identified on the invoice); and (d) sales, value-added, excise or use
taxes, tariffs, duties and customs fees and other taxes imposed with respect to
specific sales.
1.28 "NOTICE OF DEFAULT" has the meaning specified in SECTION 13.2.
1.29 "NOTICE OF TERMINATION" has the meaning specified in SECTION 13.2.
1.30 "PFIZER" has the meaning specified in SECTION 8.5.
1.31 "PURCHASE VOLUME LIMITATIONS" has the meaning specified in SECTION
3.2(C).
1.32 "Q1", "Q2, "Q3", and "Q4" have the meanings specified in SECTION
3.2(B).
1.33 "RECEIVING PARTY" has the meaning specified in SECTION 8.1.
1.34 "RESEARCH GRADE CAPTISOL" means CAPTISOL which has not been
manufactured under required conditions of current good manufacturing practices
and is not suitable for use in humans, but which meets CyDex's specifications
for Research Grade CAPTISOL.
1.35 "SEC" has the meaning specified in SECTION 8.3.
1.36 "SPECIFICATIONS" means the specifications for CAPTISOL set forth in
EXHIBIT B hereto, as such may be amended from time to time pursuant to SECTION
3.4.
1.37 "SUBLICENSEES" has the meaning specified in SECTION 2.3.
1.38 "SUPPLY FAILURE" means a failure by CyDex to supply at least [**]
percent ([**]%) of the quantities of CAPTISOL ordered by Company (provided such
purchase order was within the limits of the Purchase Volume Limitations) in each
of [**] consecutive calendar quarters, and CyDex does not cure such deficiency
within [**] days after Company notifies CyDex in writing that the quantity of
CAPTISOL due for delivery has not been delivered.
4
1.39 "TERM" has the meaning specified in SECTION 13.1.
1.40 "TESTING METHODS" has the meaning specified in SECTION 3.5(A).
1.41 "THIRD-PARTY MANUFACTURER" has the meaning specified in SECTION 3.6.
1.42 "TERRITORY" means the entire world.
1.43 "VOLUME THRESHOLD" has the meaning specified in SECTION 3.1.
2. GRANT OF RIGHTS.
2.1 LICENSE GRANTS FROM CYDEX TO COMPANY.
(A) Licensed Patents. Subject to the terms and conditions of this
Agreement, including but not limited to payment of the amounts set forth in
SECTION 4.1 below, CyDex hereby grants to Company an exclusive, nontransferable
(except as permitted under SECTION 14.15) license during the Term under the
Licensed Patents, solely to develop, make, have made, use, market, distribute,
import, offer to sell and sell the Licensed Product in the Territory.
Notwithstanding the foregoing, to the extent that any Licensed Patents are
licensed to CyDex or its Affiliates by a third party on a non-exclusive basis,
the license granted to Company in the foregoing sentence shall be exclusive as
to CyDex and non-exclusive as to any third party. Company may not use, market or
distribute the Licensed Product for any other purposes nor sublicense the
Licensed Patents, except as expressly set forth in SECTIONS 2.3 and 2.4 below.
Without limiting the generality of the foregoing, CyDex grants no rights to
Company to manufacture, import, sell or offer to sell bulk CAPTISOL.
(B) CAPTISOL Data Package. Subject to the terms and conditions of this
Agreement, including but not limited to payment of the amounts set forth in
SECTION 4.1 below, CyDex hereby grants to Company a non-exclusive,
nontransferable (except as permitted under SECTION 14.15) license during the
Term under CyDex's right in and to the CAPTISOL Data Package, solely to develop,
make, have made, use, market, distribute, import, offer to sell and sell the
Licensed Product in the Territory. Company may not sublicense its rights to the
CAPTISOL Data Package, except as expressly set forth in SECTIONS 2.3 and 2.4
below.
2.2 GRANT OF LICENSE FROM COMPANY TO CYDEX. Subject to the terms and
conditions of this Agreement, Company hereby grants to CyDex a nonexclusive,
nontransferable (except as permitted under SECTION 14.15), perpetual (other than
in the event of a termination of this Agreement), world-wide and royalty-free
license, with the right to grant sublicenses, under Company's, its Affiliates'
and Sublicensees' rights in and to CAPTISOL Improvements to develop, make, have
made, use, market, distribute, import, offer to sell and sell any CAPTISOL
Improvement and products formulated with any CAPTISOL Improvement (other than
the Licensed Product during the Term and other than the Compound after the
Term). If Company or its Affiliates or Sublicensees file any patent application
claiming CAPTISOL anywhere in the world, CyDex shall be deemed automatically to
have a nonexclusive, transferable, perpetual (other than in the event of a
termination of this Agreement), world-wide and royalty-free license, with the
right to grant sublicenses through multiple tiers, under the claims relating
specifically to CAPTISOL to make, have made, use, market, distribute, import,
offer to sell and sell
5
CAPTISOL and all products formulated with CAPTISOL (in each case, other than the
Licensed Product during the Term and other than the Compound after the Term).
Company shall provide prompt notice of any such CAPTISOL Improvement, and shall
notify and consult with CyDex at least [**] days prior to the filing of any such
patent application claiming a CAPTISOL Improvement or claiming CAPTISOL.
Notwithstanding any provision of this Agreement, Company does not grant CyDex
any right to manufacture, import, sell or offer to sell any product containing
the Compound.
2.3 SUBLICENSING. Company shall have the right to grant sublicenses to its
Affiliates and licensees of the Licensed Product (collectively "SUBLICENSEES")
under the licenses granted to Company pursuant to SECTION 2.1; provided that
each such sublicense shall be subject to, and consistent with, the terms and
conditions of this Agreement, and shall provide that any such Sublicensee shall
not further sublicense the rights granted to Company in this Agreement except on
terms consistent with this SECTION 2.3. Other than as specifically provided in
and this SECTION 2.3 and SECTION 2.4, Company shall not have the right to grant
sublicenses to any third party under the licenses granted pursuant to SECTION
2.1.
2.4 CONTRACTING. Company may manufacture the Licensed Product (but not the
bulk CAPTISOL, except as set forth in SECTION 3.7) or contract the manufacture
of the Licensed Product (but not the manufacture of bulk CAPTISOL, except as set
forth in SECTION 3.7) with third party manufacturers. Company shall notify CyDex
in writing of Company's intent to do so (such notice to include the identity and
location of the proposed third party manufacturers). To the extent necessary to
engage a third party manufacturer for the Licensed Product, Company shall be
permitted under this Agreement to grant any such third party manufacturer a
sublicense under the licenses granted to Company pursuant to SECTION 2.1 solely
for such purposes; provided that each such sublicense shall be subject to, and
consistent with, the terms and conditions of this Agreement, and shall provide
that any such sublicense may not be further sublicensed by the third party
manufacturer.
3. MANUFACTURE AND SUPPLY OF CAPTISOL.
3.1 PURCHASE OF CAPTISOL. Except as set forth in SECTION 3.7, Company
agrees that Company and its Affiliates and Sublicensees shall purchase CAPTISOL
exclusively from CyDex during the Term, and that they shall not manufacture (or
have manufactured on their behalf) CAPTISOL without CyDex's prior written
consent. CyDex agrees that CyDex shall produce (or have produced for it by a
Third-Party Manufacturer in accordance with SECTION 3.6) and sell and deliver to
Company one hundred percent (100%) of Company's and its Affiliates' and
Sublicensees' requirements for CAPTISOL, during the Term and subject to the
provisions of this Agreement and provided that in no event shall CyDex be
obligated to supply to Company or its Affiliates or Sublicensees more than an
aggregate quantity of [**] kilograms of CAPTISOL per year (the "VOLUME
THRESHOLD"). Purchases of CAPTISOL may include Research Grade CAPTISOL, Clinical
Grade CAPTISOL and/or Commercial Grade CAPTISOL. Company may place orders for
CAPTISOL on behalf of its Affiliates and Sublicensees; provided, however that:
(a) Company shall instruct CyDex as to the location for the shipment thereof;
(b) Company shall guarantee payment to CyDex of all amounts payable with respect
to all binding orders; and (c) if Company requests that CyDex deliver such
orders to Company for re-delivery thereof by Company to its Affiliates or
Sublicensees, Company shall comply with all applicable laws, rules
6
and regulations applicable to the transportation of CAPTISOL from Company to its
Affiliates and Sublicensees.
3.2 SUPPLY TERMS.
(A) LONG-TERM FORECAST. No later than [**] months prior to the
anticipated Commercial Launch Date by Company or its Affiliates or Sublicensees
of a Licensed Product in any particular country, Company shall provide CyDex
with a non-binding forecast setting forth Company's estimate of the required
quantities of Commercial Grade CAPTISOL for each of the following [**] years.
Such long-term forecast shall thereafter be updated by Company at least [**]
every quarter.
(B) BINDING DETAILED FORECAST. At least [**] calendar quarters prior
to the first order of Commercial Grade CAPTISOL, Company shall deliver to CyDex
a detailed rolling forecast setting forth Company's requirements and anticipated
delivery schedules for Commercial Grade CAPTISOL for each calendar quarter
during the succeeding [**] month period (the "DETAILED FORECAST"). For purposes
of this Agreement, a calendar quarter means the consecutive three (3) month
period ending March 31, June 30, September 30, and December 31, respectively.
The parties acknowledge and agree that the first calendar quarter covered in the
Detailed Forecast may be for a period less than the full three (3) month period
but that each subsequent calendar quarter shall be for a full three (3) month
period. The Detailed Forecast shall thereafter be updated by Company quarterly
on a rolling basis, no later than the first day of each calendar quarter, so
that each calendar quarter CyDex shall have been provided with a rolling
Detailed Forecast for each calendar quarter during the twelve (12) month period
commencing on the first day of the next calendar quarter following the date on
which such Detailed Forecast is submitted. The Detailed Forecast shall be firm
and binding on Company, subject to permissible variances set forth in SECTION
3.2(C) below, with respect to the first, second, and third calendar quarters
covered by such updated Detailed Xxxxxxxx ("X0", "X0", "X0", respectively, and
where the fourth calendar quarter shall be " Q4"). If Company fails to provide
any updated Detailed Forecast in accordance with this SECTION 3.2(B), the
Detailed Forecast last provided by Company shall be deemed to be Company's
binding Detailed Forecast for the next succeeding twelve (12) month period.
(C) DETAILED FORECAST VARIANCES.
(I) FOR THE FIRST YEAR. During the first year in which Company
orders Commercial Grade Captisol, each Detailed Forecast may modify the amount
of Commercial Grade CAPTISOL estimated in the previous Detailed Forecast in
accordance with the following limitations (the "PURCHASE VOLUME LIMITATIONS"):
(1) for the Q1 covered by such updated Detailed Forecast,
and regardless of the quantity of Commercial Grade CAPTISOL forecasted in the
Detailed Forecast provided that it does not exceed the Volume Threshold, then no
change in excess of a [**] percent ([**]%) volume increase or decrease may be
made to the forecast provided for the Q2 in the immediately preceding Detailed
Forecast without the prior express written consent of CyDex;
7
(2) for the Q2 covered by such updated Detailed Forecast,
and regardless of the quantity of Commercial Grade CAPTISOL forecasted in the
Detailed Forecast provided that it does not exceed the Volume Threshold, then no
change in excess of a [**] percent ([**]%) volume increase or decrease may be
made to the forecast provided for the Q3 in the immediately preceding Detailed
Forecast without the prior express written consent of CyDex; and
(3) for the Q3 covered by such updated Detailed Forecast,
and regardless of the quantity of Commercial Grade CAPTISOL forecasted in the
Detailed Forecast provided that it does not exceed the Volume Threshold, then no
change in excess of a [**] percent ([**]%) volume increase or decrease may be
made to the forecast provided for the Q4 in the immediately preceding Detailed
Forecast without the prior express written consent of CyDex.
(II) FOR SUBSEQUENT YEARS. After the first year in which Company
orders Commercial Grade CAPTISOL, the Purchase Volume Limitations shall be
determined in accordance with the following:
(1) for the Q1 covered by such updated Detailed Forecast,
and regardless of the quantity of Commercial Grade CAPTISOL forecasted in the
Detailed Forecast provided that it does not exceed the Volume Threshold, no
change may be made to the forecast provided for the Q2 in the immediately
preceding Detailed Forecast without the prior express written consent of CyDex;
(2) for Q2 covered by such updated Detailed Forecast:
A. if the quantity of Commercial Grade CAPTISOL
forecasted in the Detailed Forecast is less than [**] kilograms per calendar
quarter, then no change in excess of a [**] percent ([**]%) volume increase or
decrease may be made to the forecast provided for the Q3 in the immediately
preceding Detailed Forecast without the prior express written consent of CyDex;
and
B. if the quantity of Commercial Grade CAPTISOL
forecasted in the Detailed Forecast is equal to or greater than [**] kilograms
per calendar quarter but less than the Volume Threshold, then no change in
excess of a [**] percent ([**]%) volume increase or decrease may be made to the
forecast provided for the Q3 in the immediately preceding Detailed Forecast
without the prior express written consent of CyDex.
(3) for Q3 covered by such updated Detailed Forecast:
A. if the quantity of Commercial Grade CAPTISOL
forecasted in the Detailed Forecast is less than [**] kilograms per calendar
quarter, then no change in excess of a [**] percent ([**]%) volume increase or
decrease may be made to the forecast provided for the Q4 in the immediately
preceding Detailed Forecast without the prior express written consent of CyDex;
and
B. if the quantity of Commercial Grade CAPTISOL
forecasted in the Detailed Forecast is equal to or greater than [**] kilograms
per calendar quarter but less than the Volume Threshold, then no change in
excess of a [**] percent ([**]%) volume
8
increase or decrease may be made to the forecast provided for the Q4 in the
immediately preceding Detailed Forecast without the prior express written
consent of CyDex.
(D) PURCHASE ORDERS. Together with each Detailed Forecast provided
under SECTION 3.2(B) above, Company shall place a firm purchase order with CyDex
in a form mutually agreed upon by the parties, for Company's order of Commercial
Grade CAPTISOL for Q1 delivery consistent with the Detailed Forecast. Each
purchase order, for all grades of CAPTISOL, shall specify: (i) the grade of
CAPTISOL ordered (i.e., Commercial Grade CAPTISOL, Clinical Grade CAPTISOL or
Research Grade CAPTISOL); (ii) quantities; (iii) delivery dates; and (iv)
reasonable shipping instructions. CyDex shall use commercially reasonable
efforts to comply with Company's requested delivery dates; provided, however,
that the purchase order is received by CyDex at least [**] days prior to the
stipulated delivery date. No purchase order shall be binding upon CyDex until
accepted by CyDex in writing. CyDex shall accept such orders for Commercial
Grade CAPTISOL from Company to the extent that the quantities of CAPTISOL
ordered do not exceed the Purchase Volume Limitations. CyDex shall not be
obligated to accept such orders to the extent that the quantities of Commercial
Grade CAPTISOL ordered exceed the Purchase Volume Limitations, but CyDex shall
use good faith efforts to fill such orders for such excess quantities from
available supplies. If CyDex, despite the use of good faith efforts, is unable
to supply such quantities that exceed the Purchase Volume Limitations to
Company, such inability to supply shall not be deemed to be a breach of this
Agreement by CyDex or a failure (including a Supply Failure) by CyDex to supply
for any purpose. CyDex shall notify Company within [**] business days after its
receipt of Company's purchase order of its ability to fill any amounts of such
order, whether in excess of the Purchase Volume Limitations or not, which notice
shall include an explanation in reasonable detail of the reason for CyDex's
inability to comply with a particular order that does not exceed the Purchase
Volume Limitations and CyDex's proposed course of action for remedying such
failure. If any purchase order or other document submitted by Company hereunder
or any other document passing between the parties contains terms or conditions
in addition to or inconsistent with the terms of this Agreement, the terms of
this Agreement shall control and prevail and such additional or inconsistent
terms are hereby expressly rejected.
