[ ** ] = Certain confidential information contained in this document, marked by
brackets, has been omitted and filed separately with the Securities and Exchange
Commission pursuant to Rule 24b-2 of the Securities Exchange Act of 1934, as
amended.
Exhibit 10.22
LICENSE AND SUPPLY AGREEMENT
     This License and Supply Agreement (this “Agreement”) is made this 12th day
of October, 2005 (the “Effective Date”), by and between CyDex, Inc., a Delaware
corporation with offices at 10513 W. 84th Terrace, Lenexa, Kansas 66214,
(“CyDex”), and Proteolix, Inc., a Delaware corporation with offices at 225
Gateway Boulevard, South San Francisco, California 94080 (“Proteolix”).
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®, a patented
drug formulation system designed to enhance the solubility and stability of
drugs;
     Whereas, Proteolix desires to obtain a license to use such patented drug
formulation system in connection with its development and commercialization of a
certain pharmaceutical compound and CyDex is willing to grant such license to
Proteolix under the terms and conditions set forth herein; and
     Whereas, CyDex desires to sell CAPTISOL® to Proteolix, and Proteolix
desires to purchase CAPTISOL® from CyDex, in accordance with the terms and
conditions contained herein.
     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 “CAPTISOL” means CAPTISOL®, also known scientifically as
sulfobutylether b(beta) cyclodextrin, sodium salt.
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

1.

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     1.3 “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 Product.
     1.4 “CAPTISOL Improvement” means any technology or improvement specifically
related to the physical properties of CAPTISOL, whether or not patentable, that
is developed by Proteolix or its Affiliates or Sublicensees, solely or jointly
with a third party.
     1.5 “Claim” has the meaning specified in Section 10.1.
     1.6 “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> or any successor thereto,
(b) is intended for use in humans, and (iii) is intended for clinical trials for
the Product.
     1.7 “Commercial 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> or any successor thereto,
(b) is intended for use in humans, and (iii) is intended for commercial sale of
the Product.
     1.8 “Commercial Launch Date” means, in any particular country, the first
commercial sale of the Product by Proteolix, or an Affiliate or Sublicensee of
Proteolix to a third party.
     1.9 “Compound” means that certain pharmaceutical compound known as PR-171,
owned by or licensed to Proteolix and developed and manufactured by or on behalf
of Proteolix.
     1.10 “Confidential Information” has the meaning specified in Section 8.1.
     1.11 “Detailed Forecast” has the meaning specified in Section 3.2(b).
     1.12 “Disclosing Party” has the meaning specified in Section 8.1 hereof.
     1.13 “DMF” means a Drug Master File for CAPTISOL, as currently filed, or as
hereafter updated from time to time, by CyDex with the FDA.
     1.14 “FDA” means the United States Food and Drug Administration, or any
successor thereto.
     1.15 “Field” means the treatment of any and all diseases and conditions in
humans, except: (a) for the treatment or prophylaxis of fungal infections; or
(b) as a topical ocular treatment of dry eye.
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

2.

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     1.16 “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.
     1.17 “Indemnitee” has the meaning specified in Section 10.3.
     1.18 “Indemnitor” has the meaning specified in Section 10.3.
     1.19 “Initial Detailed Forecast” has the meaning specified in
Section 3.2(b).
     1.20 “Licensed Patents” means all patents and patent applications in the
Territory which cover 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.
     1.21 “Product” means the Compound combined with or formulated using
CAPTISOL in a parenteral dosage form/formulation.
     1.22 “Losses” has the meaning set forth in Section 10.1.
     1.23 “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.
     1.24 “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.
     1.25 “Net Sales” means gross amounts invoiced by Proteolix, its Affiliates
and Sublicensees for sales of the Product in the Field, 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 Product, outdated or returned 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.
“Net Sales” shall not include amounts for any Product furnished to a third party
for use in clinical trials and Product distributed as promotional and free
goods. Furthermore, “Net Sales” shall not include amounts from sales or other
dispositions of Product between Proteolix and any of its Affiliates or
Sublicensees, unless such Affiliate or Sublicensee is an end-user of such
Product.
     1.26 “Notice of Termination” has the meaning specified in Section 13.2.
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

3.

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     1.27 “Phase 1 Trial” means those clinical trials on sufficient numbers of
normal volunteers and patients that are designed to establish that a drug is
safe for its intended use, and to support its continued testing in Phase 2
Trials.
     1.28 “Phase 2 Trial” means those trials in sufficient numbers of patients
that are designed to establish the safety and biological activity of a drug for
its intended use, and to define warnings, precautions and adverse reactions that
are associated with a drug in the dosage range to be prescribed.
     1.29 “Pfizer” has the meaning specified in Section 8.5.
     1.30 “Purchase Volume Limitations” has the meaning specified in
Section 3.2(c).
     1.31 “Receiving Party” has the meaning specified in Section 8.1.
     1.32 “Ql” has the meaning specified in Section 3.2(c).
     1.33 “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 the Specifications for
Research Grade CAPTISOL.
     1.34 “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.
     1.35 “Sublicensees” has the meaning specified in Section 2.3.
     1.36 “Term” has the meaning specified in Section 13.1.
     1.37 “Testing Methods” has the meaning specified in Section 3.5(a).
     1.38 “Third-Party Manufacturer” has the meaning specified in Section 3.6.
     1.39 “Territory” means the entire world.
2. Grant of Rights.
     2.1 License Grants from CyDex to Proteolix.
          (a) Licensed Patents. Subject to the terms and conditions of this
Agreement, CyDex hereby grants to Proteolix an exclusive, nontransferable
license during the Term under the Licensed Patents, solely to develop, make,
have made, use, market, distribute, sell, offer for sale and import the Product
in the Field 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 Proteolix in the foregoing
sentence shall be exclusive as to CyDex and non-exclusive as to any third party.
Proteolix may not sublicense the Licensed Patents, except as expressly set forth
in Section 2.3 below. For purposes of clarification, CyDex grants no rights to
Proteolix to manufacture, import, sell or offer to sell bulk CAPTISOL, except as
otherwise provided in Section 3.7(c).
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

4.