3.3 DELIVERY. CyDex shall deliver to Company or Company's designee each
order of CAPTISOL, packed for shipment in accordance with CyDex's customary
practices and the Specifications, EXW (Incoterms 2000) CyDex's production point
or storage facilities. Title and risk of loss and/or damage to CAPTISOL shall
pass to Company upon delivery of CAPTISOL to Company or Company's designee at
CyDex's production point or storage facilities. If any quantities actually
delivered to Company or Company's designee pursuant to an accepted purchase
order may vary from the quantities reflected in such purchase order by up to
[**] percent ([**]%) and still be deemed to be in compliance with such purchase
order; provided, however, that Company shall only be invoiced and required to
pay for the quantities of CAPTISOL that CyDex actually delivers to Company or
Company's designee. Subject to the Company's rights to use an Alternate Supplier
in the event of a Supply Failure as provided in SECTION 3.7, CyDex will use
commercially reasonable efforts to include, in the next shipment of CAPTISOL to
Company, any quantities ordered pursuant to an accepted purchase order but not
delivered.
9
3.4 MODIFIED SPECIFICATIONS. CyDex shall have the right to change the
Specifications from time to time during the Term. In such event, CyDex shall
give Company at least [**] days notice of such change and, if requested by
Company, shall provide to Company the right to purchase an amount of CAPTISOL
not greater than a [**]-year supply prior to such change in Specifications if
such change impacts the Company's regulatory efforts related to the Licensed
Product or commercial sale of the Licensed Product. Company shall cooperate with
CyDex to have such change approved by all regulatory agencies having
jurisdiction. In addition, if any regulatory agency having jurisdiction or cGMP
requires CyDex to implement any changes to the Specifications, CyDex shall use
all reasonable efforts to make such changes. In each case, CyDex shall promptly
(but in all cases within a reasonable period of time in advance of the
anticipated implementation of such change to reasonably allow Company to
evaluate the consequences of such change) advise Company as to any lead-time
changes or other terms that may result from a change to the Specifications.
CyDex shall be responsible for all costs incurred by CyDex arising from any
change requested by CyDex and not otherwise required by cGMP or any regulatory
authority (other than Company's cost to purchase any additional supply of
CAPTISOL). Company shall be responsible for all costs incurred by CyDex
(including without limitation costs incurred for materials already purchased by
CyDex or its Third-Party Manufacturer expressly for Company, its Affiliates or
Sublicensees, in each case solely to the extent that such materials can not be
redeployed or sold to other customers at or above their actual cost) related to
implementing any change in Specifications that is (a) requested by Company or
(b) required by cGMP or any regulatory authority specifically to the Licensed
Product (i.e., is not a change made generally with respect to CAPTISOL for all
products using CAPTISOL as a component).
3.5 QUALITY CONTROL; ACCEPTANCE AND REJECTION.
(A) QUALITY CONTROL. CyDex shall conduct or have conducted quality
control testing of CAPTISOL prior to shipment in accordance with the
Specifications and other CyDex-approved quality control testing procedures (the
"TESTING METHODS"). CyDex shall retain or have retained accurate and complete
records pertaining to such testing. Each shipment of CAPTISOL hereunder shall be
accompanied by a certificate of analysis and a statement of cGMP compliance for
bulk excipients for each lot of CAPTISOL therein.
(B) TEST METHODS. CyDex shall provide to Company copies of all
CAPTISOL Testing Methods to allow the Company to conduct incoming testing in
accordance with CyDex's quality control requirements.
(C) ACCEPTANCE TESTING. Company shall have a period of [**] days from
the date of receipt to test or cause to be tested CAPTISOL supplied under this
Agreement. Company or its designee shall have the right to reject any shipment
of CAPTISOL that does not conform with the Specifications at the time of
delivery pursuant to SECTION 3.3 hereof when tested in accordance with the
Testing Methods. All shipments of CAPTISOL shall be deemed accepted by Company
unless CyDex receives written notice of rejection from Company within such [**]
day period describing the reasons for the rejection in reasonable detail. Once a
delivery of CAPTISOL is accepted or deemed accepted hereunder, Company shall
have no recourse against CyDex in the event CAPTISOL is subsequently deemed
unsuitable for use for any reason, except as provided in SECTION 3.5(E) and
SECTION 10.1 below.
10
(D) CONFIRMATION. After its receipt of a notice of rejection from
Company pursuant to SECTION 3.5(C) above, CyDex shall notify Company as soon as
reasonably practical whether it accepts Company's basis for rejection and
Company shall cooperate with CyDex in determining whether such rejection was
necessary or justified. If the parties are unable to agree as to whether a
shipment of CAPTISOL supplied by CyDex or its Third-Party Manufacturer hereunder
meets the Specifications, such question shall be submitted to an independent
quality control laboratory mutually agreed upon by the parties. The findings of
such independent laboratory shall be binding upon the parties. The cost of the
independent quality control laboratory shall be borne by the party whose results
are shown by such laboratory to have been incorrect.
(E) LATENT DEFECTS. As soon as either party becomes aware of a Latent
Defect in any shipment of CAPTISOL, but in any case within [**] days of learning
of such Latent Defect, it shall immediately notify the other party, and such
shipment of CAPTISOL shall be deemed rejected as of the date of such notice,
subject to the provisions of SECTION 3.5(D) above relating to testing by an
independent quality control laboratory in cases of disputes. Notwithstanding the
foregoing, Company shall have no right to reject or return, and CyDex shall have
no obligation to refund or replace, any CAPTISOL that has a Latent Defect if
such Latent Defect was identified by Company later than [**] months after the
date of delivery of such CAPTISOL. For purposes of this SECTION 3.5(E), "Latent
Defect" means a failure of the shipment of CAPTISOL to conform in all material
respects with the Specifications, which non-conformities were not discovered
upon reasonable and customary physical inspection and incoming quality assurance
testing carried out by Company or its designee on samples of such shipment of
CAPTISOL.
(F) RETURN OR DESTRUCTION OF REJECTED SHIPMENTS. Company may not
return or destroy any batch of CAPTISOL until it receives written notification
from CyDex that CyDex does not dispute that the batch fails to meet the
Specifications. CyDex will indicate in its notice either that Company is
authorized to destroy the rejected batch of CAPTISOL or that CyDex requires
return of the rejected CAPTISOL. Upon written authorization from CyDex to do so,
Company shall promptly destroy the rejected batch of CAPTISOL and provide CyDex
with written certification of such destruction. Upon receipt of CyDex's request
for return, Company shall promptly return the rejected batch of CAPTISOL to
CyDex. In each case, CyDex will be responsible for all documented, reasonable
costs incurred by Company for the destruction or return of the rejected
CAPTISOL.
(G) REFUND OR REPLACEMENT. Company shall not be required to pay any
invoice with respect to any shipment of CAPTISOL properly rejected pursuant to
this SECTION 3.5. Notwithstanding the foregoing, Company shall be obligated to
pay in full for any rejected shipment of CAPTISOL that is subsequently
determined by an independent quality control laboratory mutually agreed by the
parties under SECTION 3.5(D) above to meet the Specifications, irrespective of
whether Company has already paid CyDex for a replacement shipment. If Company
pays in full for a shipment of CAPTISOL and subsequently properly rejects such
shipment in accordance with this SECTION 3.5, Company shall be entitled, upon
confirmation that such shipment failed to meet the Specifications in all
material respects, at Company's option, either: (i) to a refund or credit equal
to the purchase price paid with respect to such rejected shipment; or (ii) to
require CyDex to replace such rejected shipment at no
11
additional cost to Company. Company acknowledges and agrees that, except for the
indemnification obligations set forth in SECTION 10.1 below, Company's rights to
a payment or replacement as described in this SECTION 3.5(G) shall be Company's
sole and exclusive remedy, and CyDex's sole liability, with respect to
non-conforming CAPTISOL delivered hereunder.
(H) EXCEPTIONS. Company's rights of rejection, return, refund and
replacement set forth in this SECTION 3.5 shall not apply to any CAPTISOL that
is non-conforming due to damage (i) caused by Company, its Affiliates or
Sublicensees or their respective employees or agents, including but not limited
to, misuse, neglect, improper storage, transportation or use beyond any dating
provided or (ii) that occurs subsequent to delivery of such CAPTISOL to the
carrier at the point of origin, including but not limited to any damage caused
thereafter by accident, fire or other hazard (unless such damage is attributable
to CyDex's or its Third Party Manufacturer's negligence or willful misconduct),
and CyDex shall have no liability or responsibility to Company with respect
thereto.
3.6 FACILITIES AND INSPECTIONS. Without limiting CyDex's responsibility
under this Agreement, CyDex shall have the right at any time to satisfy its
supply obligations to Company hereunder either in whole or in part through
arrangements with third parties engaged to perform services or supply facilities
or goods in connection with the manufacture or testing of CAPTISOL (each, a
"THIRD-PARTY MANUFACTURER"). CyDex shall give Company prior written notice of
any such arrangement, provided, the parties hereby acknowledge and agree that,
as of the Effective Date, The Hovione Group is a Third-Party Manufacturer. CyDex
shall permit no more than [**] of Company's authorized representatives, during
normal working hours and upon reasonable prior notice to CyDex but in no event
less than [**] days prior notice, to inspect that portion of all CyDex
facilities utilized for the manufacture, preparation, processing, storage or
quality control of CAPTISOL or such facilities of any Third-Party Manufacturer,
no more frequently than [**] per calendar year (unless the inspection reveals
material deficiencies or concerns which require additional follow-up
inspections, including without limitation, noncompliance with Specifications or
any applicable law). If such inspection is of the facilities of a Third-Party
Manufacturer, Company shall pay CyDex's cost of inspection (as of the Effective
Date, [**] Dollars ($[**]) per person per day). Company's authorized
representatives shall be accompanied by CyDex personnel at all times, shall be
qualified to conduct such manufacturing audits, and shall comply with all
applicable rules and regulations relating to facility security, health and
safety. The results of such inspection shall be deemed Confidential Information
of CyDex, which shall be governed by the terms of SECTION 8 (Confidentiality)
hereof. In no event shall any such manufacturing audit exceed [**] days in
duration. Company shall ensure that its authorized representatives conduct each
manufacturing audit in such a manner as to not interfere with the normal and
ordinary operation of CyDex or its Third-Party Manufacturer. Except as expressly
set forth in this SECTION 3.6, neither Company nor its Affiliates, Sublicensees
or their respective employees or representatives shall have access to CyDex's
facilities or the facilities of any Third-Party Manufacturer. CyDex shall inform
Company of any regulatory inspection that may impact CAPTISOL or the Licensed
Product and shall provide Company with a summary of the outcome of such
inspection or a copy of any Form 483 or other letter of deficiency received from
a regulatory agency inspection.
12
3.7 INABILITY TO SUPPLY.
(A) NOTICE. CyDex shall notify Company if CyDex is unable to supply
the quantity of (i) Commercial Grade CAPTISOL ordered by Company in accordance
with the Purchase Volume Limitations set forth in SECTION 3.2(C) or (ii)
Research Grade CAPTISOL or Clinical Grade CAPTISOL ordered by Company as set
forth in SECTION 3.2(D) above: (1) within [**] business days after CyDex's
receipt of a purchase order from Company as provided in SECTION 3.2(D); or (2)
immediately upon becoming aware of an event of force majeure or any other event
that would render CyDex unable to supply to Company the quantity of CAPTISOL
that CyDex is required to supply hereunder.
(B) ALLOCATION. Subject to SECTION 3.7(C), If CyDex is unable to
supply to Company the quantity of CAPTISOL that CyDex is required to supply
hereunder, CyDex (i) shall allocate its available CAPTISOL among Company and any
other purchasers of CAPTISOL with which CyDex then has an on-going contractual
relationship, in proportion to the quantity of CAPTISOL for which each of them
has orders pending at such time and (ii) shall take all reasonable steps
necessary to minimize supply delays. The supply allocation provided in this
SECTION 3.7(B) shall be CyDex's sole obligation and Company's sole and exclusive
remedy for any supply shortage.
(C) ALTERNATE SUPPLIERS. Notwithstanding anything in the foregoing to
the contrary, in the event of a Supply Failure, Company shall have the right to
purchase from one or more alternate suppliers ("ALTERNATE SUPPLIERS") its
requirements for sulfobutylether (beta)(beta) cyclodextrin, sodium salt, to the
extent necessary to replace CAPTISOL not provided by CyDex due to the Supply
Failure, until such time as CyDex reasonably demonstrates that CyDex is able to
resume manufacture and supply of CAPTISOL hereunder, provided, that Company
shall not be obligated to purchase any of its requirements from CyDex until
Company has fulfilled all obligations or commitments, if any, undertaken by
Company in connection with Company's arrangements with the Alternate Suppliers.
4. COMPENSATION.
4.1 PAYMENTS AND ROYALTIES FOR LICENSES.
(A) ONE-TIME FEE. Company shall pay to CyDex a non-refundable,
non-creditable, one-time fee of FIFTY THOUSAND U.S. DOLLARS ($50,000) in partial
consideration of the rights granted Company under this Agreement, which amount
shall be due and payable in full upon the Effective Date.