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          (b) CAPTISOL Data Package. Subject to the terms and conditions of this
Agreement, CyDex hereby grants to Proteolix a non-exclusive, nontransferable
license during the Term under CyDex’ right in and to the CAPTISOL Data Package,
solely to develop, make, have made, use, market, distribute, sell, offer for
sale and import the Product in the Field in the Territory. Proteolix may not
sublicense its rights to the CAPTISOL Data Package, except as expressly set
forth in Section 2.3 below.
     2.2 Grant of License from Proteolix to CyDex. Proteolix hereby grants to
CyDex a non-exclusive, transferable, perpetual, royalty-free license, with the
right to grant sublicenses, under Proteolix’, its Affiliates’ and Sublicensees’
rights in and to CAPTISOL Improvements to develop, make, have made, use, market,
distribute, sell, offer for sale and import any CAPTISOL Improvement in the
Territory. Proteolix 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 patent application with respect to such CAPTISOL
Improvement.
     2.3 Sublicensing. Proteolix shall have the right to grant sublicenses to
its Affiliates and licensees of the Product (collectively “Sublicensees”) under
the licenses granted to Proteolix pursuant to Section 2.1; provided that
(a) each such Sublicensee has agreed to be bound by all applicable terms and
obligations of the rights and licenses granted by CyDex to Proteolix under this
Agreement (including, without limitation, Proteolix’ confidentiality
obligations), (b) the terms and conditions of each such sublicense is consistent
with and no less restrictive than the terms and conditions of this Agreement,
and (c) Proteolix provides to CyDex a copy of each such sublicense agreement
with respect to the Product, provided, however, Proteolix may redact any
proprietary or financial terms from any such copy. If necessary to engage a
third party manufacturer for the Product, Proteolix shall be permitted under
this Agreement to treat any such third party manufacturer as a Sublicensee,
subject to the terms of this Section 2.3. In any event, Proteolix shall procure
from any third party manufacturer of the Product, such third party’s agreement
that all bulk CAPTISOL supplied pursuant to this Agreement shall be used solely
for the manufacture of the Product. Other than as specifically provided in and
this Section 2.3, Proteolix shall not have the right to grant sublicenses to any
third party under the licenses granted pursuant to Section 2.1.
     2.4 Reservation of Rights. This Agreement confers no right, license or
interest by implication, estoppel, or otherwise under any patents, patent
applications, know-how or other intellectual property rights of either party
except as expressly set forth in this Section 2 and elsewhere in this Agreement.
Each party hereby expressly retains and reserves all rights and interests with
respect to patents, patent applications, know-how or other intellectual property
rights not expressly granted to the other party hereunder.
3. Manufacture and Supply of CAPTISOL.
     3.1 Purchase of CAPTISOL. Proteolix agrees that Proteolix and its
Affiliates and Sublicensees shall purchase CAPTISOL for use in Product
exclusively from CyDex and that they shall not manufacture (or have manufactured
on their behalf) CAPTISOL for such use without CyDex’ prior written consent.
CyDex agrees that CyDex shall produce (or have produced for it) and sell to
Proteolix one hundred percent (100%) of Proteolix’ and its Affiliates’
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

5.

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and Sublicensees’ requirements for CAPTISOL for use in Product, during the Term
and subject to the provisions of this Agreement. Purchases of CAPTISOL may
include Research Grade CAPTISOL, Clinical Grade CAPTISOL and/or Commercial Grade
CAPTISOL. Proteolix may place orders for CAPTISOL on behalf of its Affiliates
and Sublicensees; provided, however, that: (a) Proteolix shall instruct CyDex as
to the location for the shipment thereof; (b) Proteolix shall guarantee payment
to CyDex of all amounts payable with respect thereto; and (c) if Proteolix
requests that CyDex deliver such orders to Proteolix for re-delivery thereof by
Proteolix to its Affiliates or Sublicensees, Proteolix shall comply with all
applicable laws, rules and regulations applicable to the transportation of
CAPTISOL from Proteolix 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 Proteolix or its Affiliates or
Sublicensees of a Product in any particular country, Proteolix shall provide
CyDex with a forecast setting forth Proteolix’ estimate of the required
quantities of Commercial Grade CAPTISOL for each of the following [ ** ] years.
Such long-term forecast shall thereafter be updated by Proteolix at least once
every [ ** ] months.
          (b) Detailed Forecasts.
               (i) Commercial Forecasts: At least [ ** ] calendar quarters prior
to the calendar quarter in which Proteolix anticipates the placement of its
first order for Commercial Grade CAPTISOL, and thereafter on a calendar
quarterly basis until the First Commercial Sale Date, Proteolix shall deliver to
CyDex a detailed rolling forecast setting forth Proteolix’ anticipated
requirements and anticipated delivery schedules for Commercial Grade CAPTISOL
for the calendar quarter in which the Commercial Launch Date of a Product is
anticipated to occur and, in addition, for each full calendar quarter during the
[ ** ] month period following such anticipated Commercial Launch Date (the
“Initial Detailed Forecast”). No later than the first day of the first full
calendar quarter following the Commercial Launch Date, and no later than the
first day of each full calendar quarter thereafter, Proteolix shall deliver to
CyDex a detailed rolling forecast setting forth Proteolix’ anticipated
requirements and anticipated delivery schedules for Commercial Grade CAPTISOL
for each of the [ ** ] full calendar quarters during the [ ** ] month period
following the delivery date of such forecast (each, a “Detailed Forecast”). Each
Detailed Forecast shall be firm and binding on Proteolix with respect to
Proteolix’ obligation to purchase quantities of Commercial Grade CAPTISOL for
the [ ** ] and [ ** ] full calendar quarter in such Detailed Forecast, subject
to the permissible variances set forth in Section 3.2(c) below, and estimates of
Proteolix’ requirements for the [ ** ] and [ ** ] full calendar quarters in such
Detailed Forecast. If Proteolix fails to provide any updated Detailed Forecast
in accordance with this Section 3.2(b), the Detailed Forecast last provided by
Proteolix shall be deemed to be the updated Detailed Forecast, and the next full
calendar quarter estimate of Proteolix’ requirements for Commercial Grade
CAPTISOL set forth in such Detailed Forecast shall be a firm and binding
obligation with respect to Proteolix’ obligation to purchase Commercial Grade
for such next full calendar quarter.
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

6.

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               (ii) Clinical Forecasts: Beginning [ ** ] months after the
Effective Date, Proteolix shall deliver to CyDex at least every [ ** ] months, a
rolling forecast of their estimated requirements for Clinical Grade CAPTISOL for
so long as Proteolix requires clinical grade material during the Term. Upon
commencement of the Detailed Forecast as specified in Section 3.2(b) above, the
Clinical Forecast shall be incorporated, as a separate subsection, into such
Detailed Forecast. The frequency of the Clinical Forecast shall then be the same
as for the Detailed Forecast. The Clinical Forecast shall be for planning
purposes only, and thus shall not be binding in any manner whatsoever until a PO
has been placed by Proteolix for said Clinical Grade CAPTISOL and accepted by
CyDex.
          (c) Detailed Forecast Variances. Each updated 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”):
               (i) for the first calendar quarter covered by such updated
Detailed Forecast (“Ql”), no change may be made without the prior express
written consent of CyDex;
               (ii) for the second calendar quarter covered by such updated
Detailed Forecast, no change in excess of a [ ** ] percent [ ** ] volume
increase or decrease from the prior Detailed Forecast may be made without the
prior express written consent of CyDex;
               (iii) for the third calendar quarter covered by such updated
Detailed Forecast, no change in excess of a [ ** ] percent [ ** ] volume
increase or decrease from the prior Forecast may be made without the prior
express written consent of CyDex; and
               (iv) for the fourth calendar quarter covered by such updated
Detailed Forecast, no change in excess of a [ ** ] percent [ ** ] volume
increase or decrease from the prior Forecast may be made without the prior
express written consent of CyDex.
In each case CyDex’ consent may be conditioned on such payment or other terms as
CyDex may require.
          (d) Purchase Orders. Together with each Detailed Forecast provided
under Section 3.2(b) above, Proteolix shall place a firm purchase order with
CyDex in a form mutually agreed upon by the parties, for Proteolix’ 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 Proteolix’ 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; provided, however, that CyDex shall accept such
orders for Commercial Grade CAPTISOL from Proteolix 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.
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

7.

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If CyDex, despite the use of good faith efforts, is unable to supply such
quantities that exceed the Purchase Volume Limitations to Proteolix, such
inability to supply shall not be deemed to be a breach of this Agreement by
CyDex or a failure by CyDex to supply for any purpose. Ordered quantities of
Commercial Grade CAPTISOL shall be specified in multiples of [ ** ] kilograms,
subject to a minimum order quantity of [ ** ] kilograms. CyDex shall use
reasonable efforts to notify Proteolix within [ ** ] business days after its
receipt of Proteolix’ purchase order of its ability to fill any amounts of such
order that are in excess of the Purchase Volume Limitations. If any purchase
order or other document submitted by Proteolix 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 Proteolix or Proteolix’ designee each
order of CAPTISOL, packed for shipment in accordance with CyDex’ customary
practices and the Specifications, CIP Proteolix designated location (Incoterms
2000). Title and risk of loss and/or damage to CAPTISOL shall pass to Proteolix
upon delivery of CAPTISOL to Proteolix or Proteolix’ designee at Proteolix’s
designed location. CyDex acknowledges the inherent risk that a batch of CAPTISOL
may be lost in production or shipment, and CyDex agrees to maintain an inventory
of CAPTISOL sufficient to supply at least [ ** ] days worth of Proteolix’
requirements in the event of production or delivery delays.
     3.4 Modified Specifications. CyDex shall have the right to change the
Specifications from time to time during the Term; provided that such change has
no adverse effect or consequence on Proteolix’ development or commercialization
of the Product including, for example, an effect or consequence that requires
Proteolix to conduct any clinical study requested by the FDA or other regulatory
agency. Any change in the Specifications that would have an adverse effect or
consequence on Proteolix’ development or commercialization of the Product will
require Proteolix’ prior written consent. In the event that CyDex desires to
change the Specifications, CyDex shall give Proteolix at least [ ** ] days
notice. CyDex shall cooperate with Proteolix to have any change approved by the
FDA and other regulatory agencies having jurisdiction. In the event that the FDA
or another regulatory agency having jurisdiction requires Proteolix to implement
any changes to the Specifications, CyDex shall use all reasonable efforts to
make such changes. CyDex shall promptly advise Proteolix as to any lead-time
changes or other terms that may result from a change to the Specifications,
including but not limited to price adjustments necessary to enable CyDex to
recover costs it actually incurred for materials already purchased by CyDex
expressly for Proteolix, its Affiliates or Sublicensees and rendered unusable by
a change in Specifications requested by Proteolix or as necessary to comply with
government regulatory requirements with respect to the Product If a regulatory
agency requires a change to the Specifications where such change is specific to
CAPTISOL and not specific to the Product then CyDex shall be responsible for the
costs incurred to generate such unique, modified Specifications.
     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-
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

8.

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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 for each lot of CAPTISOL therein.
          (b) Acceptance Testing. Proteolix shall have a period of [ ** ] days
after the date of receipt to test or cause to be tested CAPTISOL supplied under
this Agreement. Proteolix or its designee shall have the right to reject any
shipment of CAPTISOL that does not conform in all material respects 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 Proteolix unless CyDex receives written notice of
rejection from Proteolix within such [ ** ] day period, describing the reasons
for the rejection in reasonable detail. Once a delivery of CAPTISOL is accepted
or deemed accepted hereunder, Proteolix shall have no recourse against CyDex in
the event CAPTISOL is subsequently deemed unsuitable for use for any reason,
except as provided in Sections 7.4 and 10 below.
          (c) Confirmation. CyDex shall notify Proteolix as soon as reasonably
practical (but in any event within [ ** ] days) after its receipt of a notice of
rejection from Proteolix pursuant to Section 3.5(b) above, whether CyDex accepts
Proteolix’ basis for rejection and Proteolix 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.
          (d) Return or Destruction of Rejected Shipments. Proteolix 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; provided that if Proteolix does not receive such written notice
within [ ** ] days after its delivery of a notice of rejection to CyDex pursuant
to Section 3.5(b) above, CyDex shall be deemed to agree that such batch fails to
meet the Specifications. CyDex will indicate in its notice either that Proteolix
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,
Proteolix shall promptly destroy the rejected batch of CAPTISOL and provide
CyDex with written certification of such destruction. Upon receipt of CyDex’
request for return, Proteolix shall promptly return the rejected batch of
CAPTISOL to CyDex. In each case, CyDex will reimburse Proteolix for the
documented, reasonable costs associated with the destruction or return of the
rejected CAPTISOL.
          (e) Refund or Replacement. Proteolix 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, Proteolix shall be obligated to
pay in full for any rejected shipment of CAPTISOL that is subsequently
determined to meet the Specifications in accordance with Section 3.5(c),
irrespective of whether Proteolix has already paid CyDex for a replacement
shipment. If Proteolix pays in full for a shipment of CAPTISOL and subsequently
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

9.

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properly rejects such shipment in accordance with this Section 3.5, Proteolix
shall be entitled, upon confirmation that such shipment failed to meet the
Specifications in all material respects, 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 additional cost to
Proteolix. Proteolix acknowledges and agrees that, except for the
indemnification obligations set forth in Section 10 below, Proteolix’ rights to
a refund or credit for or to receive replacement of properly rejected shipments
of CAPTISOL hereunder shall be Proteolix’ sole and exclusive remedy, and CyDex’
sole obligation, with respect to non-conforming CAPTISOL delivered hereunder.
          (f) Exceptions. Proteolix’ 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 caused by Proteolix, 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.
     3.6 Facilities and Inspections. Without limiting CyDex’ responsibility
under this Agreement, CyDex shall have the right at any time to satisfy its
supply obligations to Proteolix 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 Proteolix prior written notice of
any such arrangement. CyDex shall permit no more than [ ** ] of Proteolix’
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. Notwithstanding the foregoing, CyDex agrees to reasonably
cooperate, and shall require any Third-Party Manufacturer to reasonably
cooperate, with all regulatory authorities and shall submit to reasonable
CAPTISOL-related inspections by such authorities. With respect to inspection of
the facilities of a Third Party Manufacturer by Proteolix, its Affiliates or
Sublicensees, Proteolix shall be responsible for any reasonable fees charged by
CyDex’ Third Party Manufacturer in connection with such inspections (as of the
Effective Date, [ ** ] Dollars [ ** ] per person per day). Proteolix’ authorized
representatives shall be accompanied by CyDex personnel at all times, shall be
qualified to conduct such manufacturing audits, shall comply with all applicable
rules and regulations relating to facility security, health and safety, and
shall execute a written confidentiality agreement with terms at least as
restrictive as those set forth in Section 8 (Confidentiality) hereof. In no
event shall any such manufacturing audit exceed [ ** ] days in duration.
Proteolix 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 Proteolix nor its Affiliates,
sublicensees or their respective employees or representatives shall have access
to CyDex’ facilities or the facilities of any Third-Party Manufacturer.
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

10.