(B) MILESTONE PAYMENTS ASSOCIATED WITH DEVELOPMENT AND REGULATORY
APPROVAL. Within [**] days following the occurrence of each of the milestone
events listed below with respect to the Licensed Product, Company shall provide
written notice to CyDex of the achievement of such milestone event, and within
[**] days of the occurrence of each of the milestone events, pay to CyDex the
applicable non-refundable milestone fee listed next to each such event in
further consideration of the rights granted Company hereunder. The milestone
payments are as follows:
13
MILESTONE MILESTONE PAYMENT IN US DOLLARS
--------- -------------------------------
First dosing of the first patient in the first
Phase III Clinical Trial $[**]
Filing NDA for Licensed Product with the
FDA in the United States $[**]
FDA's Approval of NDA for Licensed Product $[**]
(C) MILESTONE PAYMENTS ASSOCIATED WITH SALES PERFORMANCE OF LICENSED
PRODUCT Within [**] days following the occurrence of each of the milestone
events listed below with respect to the Licensed Product, Company shall provide
written notice to CyDex of the achievement of such milestone event, and within
[**] days of the occurrence of each of the milestone events, pay to CyDex the
applicable non-refundable milestone fee listed next to each such event in
further consideration of the rights granted Company hereunder. The milestone
payments are as follows:
MILESTONE MILESTONE PAYMENT IN US DOLLARS
--------- -------------------------------
One-time, Non-refundable Payment upon
aggregate Sales for Licensed Product on a
Worldwide Basis of US$[**] in a 12-month
period $[**]
One-time, Non-refundable Payment upon
aggregate Sales for Licensed Product on a
Worldwide Basis of US$[**] in a 12-month
period $[**]
All Milestones associated with SECTIONS 4.1(A), 4.1(B) and 4.1(C), shall be
payable upon the occurrence of the triggering event (provided such triggering
event occurs during the term of this Agreement), regardless of the date at which
each of these events takes place. For purposes of clarity, each milestone
payment under SECTION 4.1(A), 4.1(B) and 4.1(C) is a one-time payment (i.e., not
a one time per-Licensed Product payment) so that the total fees payable by
Company pursuant to SECTIONS 4.1(A), 4.1(B) and 4.1(C) shall not exceed
$2,975,000. It is explicitly agreed and understood that all milestone payment
obligations shall survive the expiration of this Agreement, and shall be payable
in full and within the timeframe stated above if the Licensed Product achieves
such milestones regardless of the expiration of any of the Licensed Patents.
Further, it is explicitly agreed and understood that Company shall be
responsible for any payments related to achievement of any milestones which have
accrued prior to the effective date of termination or expiration of this
Agreement. It is explicitly agreed and understood that if the Agreement is
terminated, the Company shall have no milestone payment obligations at all other
than for any milestones that were achieved prior to termination of the
Agreement.
(D) ROYALTIES.
(I) In addition to amounts payable pursuant to SECTIONS 4.1(A)
and 4.1(B) and 4.1(C) above, and subject to the reduction set forth in SECTION
4.1(D)(III) below,
14
Company shall pay to CyDex a royalty on Net Sales on the Licensed Product at the
rate(s) specified below, payable on a quarterly basis:
ANNUAL NET SALES TIER OF LICENSED PRODUCT ON ROYALTY RATE BEFORE ROYALTY RATE AFTER
A WORLDWIDE BASIS IN US DOLLARS GENERIC COMPETITION GENERIC COMPETITION
-------------------------------------------- ------------------- -------------------
Net Sales < $[**] [**]% [**]%
$[**] < or = Net Sales < $[**] [**]% [**]%
$[**] < or = Net Sales [**]% [**]%
For purposes of clarity, royalties on Net Sales of Licensed Product in a
calendar year shall be determined by applying the applicable tiered royalty rate
corresponding to incremental Net Sales. For example, if, during a calendar year,
worldwide Net Sales with respect to Licensed Product were equal to $[**],
royalties payable pursuant to clause (d)(i) above (assuming no Generic
Competition) would, subject to the other provisions of this Agreement, equal
$[**] (calculated as $[**] multiplied by [**]%, $[**] multiplied by [**]%, and
$[**] multiplied by [**]%).
(II) "GENERIC COMPETITION " will be defined as the earlier of :
(a) a bona fide generic version of CAPTISOL available for purchase in the United
States, which the FDA accepts as a straight substitute for branded CAPTISOL; (b)
a bona fide generic version of the Licensed Product within the Territory on a
country-by-country basis; and (c) the fifth anniversary of the Commercial Launch
Date of Licensed Product within the Territory on a country-by-country basis.
(III) The royalty payments owed by Company to CyDex will reduce
to zero for sales in each country where Licensed Product is commercialized at
the later of: (a) the expiry of the last relevant patent in the Licensed Patents
that claims CAPTISOL in the country, or (b) the tenth anniversary of the
Commercial Launch Date of Licensed Product in that country. Upon expiration of
Company's royalty obligations hereunder, the licenses granted to Company under
SECTION 2.1 shall become fully paid-up, perpetual and irrevocable.
(IV) In establishing the royalty structure hereunder, the parties
recognize, and Company acknowledges, the substantial value of the various
obligations being undertaken by CyDex under this Agreement, in addition to the
grant of the licenses under the Licensed Patents and CAPTISOL Data Package, to
enable the rapid and effective market introduction of the Licensed Product in
the Territory. The parties have agreed to the payment structure, including
without limitation the royalty payments, set forth herein as a convenient and
fair mechanism to compensate CyDex for these obligations.
4.2 PRICING FOR CAPTISOL.
(A) PRICING. The purchase prices for CAPTISOL are as specified in
EXHIBIT C attached hereto. CyDex reserves the right to increase the purchase
prices set forth on EXHIBIT C on each January 1 during the Term, by written
notice to Company, by a percentage equal to the aggregate percentage increase,
if any, in the Producer Price Index PCU325412 (Pharmaceutical preparations) as
reported by the Bureau of Labor Statistics, U.S. Department of Labor ("Price
15
Index"), for the 12-month period ending December 31 of the prior year, using the
year 2007 as the initial base year from which to apply price changes based on
the Price Index. The minimum order for Commercial Grade CAPTISOL shall be [**]
kilograms prior to the Commercial Launch Date and [**] kilograms after the
Commercial Launch Date. Notwithstanding the foregoing, if Company fails to place
a firm purchase order in any Q1 for a quantity of Commercial Grade CAPTISOL
equal to or greater than the quantity of Commercial Grade CAPTISOL that Company
is obligated to purchase pursuant to the applicable Detailed Forecast, then
CyDex shall invoice, and Company shall be obligated to pay, the difference in
the amount of CAPTISOL that Company did purchase in such quarter and the amount
of CAPTISOL that Company was obligated to purchase pursuant to the Detailed
Forecast for such Q1.
(B) INVOICING; PAYMENT. CyDex shall invoice Company upon shipment of
each order of CAPTISOL. All invoices shall be sent to the address specified in
the applicable purchase order, and each invoice shall state the purchase price
for CAPTISOL in such shipment, plus any insurance, taxes, shipping costs or
other costs incidental to such purchase or shipment initially paid by CyDex but
to be borne by Company hereunder; provided, however, that if such insurance,
taxes, shipping costs or other costs incidental to such purchase or shipment
initially paid by CyDex but to be borne by Company are not known at the time
CyDex invoices Company for the purchase price for the CAPTISOL ordered by
Company, CyDex may invoice such costs at a later date. Payment of such invoices
shall be made within [**] days after the date of receipt thereof.
4.3 CURRENCY. All amounts due hereunder are stated in, and shall be paid
in, U.S. dollars. Net Sales based on foreign revenue will be converted to U.S.
dollars at the rate of exchange published in Reuters Daily Rate Report or The
Wall Street Journal, Eastern U.S. Edition on the last day of each calendar
quarter. Company shall provide CyDex, together with each royalty payment owed
pursuant to SECTION 4.1(D) above, a schedule detailing the calculation of Net
Sales resulting from the conversion of foreign revenue to U.S. dollars as set
forth herein.
4.4 TAXES. All amounts due hereunder exclude all applicable sales, use, and
other taxes, and Company will be responsible for payment of all such taxes
(other than taxes based on CyDex's income), fees, duties, and charges, and any
related penalties and interest, arising from the payment of amounts due
hereunder or the sublicense or license, as the case may be, under the Licensed
Patents hereunder. Company shall make all payments to CyDex hereunder free and
clear of, and without reduction for, any withholding taxes; any such taxes
imposed on payments of amounts to CyDex hereunder will be Company's sole
responsibility, and Company will provide CyDex reasonable documentation, or such
other evidence as CyDex may reasonably request, to establish that such taxes
have been paid. Company shall indemnify and hold CyDex harmless from any and all
such taxes and any actions brought against CyDex by any taxing authority with
respect Company's failure to pay any such taxes which Company is obligated to
pay hereunder.
4.5 LATE PAYMENTS. Unpaid balances not subject to a reasonable, good-faith
dispute by Company shall accrue interest, from due date until paid, at a rate
equal to the lesser of (i) the prime rate, as reported in The Wall Street
Journal, Eastern U.S. Edition, on the date such payment is due, plus an
additional two percent (2%) or (ii) the maximum rate permitted under
16
applicable law. If any amount due hereunder and not subject to a reasonable,
good-faith dispute by Company remains outstanding for more than [**] days after
its due date, CyDex may, in addition to any other rights or remedies it may
have, refuse to ship CAPTISOL hereunder except upon payment by Company in
advance.
5. RECORDS; REPORTS; AUDIT.
5.1 RECORDS. During the Term and for a period of [**] years thereafter,
Company shall, and shall require its Affiliates and Sublicensees to maintain
complete and accurate records relating to Net Sales of Licensed Product.
5.2 REPORTS. Within [**] calendar days following the conclusion of each
calendar quarter during the Term, Company shall provide CyDex with written
reports with respect to such calendar quarter that set forth in reasonable
detail information regarding Company's, its Affiliates' and Sublicensees' Net
Sales of the Licensed Product in the Territory during such calendar quarter so
as to enable the calculation of the royalty payments due hereunder.
5.3 AUDIT. During the Term and for a period of [**] years thereafter, CyDex
shall have the right, during normal business hours and upon reasonable notice,
to inspect and audit Company's, its Affiliates' and Sublicensees' records
relevant to Net Sales, but no more often than [**] per year. The costs of such
audits shall be borne solely by CyDex; provided, however, that in the event such
an audit reveals either a failure by Company to pay any applicable milestone
payment due or an underpayment by Company of royalties owed hereunder of more
than five percent (5%), Company shall immediately (i) pay CyDex all amounts by
which Company has underpaid CyDex as revealed by the audit, plus interest
accrued thereon (from the applicable original due date) at the rate set forth in
SECTION 4.5 above and (ii) reimburse CyDex for the costs of such audit. In the
event that an audit reveals that Company's payments are in excess of those
required under this Agreement, CyDex shall credit the amount of such overpayment
plus interest accrued thereon (from the applicable original payment date)
towards any amounts payable by Company to CyDex under this Agreement within [**]
days of such audit, and shall promptly remit to Company any portion of such
overpayment which has not been credited within such [**] day period. All
information concerning royalty payments and reports, and any information learned
in the course of any audit or inspection under this SECTION 5.3, shall be deemed
to be Confidential Information of Company, subject to the terms and provisions
of SECTION 8 (Confidentiality) below, except to the extent necessary for CyDex
to enforce its rights under this Agreement.
6. DEVELOPMENT AND COMMERCIALIZATION BY COMPANY
6.1 DILIGENCE. Company agrees that, during the Term, it will use (whether
directly or through Affiliates or Sublicensees) commercially reasonable efforts
to develop and commercialize Licensed Product in the Territory. For purposes of
this SECTION 6.1, "COMMERCIALLY REASONABLE EFFORTS" shall mean efforts that are
at least as great as those efforts and resources used by a similarly situated
biotechnology company for a product at a similar stage in its development or
product life and with similar market potential, taking into account efficacy,
safety, approved labeling, the competitiveness of alternative products or
technologies in the marketplace, the patent and other proprietary position of
the product, the likelihood of regulatory
17
approval, the profitability of the product, alternative products and other
relevant factors. The parties acknowledge and agree that Company has not yet
determined whether or not it will use CAPTISOL to develop or commercialize the
Compound. If the Company decides not to use CAPTISOL in the commercialization of
the Compound, it will so notify CyDex in writing, and subject to all binding
commitments made under this Agreement prior to CyDex's receipt of such notice,
Company may terminate this Agreement.
6.2 COSTS AND EXPENSES. Company shall be solely responsible for all costs
and expenses related to its development and commercialization of the Licensed
Product, including without limitation costs and expenses associated with all
preclinical activities and clinical trials, and all regulatory filings and
proceedings relating to the Licensed Product.
6.3 PRECLINICAL IN VIVO STUDIES. If Company wishes to conduct any
preclinical in vivo study utilizing CAPTISOL in the Licensed Product as a single
agent at doses greater than those set forth in EXHIBIT D, Company shall notify
CyDex of any such study and of the protocol therefor in writing at least [**]
days prior to commencing such study. If CyDex determines in its reasonable good
faith determination that such study would materially adversely affect a product
utilizing CAPTISOL, CyDex shall notify Company within [**] days of receipt of
such notice and protocol from Company, and the parties shall discuss and attempt
to resolve the matter in good faith. If the parties cannot resolve such matter
within [**] days after CyDex notifies Company of such determination, then the
dispute shall be presented to the chief executive officer of each party, or his
or her respective designee, for resolution. If the parties' chief executive
officers, or their respective designees, cannot resolve the dispute within [**]
days of being requested by a party to resolve such dispute, either party may
initiate a short-form arbitration proceeding pursuant to SECTION 14.4(B)
(Short-Form Arbitration) below. If CyDex determines in its reasonable good faith
determination that such study would not materially adversely affect a product
utilizing CAPTISOL, CyDex shall notify Company within [**] days following
receipt of Company's notice. Company agrees to (i) promptly inform CyDex if any
adverse effects are observed and ascribed to CAPTISOL in any study conducted
under this SECTION 6.3, and (ii) provide CyDex with copies of the final and full
reports of all studies conducted under this SECTION 6.3, promptly upon
completion thereof, which reports shall be deemed Confidential Information of
Company which is subject to the terms of SECTION 8 hereunder.
6.4 RIGHT OF REFERENCE. Company shall have the right to reference the DMF
and any other CyDex regulatory documents related to CAPTISOL which are on file
with applicable regulatory authorities solely in connection Company's regulatory
filings submitted in connection with developing the Licensed Product under an
IND or obtaining Marketing Approval for the Licensed Product.
6.5 ACCESS TO COMPANY'S DATA. CyDex shall have the right to reference and
utilize all toxicology/safety and other relevant scientific data developed on
CAPTISOL alone (and not in conjunction with a product formulation) by Company,
its Sublicensees or Affiliates in connection with CyDex's development and
commercialization of CAPTISOL or compounds, at no cost to CyDex. Upon request by
CyDex, Company shall either provide CyDex with a copy of all such data or shall
make such data accessible to CyDex at such times and locations mutually agreed
upon by the parties.