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     3.7 Inability to Supply.
          (a) Notice. CyDex shall notify Proteolix if CyDex is unable to supply
the quantity of (i) Commercial Grade CAPTISOL ordered by Proteolix 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 Proteolix as
set forth in Section 3.2(d) above: (1) within [ ** ] days after CyDex’ receipt
of a purchase order from Proteolix 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 Proteolix the quantity of
CAPTISOL that CyDex is required to supply hereunder.
          (b) Allocation. If CyDex is unable to supply to Proteolix the quantity
of CAPTISOL that CyDex is required to supply hereunder, CyDex (i) shall allocate
its available CAPTISOL among Proteolix 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.
          (c) Right to Manufacture. If CyDex is not able to supply CAPTISOL to
Proteolix which meets Specifications or in the quantity requirements for
CAPTISOL ordered in accordance with this Section 3, Proteolix shall be entitled
to manufacture CAPTISOL but only for Proteolix’ clinical use, marketing, sale
and distribution of the Product. Notwithstanding the above, Proteolix may
exercise such right to manufacture CAPTISOL only if (i) CyDex’ inability to
supply CAPTISOL could reasonably be expected to result in a period of time
during which no CAPTISOL would be available to Proteolix for the clinical use,
marketing, sale and distribution of the Product, (ii) there is no reason to
believe that CyDex would be able to re-start manufacture of CAPTISOL more
quickly than Proteolix or Proteolix’ designee could start manufacture of
CAPTISOL, and (iii) CyDex’ inability to supply CAPTISOL did not result, wholly
or in part, from factors within the control of CyDex.
4. Compensation.
     4.1 Payments and Royalties for Licenses.
          (a) One-Time Fee. Proteolix shall pay to CyDex a [ ** ] one-time fee
of [ ** ] dollars ($[ ** ]) in partial consideration of the rights granted
Proteolix under this Agreement, which amount shall be due and payable in full
upon the Effective Date.
          (b) Milestone Payments. Pursuant to Section 5.2(a), written notice of
each of the milestone events listed below with respect to the Product shall be
provided to CyDex, and within [ ** ] days after such written notice of each of
the milestone events, Proteolix shall pay to CyDex the applicable non-refundable
milestone fee listed next to each such event in further consideration of the
rights granted Proteolix hereunder. The milestone payments are as follows:

      Milestone   Milestone Payment
[ ** ]
  [ ** ]

 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

11.

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      Milestone   Milestone Payment
[ ** ]
  [ ** ]
[ ** ]
  [ ** ]
[ ** ]
  [ ** ]
[ ** ]
  [ ** ]
[ ** ]
  [ ** ]
Upon first achievement of [ ** ] in annual Net Sales of Product
  [ ** ]
Upon first achievement of [ ** ] in annual Net Sales of Product
  [ ** ]
Upon first achievement of [ ** ] in annual Net Sales of Product
  [ ** ]

          (c) Royalties.
               (i) In addition to amounts payable pursuant to Sections 4.1(a)
and 4.1(b) above, Proteolix shall make royalty payments to CyDex on a calendar
quarterly basis, in an amount equal to the appropriate royalty rate, according
to the following rate schedule, to the applicable Net Sales during such quarter
arising from the sale of the Product in the Territory. All royalties payable to
CyDex pursuant to this Section 4.1(c)(i) shall be due and payable within [ ** ]
days after receipt of the Quarterly Report as set forth in Section 5.2(a).

      Aggregate Net Sales in     Each Calendar Year   Royalty Rate
Up to, and including, [ ** ]
  [ ** ]
[ ** ] to [ ** ]
  [ ** ]
[ ** ] to [ ** ]
  [ ** ]
Above [ ** ]
  [ ** ]

For clarity, the royalty rates set forth above in Section 4.1(c) shall be
applied to the total Net Sales of Product falling within the applicable range of
aggregate annual Net Sales during the quarter. For example, if at the end of the
first quarter of a particular calendar year, aggregate Net Sales of such Product
was [ ** ], then sales representing the first [ ** ] in such first quarter would
be subject to the [ ** ] royalty rate and the remaining [ ** ] would be subject
to the [ ** ] royalty rate under Section 4.1(c). In subsequent quarters of the
same calendar year, all sales of Product would be subject to the [ ** ] royalty
rate until total aggregate sales of Product in such calendar year reached [ **
], at which point all further sales of Product up to [ ** ] would be subject to
the [ ** ] royalty rate. For aggregate sales exceeding [ ** ] in the same
calendar year, such sales of Product would be subject to the [ ** ] royalty
rate.
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

12.

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               (ii) The obligation of Proteolix to pay royalties to CyDex under
this Section 4.1(c) shall commence on the first Commercial Launch Date of the
Product in the Field in the Territory and continue, on a country-by-country
basis, (1) until the expiration of the last to expire patent within the Licensed
Patents in such country, and (2) after the period described in (1), a period of
[ ** ] years with royalties to be calculated on aggregate annual Net Sales at a
rate equal to [ ** ] percent [ ** ] of the royalty rates set forth in
Section 4.1(c)(i) above. Thereafter, Proteolix shall have a paid up,
royalty-free license with respect to the Product in the Field.
     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 Proteolix, 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, for the
twelve (12) month period ending October 31 of the prior year. If Proteolix fails
to place a firm purchase order for any Q1 for a quantity of Commercial Grade
CAPTISOL to be delivered during such Q1 equal to or greater than the quantity of
Commercial Grade CAPTISOL Proteolix is obligated to purchase pursuant to the
applicable Detailed Forecast, allowing for the variances as defined in
Section 3.2(c), CyDex may adjust the purchase price of Commercial Grade CAPTISOL
ordered under this Agreement so as to permit CyDex to recover all reasonable
costs and expenses incurred by CyDex in reliance upon Proteolix’ binding
obligation, including but not limited to the costs of the raw materials and
supplies of CAPTISOL acquired or used in contemplation of fulfilling such order.
          (b) Invoicing; Payment. CyDex shall invoice Proteolix 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 Proteolix 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 Proteolix are not known at the time
CyDex invoices Proteolix for the purchase price for the CAPTISOL ordered by
Proteolix, CyDex may invoice such costs at a later date. Payment of such
invoices shall be made within [ ** ] days after the date of delivery of such
invoice pursuant to Section 14.7.
     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 The Wall Street Journal, Eastern
U.S. Edition on the last day of each calendar quarter. Proteolix shall provide
CyDex, together with each royalty payment owed pursuant to Section 4.1(c) 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 Proteolix will be responsible for payment of all such taxes
(other than taxes based on CyDex’ income), fees, duties, and charges, and any
related penalties and interest, arising from
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

13.