18
7. REGULATORY MATTERS.
7.1 CAPTISOL INFORMATION SUBMITTED FOR REGULATORY REVIEW. Except as
otherwise set forth herein, Company shall be solely responsible for all
communications with regulatory agencies in connection with the Licensed Product
and CyDex shall not, without Company's consent, correspond or communicate with
any regulatory agency regarding the Licensed Product. CyDex shall, as soon as
practicable after any contact with or receipt of any communication from any
regulatory authority regarding Licensed Product, forward a copy or description
of the same to Company. Notwithstanding the foregoing, Company shall provide
CyDex with copies of the portions of all regulatory submissions containing
CAPTISOL data alone (and not in conjunction with any product formulation) [**]
days prior to submission and shall allow CyDex to review and comment upon said
submissions. If CyDex determines in its reasonable good faith determination that
any such submission would materially adversely affect a product utilizing
CAPTISOL, CyDex shall notify Company within [**] days of receipt of such
submission, and the parties shall discuss and attempt to resolve the matter in
good faith. If the parties cannot resolve such matter within [**] days after
CyDex notifies Company of such a determination, then the dispute shall be
presented to the chief executive officer of each party, or his or her respective
designee, for resolution. If the parties' chief executive officers, or their
respective designees, cannot resolve the dispute within [**] days of being
requested by a party to resolve such dispute, either party may initiate a
short-form arbitration proceeding pursuant to SECTION 14.4(B) below. Company
shall inform CyDex of meetings with the FDA (or other regulatory agencies in the
Territory) regarding the Licensed Product [**] days prior to such event, or as
soon as possible if the FDA, or other regulatory body, requests a meeting with
less than [**] days notice, and shall provide CyDex a detailed summary of the
minutes of any such meeting to the extent such minutes relate to CAPTISOL. If
Company submits written responses to the FDA that include data on CAPTISOL
alone, CyDex shall be permitted to review such written materials prior to
submission. Such responses shall be provided by the Company to CyDex [**] days
prior to submission. CyDex shall respond with comments to Company within [**]
days. If CyDex does not provide comments within [**] business days, Company will
interpret such non-response as agreement to the proposed response by Company. If
CyDex reasonably objects to the contents of such written responses relating to
CAPTISOL, the parties agree to cooperate in working toward a reasonable and
mutually agreeable response; provided, however, that Company shall have final
decision-making authority with respect to the content of any IND or NDA for
Licensed Products (subject to the limitations set forth in this SECTION 7.1
concerning data solely concerning CAPTISOL), and with respect to the submission
of such IND or NDA.
7.2 MATERIAL SAFETY. CyDex shall provide Company, in writing, from time to
time, with (a) relevant information currently known to it regarding handling
precautions, toxicity and hazards with respect to CAPTISOL, and (b) the
then-current material safety data sheet for CAPTISOL. Notwithstanding the
foregoing or anything in this Agreement to the contrary, Company is solely
responsible for (i) use of all documentation provided by CyDex, including
without limitation, use in any regulatory submission to the FDA or any other
regulatory agency in the Territory, (ii) document control and retention, and
(iii) determining the suitability of any documentation provided by CyDex
hereunder for use in any regulatory submission.
19
7.3 ADVERSE EVENT REPORTING. Each party shall adhere, and shall require
that its Affiliates, Sublicensees, co-marketers and distributors adhere, to all
requirements of applicable law and regulations that relate to the reporting and
investigation of any adverse event, including without limitation an unfavorable
and unintended diagnosis, symptom, sign (including an abnormal laboratory
finding), syndrome or disease, whether or not considered CAPTISOL or Licensed
Product-related, which occurs or worsens following administration of CAPTISOL or
Licensed Product. Each party shall provide the other party with copies of all
reports of any such adverse event which is serious (any such adverse event
involving CAPTISOL or the Licensed Product that results in death, is
life-threatening, requires or prolongs inpatient hospitalization, results in
disability, congenital anomaly or is medically important (i.e., may require
other medical or surgical intervention to prevent other serious criteria from
occurring)) which either party has reason to believe are associated with
CAPTISOL within [**] business days following (i) submission of any such report
to any regulatory agency, or (ii) receipt from such party's Sublicensee,
co-marketer or distributor of any such report to any regulatory agency. Company
shall also advise CyDex regarding any proposed labeling or registration dossier
changes affecting CAPTISOL. Reports from Company shall be delivered to the
attention of the Chief Executive Officer, CyDex, with a copy to the Director,
Quality Control, CyDex, at the address set forth in SECTION 14.7 (Notices).
CyDex shall inform Company within [**] business days of any adverse events
following administration of CAPTISOL of which CyDex learns in accordance with
CyDex's obligations as a supplier of CAPTISOL, and provide Company with copies
of all relevant reports. The parties shall mutually cooperate with regard to
investigation of any such serious adverse event, whether experienced by Company,
CyDex or any other Affiliate, Sublicensee, co-marketer or distributor of CyDex
or Company.
7.4 PRODUCT RECALLS. If any CAPTISOL should be alleged or proven not to
meet the Specifications, Company shall notify CyDex immediately, and both
parties shall cooperate fully regarding the investigation and disposition of any
such matter. If Company should deem it appropriate to file a field alert report
or recall any Licensed Product, Company shall have final decision-making
authority concerning the course of action to be taken with respect to the
affected Licensed Product. If such recall is due to the failure of CAPTISOL to
conform to the relevant Specifications at the time of delivery by CyDex, then
CyDex agrees, upon substantiation thereof, to bear all reasonable direct costs
associated with said recall, including refund of the purchase price for such
CAPTISOL and the actual cost of conducting the recall in accordance with the
recall guidelines of the applicable governmental authority. Company shall in all
events be responsible for conducting any such recalls with respect to the
Licensed Product and shall maintain records of all sales of Licensed Product and
customers sufficient to adequately administer any such recall, for a period of
[**] years after expiration or termination of this Agreement.
8. CONFIDENTIALITY.
8.1 DEFINITION. Company and CyDex each recognizes that during the Term, it
may be necessary for a party (the "DISCLOSING PARTY") to provide Confidential
Information (as defined herein) to the other party (the "RECEIVING PARTY") that
is highly valuable, the disclosure of which would be highly prejudicial to such
party. The disclosure and use of Confidential Information will be governed by
the provisions of this SECTION 8. Neither Company nor CyDex shall use the
other's Confidential Information except as expressly permitted in this
Agreement. For purposes
20
of this Agreement, "CONFIDENTIAL INFORMATION" means all information disclosed by
the Disclosing Party to the Receiving Party (orally or in writing), including
but not limited to product specifications, data, know-how, formulations, product
concepts, sample materials, business and technical information, financial data,
batch records, trade secrets, processes, techniques, algorithms, programs,
designs, drawings, and any other information related to a party's present or
future products, sales, suppliers, customers, employees, investors or business.
To the extent practical Confidential Information will be marked to indicate its
confidential nature. In the case of Confidential Information disclosed orally or
visually, the disclosing party shall confirm in writing the fact and general
nature of each disclosure within sixty (60) days after disclosure. Without
limiting the generality of the foregoing, (a) CyDex's Confidential Information
includes all materials provided as part of the CAPTISOL Data Package, and (b)
any "Confidential Information" (as defined in the Limited Clinical Use
Agreement) disclosed by a party under the Limited Clinical Use Agreement shall
be deemed Confidential Information of such party under this Agreement, the
disclosure and use of which shall be governed by the terms of this SECTION 8.
Without limiting the generality of the foregoing, the Company's Confidential
Information includes all information provided to CyDex (whether oral or written)
regarding (a) the Company's business and financial information, (b) the
Company's products, research and development activities, including clinical
trials and results; (c) intellectual property (including without limitation
patents, patent applications, inventions, processes, compounds, discoveries,
formulae, technology, computer software, licenses, know-how, databases, and
documentation); (d) investors, manufacturers, suppliers, vendors, competitors,
and customers; (e) sales and marketing plans, research and development plans or
strategies, business development plans, and manufacturing lans; and (f) legal
and regulatory activities, communications, approvals, and disputes.
8.2 OBLIGATION. CyDex and Company each agrees that it will disclose the
other's Confidential Information to its own officers, directors, employees,
consultants and agents only if and to the extent necessary to carry out its
respective responsibilities under this Agreement or in accordance with the
exercise of its rights under this Agreement, and such disclosure shall be
limited to the maximum extent possible consistent with such responsibilities and
rights. Neither party shall disclose Confidential Information of the other to
any third party without the other's prior written consent, and any such
disclosure to a third party shall be pursuant to the terms of a non-disclosure
agreement no less restrictive than this SECTION 8. Each party shall take such
action to preserve the confidentiality of each other's Confidential Information
as it would customarily take to preserve the confidentiality of its own
Confidential Information (but in no event less than a reasonable standard of
care). Each party, upon the other's request, will return all the Confidential
Information disclosed to the other party pursuant to this Agreement, including
all copies and extracts of documents, within sixty (60) days of the request, and
in any event, promptly following the expiration or termination of this
Agreement, except that the receiving party may retain (i) one (1) copy for
archival purposes and (ii) such electronic copies that exist as part of the
party's computer systems, network storage systems and electronic backup systems.
8.3 EXCEPTIONS. The use and non-disclosure obligations set forth in this
Section 8 shall not apply to any Confidential Information, or portion thereof,
that the Receiving Party can demonstrate:
21
(A) at the time of disclosure is in the public domain;
(B) after disclosure, becomes part of the public domain, by
publication or otherwise, through no fault of the Receiving Party;
(C) at the time of disclosure is already in the Receiving Party's
possession, and such prior possession can be properly demonstrated by the
Receiving Party, with the exception of Confidential Information exchanged
between parties prior to the execution of this Agreement;
(D) is made available to the Receiving Party by an independent third
party, provided, however, that to the Receiving Party's knowledge, such
information was not obtained by said third party, directly or indirectly, from
the Disclosing Party hereunder; or
(E) is developed by Receiving Party independently of disclosure by or
through the disclosing party as evidenced by the Receiving Party's records.
In addition, the Receiving Party may disclose information that is required
to be disclosed by law, by a valid order of a court or by order or regulation of
a governmental agency including but not limited to, regulations of the United
States Securities and Exchange Commission (the "SEC") or NASDAQ or other stock
exchange, or in the course of litigation, provided that in all cases the
Receiving Party shall give the other party prompt notice of the pending
disclosure and makes a reasonable effort to obtain, at the Disclosing Party's
expense, or to assist the Disclosing Party in obtaining, a protective order
preventing or limiting the disclosure and/or requiring that the Confidential
Information so disclosed be used only for the purposes for which the law or
regulation required, or for which the order was issued.
8.4 INJUNCTION. Each party agrees that should it breach or threaten to
breach any provisions of this SECTION 8, the Disclosing Party will suffer
irreparable damages and its remedy at law will be inadequate. Upon any breach or
threatened breach by the Receiving Party of this SECTION 8, the Disclosing Party
shall be entitled to seek injunctive relief in addition to any other remedy
which it may have, without need to post any bond or security.
8.5 THIRD PARTY INFORMATION. Company acknowledges that CyDex's Confidential
Information includes information developed by Pfizer, Inc. ("Pfizer") that is
confidential to both CyDex and Pfizer. In so far as Confidential Information of
Pfizer is disclosed, Pfizer is a third-party beneficiary of this Section 8 of
this Agreement and may enforce it or seek remedies pursuant to it in accordance
with its terms.
8.6 PUBLIC COMPANY ACKNOWLEDGMENT. CyDex acknowledges and agrees that (i)
the Company is a publicly-held company listed on NASDAQ Global Market and (ii)
CyDex is aware that applicable securities laws prohibit any person who is aware
of material, non-public information about a company obtained directly or
indirectly from that company from purchasing or selling securities of such
company or from communicating such information to any other person under
circumstances in which it is reasonably foreseeable that such person is likely
to purchase or sell such securities.
9. REPRESENTATIONS AND WARRANTIES.
22
9.1 MUTUAL REPRESENTATIONS AND WARRANTIES. Each party represents and
warrants to the other as follows:
(A) it is a corporation duly organized and validly existing under the
laws of the state or country of its incorporation;
(B) it has the complete and unrestricted power and right to enter into
this Agreement and to perform its obligations hereunder;
(C) this Agreement has been duly authorized, executed and delivered by
such party and constitutes a legal, valid and binding obligation of such party
enforceable against such party in accordance with its terms except as
enforceability may be limited by applicable bankruptcy, insolvency,
reorganization, receivership, moratorium, fraudulent transfer, or other similar
laws affecting the rights and remedies of creditors generally and by general
principles of equity;
(D) the execution, delivery and performance of this Agreement by such
party do not conflict with any agreement, instrument or understanding, oral or
written, to which such party is a party or by which such party may be bound, nor
violate any law or regulation of any court, governmental body or administrative
or other agency having authority over such party;
(E) all consents, approvals and authorizations from all governmental
authorities or other third parties required to be obtained by such party in
connection with the execution and delivery of this Agreement have been obtained;
(F) no person or entity has or will have, as a result of the
transactions contemplated by this Agreement, any right, interest or valid claim
against or upon such party for any commission, fee or other compensation as a
finder or broker because of any act by such party or its agents, or, with
respect to Company, because of any act by its Affiliates or Sublicensees; and
(G) it has not entered into any agreement with any third party that is
in conflict with the rights granted to the other party pursuant to this
Agreement.
9.2 CYDEX REPRESENTATIONS AND WARRANTIES.
(A) CyDex warrants solely to Company that all CAPTISOL sold to Company
shall conform to the respective Specifications and cGMP (as applicable for
Research Grade CAPTISOL, Clinical Grade CAPTISOL or Commercial Grade CAPTISOL)
in all material respects, and shall not be adulterated or misbranded within the
meaning of the applicable FDA regulation at the time of delivery. CyDex's sole
obligation, and Company's sole and exclusive remedy, for any breach of such
warranty shall be as set forth in SECTIONS 3.5(E) (Refund or Replacement) and
10.1 (Indemnification by CyDex) hereof.
(B) CyDex represents and warrants solely to Company that it has all
rights necessary to undertake the activities contemplated under this Agreement
and to grant to Company the exclusive license under Licensed Patents as set
forth in this Agreement.
23
(C) CyDex represents and warrants solely to Company that to CyDex's
knowledge as of the Effective Date, there are not inquiries, actions,
investigations or other proceedings pending before or threatened by any
regulatory or governmental authority with respect to any of CyDex's
manufacturing facilities or with respect to CAPTISOL, and that as of the
Effective Date, CyDex has not received written notice threatening any such
inquiry, action or other proceeding.
(D) To the best of CyDex's knowledge, as of the Effective Date, (i)
the Licensed Patents are valid and enforceable and (ii) neither the manufacture,
use nor sale of CAPTISOL infringes upon any third party's patent rights or
constitutes a misappropriation of a third party's trade secrets or know-how.
9.3 DISCLAIMER. The warranties set forth in this SECTION 9 above are
provided in lieu of, and each party hereby disclaims, all other warranties,
express and implied, relating to the subject matter of this Agreement, CAPTISOL,
licensed product or the Licensed Patents, including but not limited to the
implied warranties of merchantability and fitness for a particular purpose. each
party's warranties under this Agreement are solely for the benefit of the other
party and may be asserted only by such party and not by any Affiliate,
sublicensee or any customer of such party, its Affiliates or sublicensees.
Company, its Affiliates and Sublicensees shall be solely responsible for all
representations and warranties that Company, its Affiliates or Sublicensees make
to any customer of Company, its Affiliates or Sublicensees.
10. INDEMNIFICATION.
10.1 BY CYDEX. CyDex shall defend, indemnify and hold Company and its
Affiliates and Sublicensees, and each of their respective directors, officers
and employees, harmless from and against any and all losses, damages,
liabilities, costs and expenses (including the reasonable costs and expenses of
attorneys and other professionals) (collectively "LOSSES") incurred by Company
as a result of any claim, demand, action or other proceeding (each, a "CLAIM")
by a third party, to the extent such Losses arise out of: (a) that the practice
of the compositions or methods claimed in the Licensed Patents or the sale of
CAPTISOL as included as an excipient within the Licensed Product infringe upon
such third party's patent rights provided that such claim does not arise out of
Company's or its Affiliates' or Sublicensees' unauthorized use of the Licensed
Patents; or (b) CyDex's breach of any of its representations and warranties set
forth in SECTION 9.1 or SECTION 9.2 above; provided, however, that CyDex shall
be relieved of its obligations under this SECTION 10.1 to the extent that
Company is responsible under SECTION 10.2 below. If the Licensed Patents become,
or in CyDex's opinion are likely to become, the subject of an injunction
preventing the practice of the Licensed Patents, CyDex may, at its option,
terminate this Agreement immediately upon written notice to Company, and refund
to Company all amounts paid by Company for supply of infringing CAPTISOL. This
SECTION 10.1 states CyDex's sole obligation and entire liability, and Company's,
its Affiliates' and Sublicensees' sole and exclusive remedy, for any claim of
infringement of intellectual property rights related to the Licensed Patents or
Licensed Product.
10.2 BY COMPANY. Company shall defend, indemnify and hold CyDex and its
Affiliates, and each of their respective directors, officers and employees,
harmless from and against any and all Losses incurred by CyDex as a result of
any Claim by a third party, to the
24
extent such Losses arise out of: (a) the use or sale of the Licensed Product by
Company, its Affiliates, Sublicensees, distributors, agents, or other parties;
(b) the manufacture, use, handling, promotion, marketing, distribution, sale or
use of Licensed Products; (c) Company's interactions and communications with
governmental authorities, physicians or other third parties concerning Licensed
Product; or (d) Company's breach of any of its representations and warranties
set forth in SECTION 9.1; provided, however, that Company shall be relieved of
its obligations under this SECTION 10.2 to the extent that CyDex is responsible
under SECTION 10.1 above.
10.3 EXPENSES. As the parties intend complete indemnification, all costs
and expenses of enforcing any provision of this SECTION 10 shall also be
reimbursed by the indemnifying party.
10.4 PROCEDURE. The party intending to claim indemnification under this
SECTION 10 (an "INDEMNITEE") shall promptly notify the other party (the
"INDEMNITOR") of any Claim in respect of which the Indemnitee intends to claim
such indemnification, and the Indemnitor shall assume the defense thereof
whether or not such Claim is rightfully brought; provided, however, that an
Indemnitee shall have the right to retain its own counsel, with the fees and
expenses to be paid by the Indemnitee, unless Indemnitor does not assume the
defense, in which case the reasonable fees and expenses of counsel retained by
the Indemnitee shall be paid by the Indemnitor. The Indemnitee, and its
employees and agents, shall cooperate fully with the Indemnitor and its legal
representatives in the investigations of any Claim.
11. LIMITATION OF LIABILITY.
Except for (a) a breach of a party's confidentiality obligations pursuant
to SECTION 8, and (b) damages for which each party is responsible pursuant to
its indemnification obligations set forth in SECTION 10 above, each party
specifically disclaims all liability for and shall in no event be liable to the
other party for any incidental, special, indirect or consequential damages,
expenses, lost profits, lost savings, interruptions of business or other damages
of any kind or character whatsoever arising out of or related to this Agreement
or resulting from the manufacture, handling, marketing, sale, distribution or
use of Licensed Product or use of the Licensed Patents and CAPTISOL Data
Package, regardless of the form of action, whether in contract, tort, strict
liability or otherwise, even if such party was advised of the possibility of
such damages. Company shall have no remedy, and Cydex shall have no liability,
other than as expressly set forth in this Agreement. Except with respect to the
indemnification specifically provided in SECTION 10 above, in no event shall
Cydex's's total aggregate liability for all claims arising out of or related to
this Agreement exceed the amounts paid or payable by Company to CyDex pursuant
to SECTION 4 (Compensation) of this Agreement during the twelve (12) month
period immediately preceding the event giving rise to liability, and the
Company's total aggregate liability for all claims arising out of or related to
this Agreement shall not exceed one (1) million dollars ($1,000,000). No action,
regardless of form, arising out of or related to this Agreement may be brought
by either party more than two (2) years after such party has knowledge of the
occurrence that gave rise to the cause of such action.
12. MANAGEMENT OF LICENSED PATENTS.
12.1 PROSECUTION AND MAINTENANCE. CyDex shall maintain, at its sole cost
and expense and using reasonable discretion, the Licensed Patents set forth on
EXHIBIT A. CyDex
25
shall have the sole right to control the prosecution and maintenance of patent
applications and the selection of countries where patent applications are filed
related to the Licensed Patents.
12.2 INFRINGEMENT BY THIRD PARTIES. If Company becomes aware that a third
party may be infringing a Licensed Patent, it will promptly notify CyDex in
writing, providing all information available to Company regarding the potential
infringement. CyDex shall take whatever, if any, action it deems appropriate, in
its sole discretion, against the alleged infringer. If CyDex elects to take
action, Company shall, at CyDex's request and expense, cooperate and shall cause
its employees to cooperate with CyDex in taking any such action, including but
not limited to, cooperating with the prosecution of any infringement suit by
CyDex.
13. TERM AND TERMINATION.
13.1 TERM. The term of this Agreement (the "TERM") shall commence on the
Effective Date and shall continue in effect thereafter until the expiration of
Company's obligation to pay royalties under SECTION 4.1(D), unless terminated
earlier as set forth herein.
13.2 TERMINATION BY CYDEX. If Company should violate or fail to perform any
term or covenant of this Agreement, then CyDex may give written notice of such
default (a "NOTICE OF DEFAULT") to Company. If Company should fail to cure such
default within thirty (30) days of the date of such notice or prior to the
natural expiration date of this Agreement, whichever is shorter in duration,
CyDex shall have the right to terminate this Agreement by a second written
notice (a "NOTICE OF TERMINATION") to Company. If Notice of Termination is sent
to Company, this Agreement shall automatically terminate on the effective date
of such notice. Notwithstanding the above, failure to pay milestones or
royalties as described in SECTION 4 above will result in termination of this
Agreement immediately upon delivery of a Notice of Termination to Company. In
addition, CyDex may terminate this Agreement immediately upon written notice to
Company in the event Company makes an assignment for the benefit of creditors or
has a petition in bankruptcy filed for or against it that is not dismissed
within ninety (90) days of such filing.
13.3 TERMINATION BY COMPANY. Company shall have the right at any time to
terminate this Agreement in whole by giving CyDex at least seventy-five (75)
days prior written notice.
13.4 EFFECT OF TERMINATION. Following the termination or expiration of this
Agreement, all rights granted to Company herein shall immediately terminate and
each party shall promptly make any outstanding payments and return all relevant
records and materials in its possession or control containing the other party's
Confidential Information with respect to which the former party does not retain
rights hereunder; provided, however, that each party may retain one archival
copy of such records and materials solely to be able to monitor its obligations
that survive under this Agreement.
13.5 SURVIVAL. Notwithstanding any other provisions of this Agreement, any
liability or obligation of either party to the other for acts or omissions prior
to the termination or expiration of this Agreement shall survive the termination
or expiration of this Agreement. Such termination or expiration shall not
relieve either party from obligations that are expressly
26
indicated to survive termination or expiration of this Agreement, nor shall any
termination or expiration of this Agreement relieve Company of its obligation to
pay CyDex (a) royalties for all Licensed Product sold by Company, its Affiliates
or Sublicensees prior to the effective date of such expiration or termination,
or (b) sums due in respect of conforming CAPTISOL shipped prior to termination
or expiration of this Agreement. Sections 1 (Definitions); 3.5 (Quality Control;
Acceptance and Rejection); 4.1 (Payments and Royalties for Licenses), solely to
the extent that any amounts are due but unpaid as of the effective date of
termination; 4.3 (Currency); 4.4 (Taxes); 4.5 (Late Payments); 5 (Records;
Reports; Audits); 7.4 (Product Recalls); 8 (Confidentiality); 9.3 (Disclaimer);
10 (Indemnification); 11 (Limitation of Liability); 13.4 (Effect of
Termination); 13.5 (Survival); and 14 (General Provisions) shall survive
termination or expiration of this Agreement. Notwithstanding any other provision
of this Agreement, the grant of license from Company to CyDex pursuant to
Section 2.2 shall terminate upon the termination or expiration of this
Agreement. CyDex shall not, and shall procure that its Affiliates and
Sublicensees do not, without the prior written consent of CRTX, develop, market,
manufacture or sell any dosage formulation containing the Compound.
14. GENERAL PROVISIONS.
14.1 NON-SOLICITATION. During the Term and for a period of [**] thereafter,
neither party shall solicit, induce, encourage or attempt to induce or encourage
any employee of the other party to terminate his or her employment with such
other party or to breach any other obligation to such other party. This section
is not meant to encompass general solicitations such as may be found in
newspaper advertisements and the like.
14.2 RELATIONSHIP OF PARTIES. Each of the parties hereto is an independent
contractor and nothing in this Agreement is intended or shall be deemed to
constitute a partnership, agency, employer-employee or joint venture
relationship between the parties. No party shall incur any debts or make any
commitments for the other.
14.3 COMPLIANCE WITH LAW. Company agrees that use of the Licensed Patents
by Company, its Affiliates and Sublicensees, and the manufacture, handling,
marketing, sale, distribution and use of Licensed Product will comply with all
applicable international, federal, state and local laws, rules and regulations,
including, but not limited to, import/export restrictions, laws, rules and
regulations governing use and patent, copyright and trade secret protection.
CyDex agrees that the manufacture, handling, marketing, sale, distribution and
use of CAPTISOL as contemplated by this Agreement will comply with all
applicable international, federal, state and local laws, rules and regulations,
including, but not limited to, import/export restrictions, laws, rules and
regulations governing use and patent, copyright and trade secret protection.
14.4 ARBITRATION.
(A) PROCEDURE. Except as otherwise expressly set forth in SECTION
14.4(B) below, any and all disputes or controversies arising out of or relating
to this Agreement shall be settled and decided by binding arbitration. The
arbitration shall be conducted in Chicago, Illinois by an arbitrator reasonably
knowledgeable about the pharmaceutical industry and acceptable to CyDex and
Company. If CyDex and Company cannot agree on a single arbitrator within ten
27
(10) days after a demand for arbitration has been made, CyDex shall appoint an
arbitrator, Company shall appoint an arbitrator, the two (2) arbitrators shall
appoint a third arbitrator, and the three (3) arbitrators shall hear and decide
the issue in controversy. If either party fails to appoint an arbitrator within
twenty (20) days after service of the demand for arbitration, then the
arbitrator appointed by the other party shall arbitrate any controversy in
accordance with this SECTION 14.4(A). Except as to the selection of arbitrators,
the arbitration proceedings shall be conducted promptly and in accordance with
the rules of the American Arbitration Association then in effect. The expenses
of any arbitration, including the reasonable attorney fees of the prevailing
party, shall be borne by the party deemed to be at fault or on a pro-rata basis
should the arbitration conclude in a finding of mutual fault.
(B) SHORT-FORM ARBITRATION. Any dispute subject to short-form
arbitration as provided in this Agreement shall be finally settled by binding
arbitration conducted, in accordance with the rules of the American Arbitration
Association then in effect, in Chicago, Illinois by a single arbitrator
reasonably knowledgeable about the pharmaceutical industry and appointed in
accordance with such rules. Such arbitrator shall make his or her determination
on the basis of "baseball arbitration" principles. THE FOREGOING REMEDY SHALL BE
EACH PARTY'S SOLE AND EXCLUSIVE REMEDY WITH RESPECT TO ANY SUCH DISPUTE. The
expenses of any arbitration, including the reasonable attorney fees of the
prevailing party, shall be borne by the party deemed to be at fault or on a
pro-rata basis should the arbitration conclude in a finding of mutual fault. In
each case, the parties and arbitrator shall use all diligent efforts to complete
such arbitration within thirty (30) days of appointment of the arbitrator.
(C) CONFIDENTIALITY OF PROCEEDINGS. All arbitration proceedings
hereunder shall be confidential and the arbitrator(s) shall issue appropriate
protective orders to safeguard each party's Confidential Information. Except as
permitted under SECTION 8, no party shall make (or instruct the arbitrator(s) to
make) any public announcement with respect to the proceedings or decision of the
arbitrator(s) without prior written consent of the other party.
(D) EXCEPTIONS. Notwithstanding the foregoing, neither party shall be
bound to follow the dispute resolution process described in this Section with
respect to any dispute: (i) that primarily involves or relates to the scope or
validity of the Licensed Patents; or (ii) for which interim equitable relief
from a court is necessary to prevent serious and irreparable injury to a party.
14.5 COSTS AND EXPENSES. Except as otherwise expressly provided in this
Agreement, each party shall bear all costs and expenses associated with the
performance of such party's obligations under this Agreement.
14.6 FORCE MAJEURE. Neither party shall be liable for failure to perform,
or delay in the performance of, its obligations under this Agreement (other than
payment obligations) when such failure or delay is caused by an event of force
majeure. For purposes of this Agreement, an event of force majeure means any
event or circumstance beyond the reasonable control of the affected party,
including but not limited to, war, insurrection, riot, fire, flood or other
unusual weather condition, explosion, act of God, peril of the sea, strike,
lockout or other industrial disturbance, sabotage, accident, embargo, breakage
of machinery or apparatus, injunction, act of governmental authority, compliance
with governmental order on national defense requirements,
28
or inability to obtain fuel, power, raw materials, labor, transportation
facilities. If, due to any event of force majeure, either party shall be unable
to fulfill its obligations under this Agreement (other than payment
obligations), the affected party shall immediately notify the other party of
such inability and of the period during which such inability is expected to
continue.
14.7 NOTICES. Any notice, request, or communication under this Agreement
shall be effective only if it is in writing and personally delivered; sent by
certified mail, postage pre-paid; facsimile with receipt confirmed; or by
nationally recognized overnight courier with signature required, addressed to
the parties at the addresses stated below or such other persons and/or addresses
as shall be furnished in writing by any party in accordance with this SECTION
14.7. Unless otherwise provided, all notices shall be sent:
If to CyDex, to:
CyDex, Inc.
00000 X. 00xx Xxxxxxx
Xxxxxx, XX 00000
Attention: Chief Executive Officer
Fax: (000) 000-0000
If to Company, to: Critical Therapeutics, Inc.
00 Xxxxxxxx Xxxxxx
Xxxxxxxxx, XX 00000
Attention: Chief Operating Officer
Fax: (000) 000-0000
With required copy to:
Critical Therapeutics, Inc.
00 Xxxxxxxx Xxxxxx
Xxxxxxxxx, XX 00000
Attention: General Counsel
Fax: (000) 000-0000
If sent by facsimile transmission, the date of transmission shall be deemed to
be the date on which such notice, request or communication was given. If sent by
overnight courier, the next business day after the date of deposit with such
courier shall be deemed to be the date on which such notice, request or
communication was given. If sent by certified mail, the third business day after
the date of mailing shall be deemed the date on which such notice, request or
communication was given.