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the payment of amounts due hereunder or the sublicense or license, as the case
may be, under the Licensed Patents hereunder. Proteolix 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
Proteolix’ sole responsibility, and Proteolix will provide CyDex with official
receipts issued by the appropriate taxing authority, or such other evidence as
the CyDex may reasonably request, to establish that such taxes have been paid.
Proteolix shall indemnify and hold CyDex harmless from any and all such taxes
and any actions brought against CyDex by any taxing authority with respect to
such taxes.
     4.5 Late Payments. Unpaid balances shall accrue interest, from due date
until paid, at a rate equal to the lesser of (a) the prime rate, as reported in
The Wall Street Journal, Eastern U.S. Edition, on the date such payment is due,
plus an additional [ ** ] percent [ ** ] or (b) the maximum rate permitted under
applicable law. If any amount due hereunder and not subject to a reasonable,
good-faith dispute by Proteolix 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 Proteolix in
advance.
5. Records; Reports; Audit.
     5.1 Records. During the Term and for a period of [ ** ] years thereafter,
Proteolix shall, and shall require its Affiliates and Sublicensees to, maintain
complete and accurate records relating to (a) subject enrollment in clinical
studies for the Product; (b) the achievement of each of the milestone events set
forth in Section 4.1(b) above; and (c) Net Sales of Product.
     5.2 Reports.
          (a) Quarterly Reports. Within [ ** ] calendar days following the
conclusion of each calendar quarter during the Term, Proteolix shall provide
CyDex with a written report with respect to such calendar quarter that
(i) indicates subject enrollment numbers during such calendar quarter with
respect to clinical studies conducted by Proteolix, its Affiliates or
Sublicensees for the Product; (ii) sets forth the achievement of each of the
milestone events set forth in Section 4.1(b) above during such calendar quarter
whether achieved by Proteolix, its Affiliates and Sublicensees, and (iii) sets
forth in reasonable detail complete and accurate records of Proteolix’, its
Affiliates’ and Sublicensees’ Net Sales of the Product in the Territory during
such calendar quarter.
          (b) Annual Reports. Annually, by December 1st of each calendar year
during the Term, Proteolix shall provide CyDex with a written report that:
(i) sets forth the achievement of each of the milestone events set forth in
Section 4.1(b) above during such calendar year whether achieved by Proteolix,
its Affiliates or Sublicensees; (ii) sets forth Proteolix’ anticipated
requirements of CAPITSOL for preclinical and clinical use during the next
calendar year; (iii) sets forth in reasonable detail complete and accurate
records of Proteolix’, its Affiliates’ and Sublicensees’ Net Sales of the
Product in the Territory during such calendar year.
     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 but no more often than [ ** ] per year, to inspect and audit Proteolix’,
its Affiliates’ and Sublicensees’ records relevant to
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

14.

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Net Sales. The costs of such audits shall be borne solely by CyDex; provided,
however, that in the event such an audit reveals an underpayment by Proteolix of
royalties owed hereunder of more than [ ** ] percent [ ** ], Proteolix shall
immediately (i) pay CyDex all amounts by which Proteolix 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 such an audit reveals an
overpayment by Proteolix of royalties owed hereunder, CyDex shall immediately
credit all amounts by which Proteolix has overpaid CyDex as revealed by the
audit against any amounts owed by Proteolix to CyDex in the next payment 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 Proteolix, 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 Proteolix.
     6.1 Diligence. Proteolix agrees that, during the Term, it will use, and
shall require its Affiliates and Sublicensees to use, commercially reasonable
efforts to conduct clinical development of the Product, to obtain Marketing
Approval in the United States, Japan and the European Union, and to market,
promote, and sell the Product thereafter in each country in which Marketing
Approval is obtained, in an effort to maximize Net Sales and, thus, royalties
payable under this Agreement.
     6.2 Costs and Expenses. Proteolix shall be solely responsible for all costs
and expenses related to its development and commercialization of the Product,
including without limitation costs and expenses associated with all preclinical
activities and clinical trials, and all regulatory filings and proceedings
relating to the Product.
     6.3 Preclinical In Vivo Studies. If Proteolix wishes to conduct any
preclinical in vivo study utilizing CAPTISOL (administered alone or in
conjunction with the Compound) at doses greater than those set forth in
Exhibit D, Proteolix 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 Proteolix within [ ** ] days after receipt of such notice and protocol
from Proteolix, 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 Proteolix 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 after 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 Proteolix within [ ** ] days following
receipt of Proteolix’ notice. Proteolix agrees to (a) immediately inform CyDex
if any adverse effects are observed and ascribed to CAPTISOL in any study
conducted
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

15.

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under this Section 6.3, and (b) provide CyDex with copies of the final and full
reports of all studies conducted under this Section 6.3, promptly upon
completion thereof.
     6.4 Right of Reference. Proteolix shall have the right to reference the DMF
solely in connection with Proteolix’ regulatory filings submitted in connection
with obtaining Marketing Approval for the Product.
     6.5 Access to Proteolix’ 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 Proteolix,
its Sublicensees or Affiliates in connection with CyDex’ development and
commercialization of CAPTISOL, at no cost to CyDex. Upon request by CyDex,
Proteolix 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.
7. Regulatory Matters.
     7.1 CAPTISOL Information Submitted for Regulatory Review. Except as
otherwise set forth herein, Proteolix shall be solely responsible for all
communications with regulatory agencies in connection with the Product.
Notwithstanding the foregoing, Proteolix 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 Proteolix within [ ** ] days after 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
Proteolix 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 after 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. Proteolix shall inform
CyDex of meetings with the FDA (or other regulatory agencies in the Territory)
regarding the Product [ ** ] days prior to such event and shall allow CyDex to
participate in any FDA (or other regulatory agency) review that might reasonably
include inquiries regarding CAPTISOL. If Proteolix submits written responses to
the FDA that include data on CAPTISOL alone, CyDex shall be permitted to review
such written materials prior to submission. 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.
     7.2 Material Safety. CyDex shall provide Proteolix, 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, Proteolix 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
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

16.

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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.
     7.3 Adverse Event Reporting.
          (a) Proteolix 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
confirmed diagnosis, symptom, sign, syndrome or disease, whether or not
considered CAPTISOL or Product-related, which occurs or worsens following
administration of CAPTISOL or Product. Proteolix shall provide CyDex with copies
of all reports of any such adverse event directly involving CAPTISOL 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 Proteolix has reason to believe are
associated with CAPTISOL within [ ** ] business days following Proteolix’
(a) submission of any such report to any regulatory agency, or (b) receipt from
its Sublicensee, co-marketer or distributor of any such report to any regulatory
agency, as the case may be. Proteolix shall also advise CyDex regarding any
proposed labeling or registration dossier changes affecting CAPTISOL. Reports
from Proteolix shall be delivered to the attention of Vice President, Chief
Scientific Officer, CyDex, with a copy to CEO, CyDex, at the address set forth
in Section 14.7 (Notices). The parties shall mutually cooperate with regard to
investigation of any such serious adverse event which is believed to be directly
associated with CAPTISOL, whether experienced by Proteolix, CyDex or any other
Affiliate, Sublicensee, co-marketer or distributor of CyDex or Proteolix.
          (b) CyDex 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
confirmed diagnosis, symptom, sign, syndrome or disease, whether or not
considered CAPTISOL-related, which occurs or worsens following administration of
CAPTISOL alone or upon administration of a CAPTISOL-enabled formulated product.
CyDex shall provide Proteolix with copies of all reports, some content of which
may be redacted solely to protect the confidential information of third parties,
of any such adverse event directly involving CAPTISOL 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 CyDex has reason to believe are associated with CAPTISOL within
[ ** ] business days following CyDex’ (a) submission of any such report to any
regulatory agency, or (b) receipt from its Sublicensee, co-marketer or
distributor of any such report to any regulatory agency, as the case may be.
Reports from CyDex shall be delivered to the attention of Vice President of
Development, Proteolix, with a copy to Chief Scientific Officer, Proteolix, at
the address set forth in Section 14.7 (Notices). The parties shall mutually
cooperate with regard to investigation of any such serious adverse event which
is believed to be directly associated with CAPTISOL, whether experienced by
Proteolix, CyDex or any other Affiliate, Sublicensee, co-marketer or distributor
of CyDex or Proteolix. Such written notification to Proteolix as well as
assistance
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

17.

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with any resulting investigation shall be provided in a manner such that no
third party confidential information is compromised in doing so by either
Proteolix or CyDex.
     7.4 Product Recalls. If any CAPTISOL should be alleged or proven not to
meet the Specifications, Proteolix shall notify CyDex immediately, and both
parties shall cooperate fully regarding the investigation and disposition of any
such matter. If Proteolix should deem it appropriate to recall any Product and
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. Proteolix shall in all events be responsible
for conducting any such recalls with respect to the Product and shall maintain
records of all sales of 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. Proteolix and CyDex each recognizes that during the Term,
it may be necessary for a party (the “Disclosing Party”) to provide Confidential
Information to the other party (the “Receiving Party”) that is highly valuable,
the disclosure of which would be highly prejudicial to the Disclosing Party. The
disclosure and use of Confidential Information will be governed by the
provisions of this Section 8. Neither Proteolix nor CyDex shall use the other’s
Confidential Information except as expressly permitted in this Agreement. For
purposes of this Agreement, “Confidential Information” means all information
disclosed by the Disclosing Party to the Receiving Party and designated in
writing by the Disclosing Party as “Confidential” (or equivalent), and all
material disclosed orally which is declared to be confidential by the Disclosing
Party at the time of such disclosure and confirmed in a writing marked as
“Confidential” (or equivalent) and delivered to the Receiving Party within
thirty (30) days after such disclosure, 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. Without limiting
the generality of the foregoing, CyDex’ Confidential Information includes all
materials provided as part of the CAPTISOL Data Package.
     8.2 Obligation. The Receiving Party agrees that it will disclose the
Disclosing Party’s Confidential Information to its own officers, employees,
consultants and agents only if and to the extent necessary to carry out its
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. The Receiving
Party shall not disclose Confidential Information of the Disclosing Party to any
third party without such Disclosing Party’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. The Receiving Party shall
take such action to preserve the confidentiality of the Disclosing Party’s
Confidential Information as it would customarily take to preserve the
confidentiality of its own
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

18.

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Confidential Information (but in no event less than a reasonable standard of
care). The Receiving Party, upon the Disclosing Party’s request, will return all
of the Disclosing Party’s Confidential Information, 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; provided,
however; that each party may retain one archival copy of such Confidential
Information solely to be able to monitor its obligations that survive under this
Agreement.
     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:
               (i) at the time of disclosure is in the public domain;
               (ii) after disclosure, becomes part of the public domain, by
publication or otherwise, through no fault of the Receiving Party;
               (iii) is in the Receiving Party’s possession prior to receipt
from the Disclosing Party as long as obtained lawfully;
               (iv) 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
               (v) is developed by Receiving Party without use of, application
of or access to the Disclosing Party’s Confidential Information 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, 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, 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 may suffer
irreparable damages and its remedy at law may 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. Proteolix acknowledges that CyDex’
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-
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

19.

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party beneficiary of this Section 8 of this Agreement and may enforce it or seek
remedies pursuant to it in accordance with its terms.
9. Representations and Warranties.
     9.1 Mutual Representations and Warranties. Each party represents and
warrants to the other that:
          (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 Proteolix, 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, Warranties and Covenants. CyDex represents and
warrants to Proteolix that:
          (a) CyDex owns all title in and to the CAPTISOL to be provided to
Proteolix under the terms and conditions of this Agreement, and has the right to
sell CAPTISOL to Proteolix pursuant to the terms and conditions of this
Agreement;
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

20.

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          (b) As of the Effective Date, there are no actions, suits,
investigations, claims or proceedings pending or threatened relating to the
Licensed Patents, and that CyDex will notify Proteolix in writing within [ ** ]
days if any such actions, suits, investigations, claims or proceedings are
initiated that could have material negative impact on Proteolix’ development of
the Product;
          (c) All CAPTISOL supplied to Proteolix under the terms and conditions
of this Agreement (as applicable for Research Grade CAPTISOL, Clinical Grade
CAPTISOL or Commercial Grade CAPTISOL, as the case may be) shall be manufactured
in accordance with all laws, rules and regulations relating to such manufacture,
current and future; and
          (d) CyDex [ ** ].
     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
or the licensed patents, including but not limited to the implied warranties of
merchantability and fitness for a particular purpose, title and non-infringement
of third party rights. CyDex warranties under this Agreement are solely for the
benefit of Proteolix and may be asserted only by Proteolix and not by any
affiliate, sublicensee or any customer of Proteolix, its affiliates or
sublicensees. Proteolix, its affiliates and sublicensees shall be solely
responsible for all representations and warranties that Proteolix, its
affiliates or sublicensees make to any customer of Proteolix, its affiliates or
sublicensees.
10. Indemnification.
     10.1 By CyDex. CyDex shall defend, indemnify and hold Proteolix 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 Proteolix
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) any claim by such
third party 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
Product infringe upon such third party’s patent rights; (b) injury or other harm
arising from the use of CAPTISOL alone, or (c) CyDex’ breach of any of its
representations, warranties and covenants set forth in Section 9 above;
provided, however, that the foregoing obligation to indemnify shall not apply to
the extent that Proteolix is obligated under Section 10.2 below to indemnify
CyDex with respect to a Claim, and CyDex shall be relieved of its obligations
under clause (a) of this Section 10.1 for any infringement claim that arises out
of: (i) the unauthorized use of the Licensed Patents by Proteolix; or (ii) the
manufacture, handling, marketing, sale, distribution or use of Product by
Proteolix. If an
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

21.

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injunction is issued preventing the practice of the Licensed Patents, CyDex may,
at its option, terminate this Agreement immediately upon written notice to
Proteolix; provided that such termination shall have no effect on CyDex’
indemnification obligations pursuant to this Section 10.1 incurred prior to the
effective date of such termination. This Section 10 states CyDex’ sole
obligation and entire liability, and Proteolix’, its affiliates’ and
sublicensees’ sole and exclusive remedy, for any claim of infringement of
intellectual property rights relayed to the Licensed Patents or Product.
     10.2 By Proteolix. Proteolix 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 extent such Losses arise out of: (a) the use
or sale of the Product by Proteolix, its Affiliates, Sublicensees, distributors,
agents, or other parties (except to the extent such Losses arise from the use of
CAPTISOL); (b) the manufacture, use, handling, promotion, marketing,
distribution, sale or use of Product (except to the extent such Losses arise
from the use of CAPTISOL); (c) interactions and communications with governmental
authorities, physicians or other third parties; or (d) Proteolix’ breach of any
of its representations and warranties set forth in Section 9.1; provided,
however, the foregoing obligation to indemnify shall not apply to the extent
that CyDex is obligated under Section 10.1 above to indemnify Proteolix with
respect to a Claim.
     10.3 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 damages for which CyDex is responsible pursuant to its
indemnification obligations set forth in Section 10 above, CyDex specifically
disclaims all liability for and shall in no event be liable 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 the 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 CyDex
was advised of the possibility of such damages. Proteolix 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 total aggregate liability for all
claims arising out of this Agreement exceed [ ** ] the amounts paid by
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

22.