14.8 USE OF NAME. Each party hereby grants to the other party a
non-exclusive, non-transferable license to use its name, logo and other
trademarks in connection with marketing and other materials for customers,
investors and potential customers and investors, including but not limited to
use in connection with materials filed with the SEC or other regulatory
agencies. Except as otherwise provided herein, neither party shall have any
right, express or implied, to use
29
in any manner the name or other designation of the other party or any other
trade name or trademark of the other party for any purpose, except as may be
required by applicable law or regulation.
14.9 PUBLIC ANNOUNCEMENTS. Except for such disclosure as is deemed
necessary, in the reasonable judgment of a party, to comply with applicable laws
or regulations, securities filings or the rules of the NYSE or NASDAQ, no
announcement, news release, public statement, publication, or presentation
relating to the existence of this Agreement, or the terms hereof, will be made
without the other party's prior written approval, which approval shall not be
unreasonably withheld. Notwithstanding the above, once the content and timing of
a public announcement of the fact that the parties have entered into this
Agreement has been agreed to between the parties and such announcement has been
made, each party shall be free to disclose to third parties the fact that it has
entered into the Agreement with the other party (including a description of the
field of use of the Licensed Product, but without disclosing the economic terms
thereof), as well as any other information contained in said public
announcement. In the event of a required public announcement, the party making
such announcement shall provide the other party with a copy of the proposed text
prior to such announcement sufficiently in advance of the scheduled release of
such announcement to afford such other party a reasonable opportunity to review
and comment upon the proposed text and the timing of such disclosure.
14.10 GOVERNING LAW. This Agreement shall be governed by and construed in
accordance with the laws of the State of Delaware (without giving effect to any
conflicts of law principles that require the application of the law of a
different state).
14.11 ENTIRE AGREEMENT; AMENDMENT. This Agreement and all Exhibits attached
hereto or thereto contain the entire agreement of the parties relating to the
subject matter hereof and supersede any and all prior agreements, written or
oral, between CyDex and Company relating to the subject matter of this
Agreement, including without limitation, the Limited Clinical Use Agreement,
which is hereby terminated in all respects with no surviving rights or
obligations other than as specifically set forth under this Agreement. This
Agreement may not be amended unless agreed to in writing by both parties.
14.12 BINDING EFFECT. This Agreement shall be binding upon, and the rights
and obligations hereof shall apply to the CyDex and the Company and any
successor(s) and permitted assigns. The name of a party appearing herein shall
be deemed to include the names of such party's successors and permitted assigns
to the extent necessary to carry out the intent of this Agreement.
14.13 WAIVER. The rights of either party under this Agreement may be
exercised from time to time, singularly or in combination, and the exercise of
one or more such rights shall not be deemed to be in waiver of any one or more
of the other. No waiver of any breach of a term, provision or condition of this
Agreement shall be deemed to have been made by either party unless such waiver
is addressed in writing and signed by an authorized representative of that
party. The failure of either party to insist upon the strict performance of any
of the terms, provisions or conditions of this Agreement, or to exercise any
option contained in this Agreement, shall not be construed as a waiver or
relinquishment for the future of any such term,
30
provision, condition or option or the waiver or relinquishment of any other
term, provision, condition or option.
14.14 SEVERABILITY. If a final judicial determination is made that any
provision of this Agreement is unenforceable, this Agreement shall be rendered
void only to the extent that such judicial determination finds such provisions
unenforceable, and such unenforceable provisions shall be automatically
reconstituted and become a part of this Agreement, effective as of the date
first written above, to the maximum extent they are lawfully enforceable.
14.15 ASSIGNMENT. Neither party may assign its rights or delegate its
obligations under this Agreement, in whole or in part, by operation of law or
otherwise, to any third party without the prior written consent of the other
party, which consent shall not be unreasonably withheld. Notwithstanding the
foregoing, each party may assign its rights and delegate its obligations under
this Agreement to an Affiliate or to a third party successor, whether by way of
merger, sale of all or substantially all of its assets, sale of stock or
otherwise, without the other party's prior written consent. As a condition to
any permitted assignment hereunder, the assignor must guarantee the performance
of any assignee to the terms and obligations of this Agreement. Any assignment
not in accordance with this SECTION 14.15 shall be void.
14.16 HEADINGS. The descriptive headings of this Agreement are for
convenience only, and shall be of no force or effect in construing or
interpreting any of the provisions of this Agreement.
14.17 COUNTERPARTS. This Agreement may be executed in two counterparts,
each of which shall constitute an original document, but both of which shall
constitute one and the same instrument.
***
31
IN WITNESS WHEREOF, the parties have executed this Agreement as of the date
first written above.
CYDEX, INC.
By: /s/ Xxxxx X. Xxxxxxxx
---------------------------------
Name: Xxxxx X. Xxxxxxxx
Title: Vice President--Finance and
Administration
CRITICAL THERAPEUTICS, INC.
By: /s/ Xxxxxx Xxxxxxxx
---------------------------------
Name: Xxxxxx Xxxxxxxx, Ph.D.
Title: Chief Operating Officer
CyDex - Critical Therapeutics License and Supply Agreement, May 2007.
32
EXHIBIT A
PATENTS
PATENT 1: "Derivatives of Cyclodextrins Exhibiting Enhanced Aqueous Solubility
and the Use Thereof"
Expiration
Country Filing Date Serial No. Patent No. Date
------- ----------- -------------- ---------- ----------
United States 01/23/90 07/469087 5,134,127 01/23/10
PCT 01/22/91 PCT/US91/00326 WO91/11172
(U.S. 5,134,127)
Australia 01/22/91 72364/91 646020 01/22/07
EPO 01/22/91 91903891.9 0512050 01/22/11
Austria 01/22/91 91903891.9 E-170742 01/22/11
Belgium 01/22/91 91903891.9 0512050 01/22/11
France 9/11/98 91903891.9 0512050 01/22/11
Germany 01/22/91 69130165.4 69130165 01/22/11
Great Britain (UK) 01/22/91 91903891.9 0512050 01/22/11
Greece 11/30/98 980402865 3028691 01/23/11
Italy 12/01/98 70988BE/98 0512050 01/22/11
Luxembourg 01/22/91 91903891.9 0512050 01/22/11
Netherlands 12/03/98 91903891.9 0512050 01/22/11
Sweden 01/22/91 91903891.9 0512050 01/22/11
Switzerland 11/10/98 91903891.9 0512050 01/22/11
Korea 07/22/92 92-701734 166088 01/22/11
Canada 01/22/91 2,074,186 2,074,186 01/22/11
Russia 07/22/92 5052811.04 2099354 01/22/11
Japan 01/22/91 3-504051 2722277 1/22/11
* Awaiting confirmation documents
Exhibit A-1
PATENT 2: CIP of 5,134,127 - "Derivatives of Cyclodextrins Exhibiting Enhanced
Aqueous Solubility and the Use Thereof"
Expiration
Country Filing Date Serial No. Patent No. Date
------- ----------- -------------- ---------- ----------
United States 07/27/92 07/918,702 5,376,645 01/23/10
PCT (U.S. 5,376,645) 07/26/93 PCT/US93/06880 WO94/02518
Australia 07/26/93 47799/93 672814 07/26/13
EPO 07/26/93 93918302.6 620828 07/26/13
Austria 07/26/93 93918302.6 E 217325 07/26/13
Belgium 07/26/93 93918302.6 620828 07/26/13
Denmark 07/26/03 93918302.6 620828 07/31/13
Djibouti 05/08/02 93918302.6 620828 05/08/22
France 07/26/93 93918302.6 620828 07/31/13
Germany 07/26/93 69331900 69331900 07/31/13
Great Britain (UK) 05/17/02 93918302.6 620828 07/26/13
Greece 07/26/93 93918302.6 3040489 07/26/13
Ireland 07/26/03 93918302.6 620828 07/31/13
Italy 07/26/03 93918302.6 620828 07/26/13
Luxembourg 07/26/03 93918302.6 620828 07/26/13
Monaco 07/26/03 93918302.6 620828 07/26/13
Netherlands 07/26/03 93918302.6 620828 07/26/13
Portugal 07/26/93 93918302.6 620828 07/26/13
Spain 07/26/93 93918302.6 620828 07/26/13
Sweden 07/26/93 93918302.6 620828 07/26/13
Switzerland/Liechtenstein 07/26/93 93918302.6 620828 07/26/13
Korea 03/23/94 94-700951 279111 07/26/13
Canada 07/26/93 2,119,154 2,119,154 07/26/13
Japan 07/26/93 6-504678 3393253 07/26/13
Russia 07/26/93 94028890/04 2113442 07/26/13
Georgia 03/17/95 691/01-95 1649 07/26/13
Armenia 07/26/93 96237 822 07/22/13
Kyrgyzstan 08/09/96 960481.1 333 05/10/16
Xxxxxxx 00/00/00 960306/PCT 1813 07/26/13
Tajikistan 07/26/93 96000377 275 07/26/13
Turkmenistan 08/08/96 393 430 07/26/13
Uzbeckistan 09/15/94 IHAP9400808.2 5799 04/28/19
Exhibit A-1
EXHIBIT B
SPECIFICATIONS
SPECIFICATIONS - Commercial Grade and Clinical Grade Captisol (cGMP
Captisol)
TEST SPECIFICATION TEST METHOD
---- ------------- -----------
Appearance White to off-white solid essentially CY-VI-005
free from foreign matter
Identification (IR) Spectrum is consistent with the SBECD CY-IR-100
standard
Sodium Identity Sodium identity tests are positive CY-PR-200
Solution Clarity A 30% w/v solution in water is clear, CY-VI-002
colorless and essentially free from
particles of foreign matter
Average Degree of
Substitution (CE) 6.0-7.1 XX-XX-603
Solution pH The pH of a 30% w/v solution in water is CY-PH-100
within the range of 4.0 - 6.8
[ ]-cyclodextrin Content Maximum 0.2% CY-IC-203
Sodium Chloride Maximum 0.2% CY-IC-303
1,4-Butane Sultone Maximum 1 ppm CY-GC-104
Water (by KF) Maximum 10.0% XX-XX-100
Heavy Metals Maximum 10 ppm XX-XX-222
Assay (anhydrous basis) Minimum 95% XX-XX-903
Bacterial Endotoxins Not more than 50 EU/g CY-LAL-002
Microbiology
Aerobic microorganisms 1000 CFU/g Maximum CY-MB-105
Escherichia coli Meets test requirements for absence
Salmonella species Meets test requirements for absence
Molds & Yeasts For Information Only
Exhibit B-1
EXHIBIT C
PURCHASE PRICE FOR CAPTISOL
Subject to the terms of this Agreement and in accordance with Section 3 in its
entirety and Section 4.2, Company shall purchase 100% of its cGMP Captisol needs
from CyDex during the Term of the Agreement at the Prices per Kilogram Related
to the Activities outlined in table below:
PRICE OF CAPTISOL PER
ACTIVITY WITHIN LICENSED PRODUCT PROGRAM KILOGRAM (IN US DOLLARS)
---------------------------------------- ------------------------
Pre-Clinical and Phase I Clinical Trials $[**]
Phase II Clinical Trials and Phase III Clinical Trials $[**]
Scale Up and Validation Strictly for Activities Directly
Associated with Pre-launch activities $[**]
Manufacturing of Licensed Product for Commercial Sales $[**]
Research Grade CAPTISOL $[**]
Exhibit C-1
EXHIBIT D
DOSAGES OF CAPTISOL IN SINGLE AGENT
Exhibit D-1
Version 1, Page 1
07/17/00
(CYDEX, INC. LOGO)
CONTRACTUAL PROVISIONS ATTACHMENT
These pages contain mandatory contractual provisions and must be attached to or
incorporated in all copies of the foregoing Agreement.
CAPTISOL(R) DOSING MATRIX
IN-VIVO PRECLINICAL STUDIES
BACKGROUND INFORMATION FOR USING THE CAPTISOL(R) DOSING MATRIX ............ 2
TABLE 1: ALLOWABLE IV BOLUS CAPTISOL(R) DOSES BY DURATION OF STUDY ........ 3
TABLE 2: ALLOWABLE IV INFUSION CAPTISOL(R) DOSES BY DURATION OF STUDY ..... 4
TABLE 3: ALLOWABLE IM CAPTISOL(R) DOSES BY DURATION OF STUDY .............. 5
TABLE 4: ALLOWABLE IP CAPTISOL(R) DOSES BY DURATION OF STUDY .............. 6
TABLE 5: ALLOWABLE SC INJECTION CAPTISOL(R) DOSES BY DURATION OF STUDY .... 7
TABLE 6: ALLOWABLE SC IMPLANTABLE DEVICE CAPTISOL(R) DOSES BY
DURATION OF STUDY ...................................................... 8
TABLE 7: ALLOWABLE ORAL SOLUTION CAPTISOL(R) DOSES BY DURATION OF STUDY ... 9
TABLE 8: ALLOWABLE ORAL SOLID CAPTISOL(R) DOSES BY DURATION OF STUDY ...... 10
APPENDIX A ................................................................ 11
Parenteral Formulation Protocol ........................................ 12
Oral Solution Formulation Protocol ..................................... 13
Oral Solid Formulation Protocol ........................................ 00
XXXXXXXX X ................................................................ 15
Results Summary ........................................................ 16
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx, XX 00000 - (000) 000-0000
- FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 2
07/17/00
(CYDEX, INC. LOGO)
BACKGROUND INFORMATION FOR USING THE CAPTISOL(R) DOSING MATRIX
The enclosed tables contain summary dosing information for Captisol(R) by
different routes for various species. There is one summary page for each route,
which contains information for mice, rats, rabbits, dogs, and non-human
primates. Routes of administration discussed include intravenous, subcutaneous,
intramuscular, intraperitoneal and oral. For intravenous studies, an extensive
database is available for the rat and dog, with less information being available
for the mouse, rabbit and monkey. For other routes of administration data are
limited to rats, rabbits and monkeys for subcutaneous administration, rats for
intramuscular administration, and rats and dogs for oral administration. Because
data is limited for some routes and species, extrapolations were sometimes used
in determining the allowable dose. In other instances where data is limited,
CyDex requires consultation prior to dosing.
In each case the allowable dose is the Captisol(R) dose that can be administered
without prior consultation and/or specific approval of CyDex. The doses listed
are based on data from studies conducted with Captisol(R) or are an
extrapolation from those studies. At the doses listed in the matrix adaptive
responses may be present, but toxic effects would not be anticipated. In
addition to considering the allowable Captisol(R) dose, one must be cognizant of
the two variables (concentration and dose volume) determining the dose. In using
the matrix table, these two variables may be adjusted to best fit the needs of
the client. However, the allowable Captisol(R) dose and allowable Captisol(R)
concentration may not be exceed without prior approval from CyDex. The
concentration listed on the matrix is based on the concentration used in the
majority of the toxicity studies conducted with Captisol(R). As implied above,
lesser concentrations may be administered as long as the total dose does not
exceed the approved limit set forth in the Dosing Matrix.