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Proteolix to CyDex pursuant to Section 4 (Compensation) of this Agreement during
the [ ** ] month period immediately preceding the event giving rise to
liability. No action, regardless of form, arising out of or relayed to this
Agreement may be brought by [ ** ] 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 shall have the 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 Proteolix becomes aware that a third
party may be infringing a Licensed Patent, it will promptly notify CyDex in
writing, providing all information available to Proteolix 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, Proteolix shall, at CyDex’ 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
Proteolix’ obligation to pay royalties under Section 4.1(c), unless terminated
earlier as set forth herein.
     13.2 Termination for Cause. If either party should violate or fail to
perform any material term or material covenant of this Agreement, then the
non-breaching party may give written notice of such default to the breaching
party. If the breaching party should fail to cure such default within thirty
(30) days after the date of such notice, the non-breaching party shall have the
right to terminate this Agreement by a second written notice (a “Notice of
Termination”) to the breaching party, such termination to be effective as of the
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 by CyDex to
Proteolix. In addition, either party may terminate this Agreement immediately
upon written notice to the other party in the event such other party makes an
assignment for the benefit of creditors or has a petition in bankruptcy filed
for or against it that is [ ** ].
     13.3 Termination by Proteolix. Proteolix shall have the right at any time
to terminate this Agreement in whole by giving CyDex at least [ ** ] days prior
written notice.
     13.4 Effect of Expiration or Termination. Following the expiration or
termination of this Agreement, except as otherwise provided in
Section 4.1(c)(ii), all rights granted to Proteolix herein shall immediately
terminate and, in the event of termination of this Agreement by Proteolix
pursuant to Section 13.2, all rights granted to CyDex herein shall immediately
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

23.

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terminate, and each party shall promptly 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 indicated to survive
termination or expiration of this Agreement, nor shall any termination or
expiration of this Agreement relieve Proteolix of its obligation to pay CyDex
(a) royalties for all Product sold by Proteolix, its Affiliates or Sublicensees
prior to the effective date of such expiration or termination, or (b) sums due
in respect of CAPTISOL shipped prior to termination or expiration of this
Agreement. Sections 1 (Definitions); 2.1 (License Grants from CyDex to
Proteolix); 2.2 (Grant of License from Proteolix to CyDex); 5 (Records; Reports;
Audits); 7.4 (Product Recalls); 8 (Confidentiality); 9.4 (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; provided, however, that Section 2.2 (Grant of
License from Proteolix to CyDex) shall not survive termination of this Agreement
by Proteolix pursuant to Section 13.2 and Section 2.1 (License Grants from CyDex
to Proteolix) shall not survive termination of this Agreement by CyDex pursuant
to Section 13.2 or by Proteolix pursuant to Section 13.3. Proteolix’s exercise
of the license under Section 2.1 (if it survives termination) is subject to
compliance with Proteolix’s continued compliance with Section 4 (Compensation).
14. General Provisions.
     14.1 Non-Solicitation. During the Term and for a period of [ ** ] year
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.
          (a) Proteolix agrees that use of the Licensed Patents by Proteolix,
its Affiliates and Sublicensees, and the manufacture, handling, marketing, sale,
distribution and use of 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.
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

24.

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          (b) CyDex agrees the manufacture and supply of CAPTISOL to Proteolix
(as applicable for Research Grade CAPTISOL, Clinical Grade CAPTISOL or
Commercial Grade CAPTISOL, as the case may be) 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 New York, New York by an arbitrator
reasonably knowledgeable about the pharmaceutical industry and acceptable to
CyDex and Proteolix. If CyDex and Proteolix cannot agree on a single arbitrator
within ten (10) days after a demand for arbitration has been made, CyDex shall
appoint an arbitrator, Proteolix 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 New York, New York 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 after 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
required by law, 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
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

25.

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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; provided, however, that the affected party resumes performance
hereunder as soon as reasonably possible following cessation of such force
majeure event; and provided further that no such delay or failure in performance
shall continue for more than three (3) months. 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, injunction, act of governmental authority, compliance with
governmental order on national defense requirements, 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. In the event that a delay or
failure in performance by a party under this Section 14.6 continues longer than
three (3) months, the other party may terminate this Agreement in accordance
with the terms and conditions of Section 13.2.
     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.
10513 W. 84th Terrace
Lenexa, KS 66214
Attention: CEO
Fax: (913) 685-8856
     If to Proteolix, to:
Proteolix, Inc.
225 Gateway Boulevard
South San Francisco, CA 94080
Attention: VP, Development
(Fax) 650-866-6351
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

26.

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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. Neither party shall have any right, express or implied,
to use 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 (including a description of the Field), but without
disclosing the economic terms hereof, 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 New York (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 and contemporaneous
agreements, written or oral, between CyDex and Proteolix relating to the subject
matter of 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 Proteolix 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
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

27.

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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, 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, either 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.
* * *
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

28.

--------------------------------------------------------------------------------

 

     IN WITNESS WHEREOF, the parties have executed this Agreement as of the date
first written above.
CYDEX, INC.

         
By:
  /s/ John M. Siebert
 
   
Name:
  John M. Siebert    
Title:
  Chairman & CEO    
 
        PROTEOLIX, INC.    
 
       
By:
Name:
  /s/ Susan M. Molineaux
 
Susan M. Molineaux    
Title:
  CSO    

 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

29.

--------------------------------------------------------------------------------

 

EXHIBIT A

LICENSED 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
(U.S. 5,134,127)
    01/22/91     PCT/US91/00326     W091/11172          
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   [ ** ] =   Certain confidential
information contained in this document, marked by brackets, has been omitted and
filed separately with the Securities and Exchange Commission pursuant to Rule
24b-2 of the Securities Exchange Act of 1934, as amended.

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     W094/02518          
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  

 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

2.

--------------------------------------------------------------------------------

 

                                                              Expiration Country
  Filing Date   Serial No.   Patent No.   Date
Armenia
    07/26/93       96237       822       07/22/13  
Kyrgyzstan
    08/09/96       960481.1       333       05/10/16  
Moldova
    08/08/96     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  

 

*   Awaiting confirmation documents   [ ** ] =   Certain confidential
information contained in this document, marked by brackets, has been omitted and
filed separately with the Securities and Exchange Commission pursuant to Rule
24b-2 of the Securities Exchange Act of 1934, as amended.

3.

--------------------------------------------------------------------------------

 

EXHIBIT B
SPECIFICATIONS — Commercial Grade and Clinical Grade CAPTISOL

          Test   Specification   Test Method
Appearance
  White to off-white solid essentially free from foreign matter   CY-VI-005
 
       
Identification (IR)
  Spectrum is consistent with the SBECD standard   CY-IR-100
 
       
Sodium Identity
  Sodium identity tests are positive   CY-PR-200
 
       
Solution Clarity
  A 30% w/v solution in water is clear, colorless and essentially free from
particles of foreign matter   CY-VI-002
 
       
Average Degree of Substitution (CE)
  6.0-7.1   CY-CE-603
 
       
Solution pH
  The pH of a 30% w/v solution in water is within the range of 5.4 — 6.8  
CY-PH-100
 
       
b-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%   CY-KF-100
 
       
Heavy Metals
  Maximum 10 ppm   CY-HM-222
 
       
Specific Rotation
(anhydrous basis)
  For information only   CY-SR-163
 
       
Assay (anhydrous basis)
  Minimum 95%   CY-LC-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    

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

EXHIBIT C
PURCHASE PRICE FOR CAPTISOL
1. Clinical Grade CAPTISOL: US$[ ** ] per kg, until such time as Proteolix
orders more than [ ** ] of Clinical Grade CAPTISOL, at which time the price of
Clinical Grade CAPTISOL will [ ** ] US$[ ** ] per kg.
2. Commercial Grade CAPTISOL: The price of Commercial Grade CAPTISOL shall be
determined pursuant to the following table, but subject to adjustment pursuant
to Section 4.2(a) of the Agreement.