With respect to dose volumes, those listed in the Captisol(R) dosing matrix
represent volumes that are recognized as appropriate for the species and route
(based on published literature). CyDex recognizes that individual laboratories
may have established different dosing volumes for use in a particular species
for a given route. In those instances, CyDex does not wish to restrict the
laboratory to the volumes listed in the matrix table. However without prior
consultation and permission of CyDex, the total Captisol(R) dose administered
must remain at or below the dose listed in the dosing matrix for the route and
species. For example, in the rat a single intravenous bolus dose of 4000 mg/kg
can be administered using a dosing volume of 13.3 mL/kg with a Captisol(R)
concentration of 300 mg/mL (30% w/v). If your laboratory routinely uses a higher
dose volume, say 15 ml/kg for a single intravenous bolus dose in rats, then the
concentration would need to be adjusted to 267 mg/mL (26.7% w/v) for a 4000
mg/kg dose.
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx, XX 00000 - (000) 000-0000
- FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
(CYDEX, INC. LOGO)
TABLE 1
CAPTISOL(R): ALLOWABLE DOSING MATRIX - INTRAVENOUS (IV) BOLUS SUMMARY
NOTES: 1) THE ALLOWABLE DOSE MAY NOT BE EXCEEDED WITHOUT CYDEX APPROVAL. THESE
DOSES AND THE 30% W/V CONCENTRATION DO NOT NECESSARILY REPRESENT THE
HIGHEST SAFE DOSING CONDITIONS. HOWEVER, THEY ARE THE HIGHEST VALUES
TO WHICH CYDEX HAS GIVEN LIMITED APPROVAL FOR USE.
2) IF CAPTISOL CONCENTRATION USED IS <30% W/V, THEN THE VOLUME
ADMINISTERED MAY BE INCREASED ACCORDINGLY, BUT THE DOSE DELIVERED
MAY NOT EXCEED THAT GRANTED UNDER THIS LIMITED APPROVAL.
TABLE 1: ALLOWABLE IV BOLUS CAPTISOL(R) DOSES BY DURATION OF STUDY
EXAMPLE VOLUME (2)
(BASED
ON USE OF 30% W/V
CAPTISOL DELIVERING DAILY ALLOWABLE
IV BOLUS INDICATED DOSE) EXAMPLE CONCENTRATION CAPTISOL(R) DOSE (1)
------------------------------- ---------------------- --------------------- --------------------
SPECIES DURATION (ML/DOSE) (ML/KG)(A) (% W/V) (MG/ML) (MG/KG)
----------------- ----------- --------- ---------- --------- --------- --------------------
mouse single dose 0.27 13.33 4000
14 days 0.20 10.00 3000
1 month 0.07 3.33 1000
rat single dose 3.33 13.33 4000
14 days 2.50 10.00 3000
1 month 0.83 3.33 THE HIGHEST 1000
CONCENTRATION GRANTED
UNDER THIS LIMITED
rabbit single dose 25.00 10.00 APPROVAL IS 30% W/V 3000
14 days 16.67 6.67 (300 MG/ML).(1) 2000
1 month 8.33 3.33 1000
dog single dose 100.00 10.00 3000
14 days 66.67 6.67 2000
1 month 50.00 5.00 1500
non-human primate single dose 50.00 10.00 3000
14 days 33.33 6.67 2000
1 month 25.00 5.00 1500
FOOTNOTES:
----------
a - conversions between mL/dose and mL/kg assumes mouse weight of 0.02 kg
a - conversions between mL/dose and mL/kg assumes rat weight of 0.25 kg
a - conversions between mL/dose and mL/kg assumes rabbit weight of 2.5 kg
a - conversions between mL/dose and mL/kg assumes dog weight of 10 kg
a - conversions between mL/dose and mL/kg assumes monkey weight of 5 kg
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx, XX 00000 - (000) 000-0000
- FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 3
07/17/00
(CYDEX, INC. LOGO)
TABLE 2
CAPTISOL(R): ALLOWABLE DOSING MATRIX - INTRAVENOUS (IV) INFUSION SUMMARY
NOTES: 1) THE ALLOWABLE DOSE MAY NOT BE EXCEEDED WITHOUT CYDEX APPROVAL. THESE
DOSES AND THE 30% W/V CONCENTRATION DO NOT NECESSARILY REPRESENT THE
HIGHEST SAFE DOSING CONDITIONS. HOWEVER, THEY ARE THE HIGHEST VALUES
TO WHICH CYDEX HAS GIVEN LIMITED APPROVAL FOR USE.
2) IF CAPTISOL CONCENTRATION USED IS <30% W/V, THEN THE VOLUME
ADMINISTERED MAY BE INCREASED ACCORDINGLY, BUT THE DOSE DELIVERED
MAY NOT EXCEED THAT GRANTED UNDER THIS LIMITED APPROVAL.
THE CURRENT CONTINUOUS INTRAVENOUS INFUSION DOSING MATRIX ONLY
PROVIDES INFORMATION FOR 24-HOUR CONTINUOUS INFUSION WITH THE CAPTISOL
CONCENTRATION LIMITED TO 30% (300 MG/ML) AND THE MAXIMUM DOSE LIMITED
TO THAT LISTED IN THE DOSING MATRIX.
TABLE 2: ALLOWABLE IV INFUSION CAPTISOL(R) DOSES BY DURATION OF STUDY
EXAMPLE VOLUME(2)
IV (BASED EXAMPLE DAILY ALLOWABLE
CONTINUOUS INFUSION ON USE OF 30% W/V CAPTISOL DELIVERING INDICATED DOSE) CONCENTRATION CAPTISOL(R) DOSE(1)
------------------- ---------------------------------------------------------- ---------------- -----------------------------
SPECIES DURATION (ML/DOSE/HR) (ML/DOSE/DAY) (ML/KG/HR)(A) (ML/KG/DAY)(A) (% W/V) (MG/ML) (MG/KG/HR)(B) (MG/KG/DAY)(B)
--------- -------- ------------ ------------- ------------- -------------- ------- ------- ------------- --------------
mouse 14 days 0.01 0.20 0.42 10.00 125 3000
THE HIGHEST
rat 14 days 0.10 2.50 0.42 10.00 CONCENTRATION 125 3000
GRANTED
rabbit 14 days 1.04 25.00 0.42 10.00 UNDER THIS 125 3000
LIMITED
dog 14 days 4.20 100.00 0.42 10.00 APPROVAL IS 125 3000
30% W/V
non-human 14 days 2.08 50.00 0.42 10.00 (300 MG/ML).(1) 125 3000
primate
FOOTNOTES:
----------
a - conversions between mL/dose and mL/kg assumes mouse weight of 0.02 kg
a - conversions between mL/dose and mL/kg assumes rat weight of 0.25 kg
a - conversions between mL/dose and mL/kg assumes rabbit weight of 2.5 kg
a - conversions between mL/dose and mL/kg assumes dog weight of 10 kg
a - conversions between mL/dose and mL/kg assumes monkey weight of 5 kg
b - doses are mg/kg/day except for continuous infusion which is reported as
both mg/kg/hour and mg/kg/day
CYDEX RECOGNIZES THAT CONTINUOUS IV INFUSION PROTOCOLS VARY GREATLY
FROM STUDY TO STUDY AND THAT WHEN DESIGNING CONTINUOUS IV INFUSION
PROTOCOLS SEVERAL VARIABLES MUST BE CONSIDERED, SUCH AS INFUSION RATE,
INFUSION DURATION, USE OF A BOLUS PLUS INFUSION, ETC. THE DOSES
PERMITTED UNDER THIS LIMITED AGREEMENT ARE BASED UPON A PROTOCOL THAT
REQUIRES 24-HOUR CONTINUOUS IV INFUSION PER THE DOSING MATRIX.
FOR ALL OTHER INTRAVENOUS INFUSION STUDY DESIGNS WE REQUIRE THAT CYDEX
BE CONSULTED FOR APPROVAL PRIOR TO INITIATION OF THE STUDY.
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx, XX 00000 - (000) 000-0000
- FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 4
07/17/00
(CYDEX, INC. LOGO)
TABLE 3
CAPTISOL(R): ALLOWABLE DOSING MATRIX - INTRAMUSCULAR (IM) SUMMARY
NOTES: 1) THE ALLOWABLE DOSE MAY NOT BE EXCEEDED WITHOUT CYDEX APPROVAL. THESE
DOSES AND THE 30% W/V CONCENTRATION DO NOT NECESSARILY REPRESENT THE
HIGHEST SAFE DOSING CONDITIONS. HOWEVER, THEY ARE THE HIGHEST VALUES
TO WHICH CYDEX HAS GIVEN LIMITED APPROVAL FOR USE.
2) IF CAPTISOL CONCENTRATION USED IS <30% W/V, THEN THE VOLUME
ADMINISTERED MAY BE INCREASED ACCORDINGLY, BUT THE DOSE DELIVERED MAY
NOT EXCEED THAT GRANTED UNDER THIS LIMITED APPROVAL.
TABLE 3: ALLOWABLE IM CAPTISOL(R) DOSES BY DURATION OF STUDY
EXAMPLE VOLUME (2)
(BASED ON USE OF 30%
W/V CAPTISOL
DELIVERING EXAMPLE DAILY ALLOWABLE
INTRAMUSCULAR INDICATED DOSE) CONCENTRATION CAPTISOL(R) DOSE (1)
------------------------------- ---------------------- ----------------- --------------------
SPECIES DURATION (ML/SITE) (ML/KG)(A) (% W/V) (MG/ML) (MG/KG)
------- ----------- --------- ---------- ------- ------- --------------------
mouse single dose * * * * *
14 days * * * * *
1 month * * * * *
rat single dose * * * * *
14 days * * * * *
1 month * * * * *
rabbit single dose * * * * *
14 days * * * * *
1 month * * * * *
dog single dose * * * * *
14 days * * * * *
1 month * * * * *
non-human primate single dose * * * * *
14 days * * * * *
1 month * * * * *
* LIMITED TO NO DATA EXISTS FOR THESE SPECIES. CONTACT CYDEX FOR APPROVAL OF
DOSING CONDITIONS.
FOOTNOTES:
----------
a - conversions between mL/dose and mL/kg assumes mouse weight of 0.02 kg
a - conversions between mL/dose and mL/kg assumes rat weight of 0.25 kg
a - conversions between mL/dose and mL/kg assumes rabbit weight of 2.5 kg
a - conversions between mL/dose and mL/kg assumes dog weight of 10 kg
a - conversions between mL/dose and mL/kg assumes monkey weight of 5 kg
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx, XX 00000 - (000) 000-0000
- FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 5
07/17/00
(CYDEX, INC. LOGO)
TABLE 4
CAPTISOL(R): ALLOWABLE DOSING MATRIX - INTRAPERITONEAL (IP) SUMMARY
NOTES: 1) THE ALLOWABLE DOSE MAY NOT BE EXCEEDED WITHOUT CYDEX APPROVAL. THESE
DOSES AND THE 30% W/V CONCENTRATION DO NOT NECESSARILY REPRESENT THE
HIGHEST SAFE DOSING CONDITIONS. HOWEVER, THEY ARE THE HIGHEST VALUES
TO WHICH CYDEX HAS GIVEN LIMITED APPROVAL FOR USE.
2) IF CAPTISOL CONCENTRATION USED IS < 30% W/V, THEN THE VOLUME
ADMINISTERED MAY BE INCREASED ACCORDINGLY, BUT THE DOSE DELIVERED MAY
NOT EXCEED THAT GRANTED UNDER THIS LIMITED APPROVAL.
TABLE 4: ALLOWABLE IP CAPTISOL(R) DOSES BY DURATION OF STUDY
EXAMPLE VOLUME (2)
(BASED ON USE OF 30%
W/V CAPTISOL
DELIVERING EXAMPLE DAILY ALLOWABLE
INTRAPERITONEAL INDICATED DOSE) CONCENTRATION CAPTISOL(R) DOSE (1)
------------------------------- ---------------------- ----------------- --------------------
SPECIES DURATION (ML/SITE) (ML/KG)(A) (% W/V) (MG/ML) (MG/KG)
------- ----------- --------- ---------- ------- ------- --------------------
mouse single dose * * * * *
14 days * * * * *
1 month * * * * *
rat single dose * * * * *
14 days * * * * *
1 month * * * * *
rabbit single dose * * * * *
14 days * * * * *
1 month * * * * *
dog single dose * * * * *
14 days * * * * *
1 month * * * * *
non-human primate single dose * * * * *
14 days * * * * *
1 month * * * * *
* LIMITED TO NO DATA EXISTS FOR THESE SPECIES. CONTACT CYDEX FOR APPROVAL OF
DOSING CONDITIONS.
FOOTNOTES:
----------
a - conversions between mL/dose and mL/kg assumes mouse weight of 0.02 kg
a - conversions between mL/dose and mL/kg assumes rat weight of 0.25 kg
a - conversions between mL/dose and mL/kg assumes rabbit weight of 2.5 kg
a - conversions between mL/dose and mL/kg assumes dog weight of 10 kg
a - conversions between mL/dose and mL/kg assumes monkey weight of 5 kg
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx,XX 00000 - (000) 000-0000
- FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxxx
Version 1, Page 6
07/17/00
(CYDEX, INC. LOGO) TABLE 5
CAPTISOL(R): ALLOWABLE DOSING MATRIX - SUBCUTANEOUS (SC) INJECTION SUMMARY
NOTES: 1) THE ALLOWABLE DOSE MAY NOT BE EXCEEDED WITHOUT CYDEX APPROVAL. THESE
DOSES AND THE 30% W/V CONCENTRATION DO NOT NECESSARILY REPRESENT THE
HIGHEST SAFE DOSING CONDITIONS. HOWEVER, THEY ARE THE HIGHEST VALUES
TO WHICH CYDEX HAS GIVEN LIMITED APPROVAL FOR USE.
2) IF CAPTISOL CONCENTRATION USED IS <30% W/V, THEN THE VOLUME
ADMINISTERED MAY BE INCREASED ACCORDINGLY, BUT THE DOSE DELIVERED
MAY NOT EXCEED THAT GRANTED UNDER THIS LIMITED APPROVAL.
TABLE 5: ALLOWABLE SC INJECTION CAPTISOL(R) DOSES BY DURATION OF STUDY
EXAMPLE VOLUME(2)
(BASED ON USE OF 30% DAILY ALLOWABLE
W/V CAPTISOL DELIVERING CAPTISOL(R)
SUBCUTANEOUS INJECTION INDICATED DOSE) EXAMPLE CONCENTRATION DOSE(1)
---------------------------------------------------------- ----------------------- --------------------- ---------------
SPECIES SITES DURATION (ML/SITE) (ML/KG)(A) (% W/V) (MG/ML) (MG/KG)
----------------- -------------------------- ----------- ---------- ---------- ---------- --------- ---------------
mouse 1 site possible single dose 0.27 13.33 4000
14 days 0.20 10.00 3000
1 month 0.07 3.33 1000
rat 1 site possible single dose 3.33 13.33 THE HIGHEST 4000
14 days 2.50 10.00 CONCENTRATION 3000
1 month 0.83 3.33 GRANTED UNDER THIS 1000
rabbit 1 site possible single dose 25.00 10.00 LIMITED APPROVAL 3000
14 days 16.67 6.67 IS 30% W/V 2000
1 month 8.33 3.33 (300 MG/ML).(1) 1000
dog 3 sites of 2 ml/kg each Single dose 20.00 6.00 1800
3 sites of 2 ml/kg each 14 days 20.00 6.00 1800
3 sites of 1.67 ml/kg each 1 month 16.67 5.00 1500
non-human primate 2 sites of 5 ml/kg each Single dose 25.00 10.00 3000
2 sites of 3.33 ml/kg each 14 days 16.67 6.66 2000
2 sites of 2.5 ml/kg each 1 month 12.50 5.00 1500
FOOTNOTES:
----------
a - conversions between mL/dose and mL/kg assumes mouse weight of 0.02 kg
a - conversions between mL/dose and mL/kg assumes rat weight of 0.25 kg
a - conversions between mL/dose and mL/kg assumes rabbit weight of 2.5 kg
a - conversions between mL/dose and mL/kg assumes dog weight of 10 kg
a - conversions between mL/dose and mL/kg assumes monkey weight of 5 kg
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx, XX 00000 - (000) 000-0000
- FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version, Page 7
07/17/00
(CYDEX, INC. LOGO) TABLE 6
CAPTISOL(R): ALLOWABLE DOSING MATRIX - SUBCUTANEOUS (SC) IMPLANTABLE DEVICE
SUMMARY
NOTES: 1) THE ALLOWABLE DOSE MAY NOT BE EXCEEDED WITHOUT CYDEX APPROVAL. THESE
DOSES AND THE 30% W/V CONCENTRATION DO NOT NECESSARILY REPRESENT THE
HIGHEST SAFE DOSING CONDITIONS. HOWEVER, THEY ARE THE HIGHEST VALUES
TO WHICH CYDEX HAS GIVEN LIMITED APPROVAL FOR USE.
2) IF CAPTISOL CONCENTRATION USED IS <30% W/V, THEN THE VOLUME
ADMINISTERED MAY BE INCREASED ACCORDINGLY, BUT THE DOSE DELIVERED
MAY NOT EXCEED THAT GRANTED UNDER THIS LIMITED APPROVAL.
TABLE 6: ALLOWABLE SC IMPLANTABLE DEVICE CAPTISOL(R) DOSES BY DURATION OF STUDY
EXAMPLE VOLUME(2)
(BASED ON USE OF 30% DAILY
W/V CAPTISOL DELIVERING ALLOWABLE
SUBCUTANEOUS IMPLANTABLE DEVICE INDICATED DOSE) EXAMPLE CONCENTRATION CAPTISOL(R)
---------------------------------------------------------------------- ----------------------- --------------------- DOSE(1)
SPECIES MINIPUMPS DURATION (ML/SITE) (ML/KG)(A) (% W/V) (MG/ML) (MG/KG)
----------------- -------------------------------------- ----------- ---------- ----------- ---------- --------- -----------
mouse 1 pump @ 1 uL/hr = 0.024 mL/day 7 days 0.024 1.20 THE HIGHEST 360
1 pump @ 0.5 uL/hr = 0.012 mL/day each 14 days 0.012 0.60 CONCENTRATION 180
1 pump @ 0.25 uL/hr = 0.006 mL/day 1 month 0.006 0.30 GRANTED UNDER THIS 90
rat 2 pumps @ 10 uL/hr = 0.24 mL/day each 7 days 0.480 1.92 LIMITED APPROVAL 576
2 pumps @ 5 uL/hr = 0.12 mL/day each 14 days 0.240 0.96 IS 30% W/V 288
2 pumps @ 2.5 uL/hr = 0.06 mL/day each 1 month 0.120 0.48 (300 MG/ML). (1) 144
rabbit * * * * * *
dog * * * * * *
non-human primate * * * * * *
*LIMITED TO NO DATA EXISTS FOR THESE SPECIES. CONTACT CYDEX FOR APPROVAL OF
DOSING CONDITIONS.
FOOTNOTES:
----------
a - conversions between mL/dose and mL/kg assumes mouse weight of 0.02 kg
a - conversions between mL/dose and mL/kg assumes rat weight of 0.25 kg
a - conversions between mL/dose and mL/kg assumes rabbit weight of 2.5 kg
a - conversions between mL/dose and mL/kg assumes dog weight of 10 kg
a - conversions between mL/dose and mL/kg assumes monkey weight of 5 kg
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx, XX 00000 - (000) 000-0000
- FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 8
07/17/00
(CYDEX, INC. LOGO) TABLE 7
CAPTISOL(R): ALLOWABLE DOSING MATRIX - ORAL SOLUTION SUMMARY
NOTES: 1) THE ALLOWABLE DOSE MAY NOT BE EXCEEDED WITHOUT CYDEX APPROVAL. THESE
DOSES AND THE 30% W/V CONCENTRATION DO NOT NECESSARILY REPRESENT THE
HIGHEST SAFE DOSING CONDITIONS. HOWEVER, THEY ARE THE HIGHEST VALUES
TO WHICH CYDEX HAS GIVEN LIMITED APPROVAL FOR USE.
2) IF CAPTISOL CONCENTRATION USED IS <30% W/V, THEN THE VOLUME
ADMINISTERED MAY BE INCREASED ACCORDINGLY, BUT THE DOSE DELIVERED
MAY NOT EXCEED THAT GRANTED UNDER THIS LIMITED APPROVAL.
TABLE 7: ALLOWABLE ORAL SOLUTION CAPTISOL(R) DOSES BY DURATION OF STUDY
EXAMPLE VOLUME (2)
(BASED ON USE OF 30%
W/V CAPTISOL DELIVERING DAILY ALLOWABLE
ORAL SOLUTION (GAVAGE) INDICATED DOSE) EXAMPLE CONCENTRATION CAPTISOL(R) DOSE (1)
---------------------- ----------------------- ------------------------- --------------------
SPECIES DURATION (ML/DOSE) (ML/KG)(A) (% W/V) (MG/ML) (MG/KG)
--------- ----------- --------- ---------- ----------- ------------ --------------------
mouse single dose 0.33 16.67 5000
14 days 0.27 13.33 THE HIGHEST CONCENTRATION 4000
1 month 0.13 6.67 GRANTED UNDER THIS 2000
rat single dose 4.17 16.67 LIMITED APPROVAL IS 30% 5000
14 days 3.33 13.33 W/V (300 MG/ML).(1) 4000
1 month 1.67 6.67 2000
rabbit single dose * * * * *
14 days * * * * *
1 month * * * * *
dog single dose * * * * *
14 days * * * * *
1 month * * * * *
non-human
primate single dose * * * * *
14 days * * * * *
1 month * * * * *
* LIMITED TO NO DATA EXISTS FOR THESE SPECIES. CONTACT CYDEX FOR APPROVAL OF
DOSING CONDITIONS.
FOOTNOTES:
----------
a - conversions between mL/dose and mL/kg assumes mouse weight of 0.02 kg
a - conversions between mL/dose and mL/kg assumes rat weight of 0.25 kg
a - conversions between mL/dose and mL/kg assumes rabbit weight of 2.5 kg
a - conversions between mL/dose and mL/kg assumes dog weight of 10 kg
a - conversions between mL/dose and mL/kg assumes monkey weight of 5 kg
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx, XX 00000 - (000) 000-0000 - FAX (913)
685-8856 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 9
07/17/00
(CYDEX, INC. LOGO) TABLE 8
CAPTISOL(R): ALLOWABLE DOSING MATRIX - ORAL SOLID SUMMARY
NOTES: 1) THE ALLOWABLE DOSE MAY NOT BE EXCEEDED WITHOUT CYDEX APPROVAL. AT
THIS TIME, LIMITED DATA EXISTS FOR THE ORAL DOSING OF SOLID
CAPTISOL. PLEASE CONTACT CYDEX FOR APPROVAL OF DOSING CONDITIONS.
TABLE 8: ALLOWABLE ORAL SOLID CAPTISOL(R) DOSES BY DURATION OF STUDY
DAILY ALLOWABLE
ORAL SOLID EXAMPLE FORMULATION CAPTISOL(R) DOSE
------------------------------ ---------------------------- ----------------
SPECIES DURATION (MG/DOSE) (NUMBER OF DOSES) EXAMPLE DOSAGE FORMS (MG/KG)
----------------- ----------- --------- ----------------- ------------------------------ ----------------
mouse single dose * * POWDERS *
14 days * * CAPSULES *
1 month * * TABLETS *
rat single dose * * *
14 days * * *
1 month * * *
rabbit single dose * * AT THIS TIME, LIMITED *
14 days * * DATA EXISTS FOR THE ORAL *
1 month * * DOSING OF SOLID CAPTISOL *
dog single dose * * PLEASE CONTACT CYDEX FOR *
14 days * * APPROVAL OF DOSING CONDITIONS. *
1 month * * *
non-human primate single dose * * *
14 days * * *
1 month * * *
* LIMITED TO NO DATA EXISTS FOR THESE SPECIES. CONTACT CYDEX FOR APPROVAL OF
DOSING CONDITIONS.
FOOTNOTES:
----------
a - conversions between mg/dose and mg/kg assumes mouse weight of 0.02 kg
a - conversions between mg/dose and mg/kg assumes rat weight of 0.25 kg
a - conversions between mg/dose and mg/kg assumes rabbit weight of 2.5 kg
a - conversions between mg/dose and mg/kg assumes dog weight of 10 kg
a - conversions between mg/dose and mg/kg assumes monkey weight of 5 kg
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx, XX 00000 - (000) 000-0000 - FAX (913)
685-8856 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 10
07/17/00
(CYDEX, INC. LOGO) Verson 1, Page 11
07/17/00
APPENDIX A
Version 1, Page 12
07/17/00
(CYDEX, INC. LOGO)
PARENTERAL FORMULATION PROTOCOL
CYDEX PROTOCOL TRACKING FORM PROTOCOL #___________
Title of Study: ________________________________________________________________
Purpose: _______________________________________________________________________
Animal: (include species, age, and weight)
STUDY DESIGN
FORMULATION
----------------- DRUG EXPOSURE (OPTIONAL) CAPTISOL EXPOSURE # OF ANIMALS
Volume Doses ------------------------- ------------------------- -------------
(ml/kg) per Day mg/ml mg/kg mg/kg/day mg/ml mg/kg mg/kg/day Male Female
------- ------- ----- ----- --------- ----- ----- --------- ---- ------
Route: _________________________________________________________________________
Duration: ______________________________________________________________________
Injection Speed: _______________________________________________________________
Injection Volume: ______________________________________________________________
Vehicle: _______________________________________________________________________
Examination: (check all that apply)
[ ] Clinical Observation [ ] Body Weight [ ] Clinical Chemistry
[ ] Food Consumption [ ] Electrocardiograms [ ] Toxicokinetics
[ ] Ophthalmology [ ] Urinalysis [ ] Hematology
[ ] Organ Weight [ ] Necropsy [ ] Microscopy
[ ] Others: ____________________________________________________________________
Performing Laboratory:
_________________________________________________________
Dosing Schedule:
_______________________________________________________________
Expected Report Submission:
____________________________________________________
GLP: This study _________________ be conducted in accordance with GLP standards.
(will or will not)
Necessary amount of Captisol needed for study:
_________________________________
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx,
XX 00000 - (000) 000-0000 - FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 13
07/17/00
(CYDEX, INC. LOGO)
ORAL SOLUTION FORMULATION PROTOCOL
CYDEX PROTOCOL TRACKING FORM PROTOCOL #___________
Title of Study:
________________________________________________________________
Purpose:
_______________________________________________________________________
Animal: (include species, age, and weight)
STUDY DESIGN
FORMULATION
----------------- DRUG EXPOSURE (OPTIONAL) CAPTISOL EXPOSURE # OF ANIMALS
Volume Doses ------------------------- ------------------------- -------------
(ml/kg) per Day mg/ml mg/kg mg/kg/day mg/ml mg/kg mg/kg/day Male Female
------- ------- ----- ----- --------- ----- ----- --------- ---- ------
Route:
_________________________________________________________________________
Dosing Regime:
_________________________________________________________________
Vehicle:
_______________________________________________________________________
Examination: (check all that apply)
[ ] Clinical Observation [ ] Body Weight [ ] Clinical Chemistry
[ ] Food Consumption [ ] Electrocardiograms [ ] Toxicokinetics
[ ] Ophthalmology [ ] Urinalysis [ ] Hematology
[ ] Organ Weight [ ] Necropsy [ ] Microscopy
[ ] Others:
____________________________________________________________________
Performing Laboratory:
_________________________________________________________
Dosing Schedule:
_______________________________________________________________
Expected Report Submission:
____________________________________________________
GLP: This study _________________ be conducted in accordance with GLP standards.
(will or will not)
Necessary amount of Captisol needed for study:
_________________________________
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx,
XX 00000 - (000) 000-0000 - FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 14
07/17/00
(CYDEX, INC. LOGO)
ORAL SOLID FORMULATION PROTOCOL
CYDEX PROTOCOL TRACKING FORM PROTOCOL #___________
Title of Study:
________________________________________________________________
Purpose:
_______________________________________________________________________
Animal: (include species & age)
Mean Weight Range:
_____________________________________________________________
STUDY DESIGN
DOSES DRUG EXPOSURE (OPTIONAL) CAPTISOL EXPOSURE # OF ANIMALS
--------- --------------------------------- -------------------------------- -------------
doses/day mg/dose mg/kg /dose mg/kg/day mg/dose mg/kg/dose mg/kg/day Male Female
--------- ------- ----------- --------- ------- ---------- --------- ---- ------
Dosing Regime:
_________________________________________________________________
Vehicle:
_______________________________________________________________________
Examination: (check all that apply)
[ ] Clinical Observation [ ] Body Weight [ ] Clinical Chemistry
[ ] Food Consumption [ ] Electrocardiograms [ ] Toxicokinetics
[ ] Ophthalmology [ ] Urinalysis [ ] Hematology
[ ] Organ Weight [ ] Necropsy [ ] Microscopy
[ ] Others:
____________________________________________________________________
Performing Laboratory:
_________________________________________________________
Dosing Schedule:
_______________________________________________________________
Expected Report Submission:
____________________________________________________
GLP: This study _________________ be conducted in accordance with GLP standards.
(will or will not)
Necessary amount of Captisol needed for study:
_________________________________
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx,
XX 00000 - (000) 000-0000 - FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
Version 1, Page 15
07/17/00
(CYDEX, INC. LOGO)
APPENDIX B
Version 1, Page 16
07/17/00
(CYDEX, INC. LOGO)
RESULTS SUMMARY
PROTOCOL # ______________________
Title:
_________________________________________________________________________
_________________________________________________________________________
Studies conducted under protocol:
STUDY NUMBER DATES OF STUDY VARIATIONS FROM PROTOCOL? (IF SO, PLEASE EXPLAIN)
------------ -------------- -------------------------------------------------
RESULTS SUMMARY
Attach any supporting documents as needed.
CyDex Inc. 00000 X. 00xx Xxxx., Xxxxxx,
XX 00000 - (000) 000-0000 - FAX (000) 000-0000 - E-mail: XX_Xxxx@xxxxxxxx.xxx