      Supplied CAPTISOL   Cost (Metric Tons Per Year)   (US$ per kg) [ ** ]   [
** ] [ ** ]   [ ** ] [ ** ]   [ ** ] [ ** ]   [ ** ]

3. Research Grade CAPTISOL:

          Catalog No.   Package Size   Price (USD) NC-CAP-103   100 grams   [ **
] NC-CAP-105   500 grams   [ ** ] NC-CAP-106   1 kilogram   [ ** ] NC-CAP-107  
5 kilograms   [ ** ]     > 5 kilograms   [ ** ]

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

EXHIBIT D
DOSING MATRIX FOR IN-VIVO PRE-CLINICAL STUDIES
The following eight tables specify the maximum allowable CAPTISOL doses for
intravenous, intramuscular, intraperitoneal, subcutaneous and oral routes of
administration. These doses do not necessarily represent the highest safe dosing
conditions but represent the current knowledge base. For many of these routes,
available data is limited to only a few studies and species. Therefore, some
doses have been based on assumptions and extrapolation from those studies and
species. Adaptive responses may still be present at some of the doses identified
in these tables; however, toxic responses affecting organ function should not be
elicited at these doses. As additional data becomes available, these tables may
be revised.
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

(CYDEX INC LOGO) [f55044f5504402.gif]   Version 1, Page 4
07/17/00

CONTRACTUAL PROVISIONS ATTACHMENT
These pages contain mandatory contractual provisions and must be attached to or
incorporated in all copies of the foregoing Agreement.
Captisol® Dosing Matrix
In-Vivo Preclinical Studies

         
BACKGROUND INFORMATION FOR USING THE CAPTISOL® DOSING MATRIX
    5  
Table 1: Allowable IV Bolus Captisol® Doses by Duration of Study
    6  
Table 2: Allowable IV Infusion Captisol® Doses by Duration of Study
    7  
Table 3: Allowable IM Captisol® Doses by Duration of Study
    8  
Table 4: Allowable IP Captisol® Doses by Duration of Study
    9  
Table 5: Allowable SC Injection Captisol® Doses by Duration of Study
    10  
Table 6: Allowable SC Implantable Device Captisol® Doses by Duration of Study
    11  
Table 7: Allowable Oral Solution Captisol® Doses by Duration of Study
    12  
Table 8: Allowable Oral Solid Captisol® Doses by Duration of Study
    13  
Appendix A
    14  
Parenteral Formulation Protocol
    16  
Oral Solution Formulation Protocol
    15  
Oral Solid Formulation Protocol
    17  
Appendix B
    18  
Results Summary
    1  

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.   CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS
66213 • (913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,com

 

--------------------------------------------------------------------------------

 

Version 1, Page 5
07/17/00
BACKGROUND INFORMATION FOR USING THE CAPTISOL® DOSING MATRIX
The enclosed tables contain summary dosing information for Captisol® 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® 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® 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® 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® dose and allowable Captisol® 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®. 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® 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® 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®
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.
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.   CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS
66213 • (913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,com

 

--------------------------------------------------------------------------------

 

(CYDEX INC LOGO) [f55044f5504402.gif]  
a                                                                      
     Table 1
Captisol®: 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® Doses by Duration of Study

                                                              Example Volume2  
                Daily Allowable IV Bolus     (based on use of 30% w/v Captisol
delivering indicated dose)   Example Concentration     Captisol® Dose1 Species  
Duration     (mL/dose)   (mL/kg)2   (% 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                       1000  
rabbit
  single dose     25.00       10.00     The highest concentration granted under
this limited approval is 30% w/v (300 mg/mL).1     3000  
 
  14 days     16.67       6.67         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
   

 

      [ ** ]  =  Certain confidential information contained in this document,
marked by brackets, has been omitted and filed separately with the Securities
and Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

      CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,  

          Page 6
07/17/00

 

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(CYDEX, INC. LOGO) [f55044f5504402.gif]
  Table 2
Captisol®: Allowble 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® Doses by Duration of Study

                                                                         
Example Volume2   Example   Daily Allowable IV Continuous Infusion   (based on
use 0130% w/v Captisol delivering indicated dose)   Concentration  
Captisol®Dose Species   Duration   mL/dose/HR)   (mL/dose/DAY)   (mL/kg/HR)a  
(roL/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     The highest     125       3000  
rat
  14 days     0.10       2.50       0.42       10.00     concentration     125  
    3000  
rabbit
  14 days     1.04       25.00       0.42       10.00     granted under this    
125       3000  
dog
  14 days     4.20       100.00       0.42       10.00     limited approval is  
  125       3000  
non-human primate
  14 days     2.08       50.00       0.42       10.00     30% w/v (300 mg/mL).1
    125       3000  

 
FOOTNOTES:

  a   — conversions between mi./dose and mL/kg assumes mouse weight of 0,02 kg  
a   — conversions between mL/dose and mL/kg assumes rabbit weight of 2,5 kg   a
  — conversions between mi./dose and mL/kg assumes monkey weight of 5 kg   a   —
conversions between triL/dose and mL/kg assumes rat weight of 0.25 kg   a   —
conversions between mL/dose and mL/kg assumes dog weight of 10 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.
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 
CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail:
CDInfo@cydexinc,comVersion 1,

     

  Page 7
 
  07/17/00

 

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(CYDEX, INC. LOGO) [f55044f5504402.gif]
  Table 3
Captisol®: Allowble 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® Doses by Duration of Study

                                  Example Volume2           Daily Allowable
Intramuscular   (based on use of 30% w/v Captisol delivering indicated dose)  
Example Concentration   Captisol® Dose1 Species   Duration   (mL/dose)   (mL/kg)
  (% 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  

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 
CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

     

  Page 8
 
  07/17/00

 

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(CYDEX, INC. LOGO) [f55044f5504402.gif]
  Table 4
Captisol®: Allowble 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® Doses by Duration of Study

                                  Example Volume2           Daily Allowable
Intraperitoneal   (based on use of 30% w/v Captisol delivering indicated dose)  
Example Concentration   Captisol® Dose1 Species   Duration   (mL/dose)   (mL/kg)
  (% 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

  [ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 
CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

     

  Page 9
 
  07/17/00

 

--------------------------------------------------------------------------------

 

(LOGO) [f55044f5504402.gif]   Table 5
Captisol®: Allowble 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®Doses by Duration of Study

                                          Example Volume2                      
(based on use of 30% w/v Captisol delivering   Example   Daily Allowable
Subcutaneous Injection   indicated dose)   Concentration   Captisol® Dose1
Species       Duration   (mL/dose)   (mL/kg)   (% 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           4000
 
      14 days   2.50   10.00           3000
 
      1 month   0.83   3.33           1000
rabbit
  1 site possible   single dose 14 days 1 month   25.00
16.67
8.33   10.00
6.67
3.33   The highest
concentration
granted under
this limited
approval is 30%
w/v (300
mg/mL).1
  3000
2000
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 site of 2.5 ml/kg   1 month   12.50   5.00           1500
 
  each                        

 

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

 

  [ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 
CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

Page 10
07/17/00

 

--------------------------------------------------------------------------------

 

(CYDEX LOGO) [f55044f5504402.gif]   Table 6
Captisol®: Allowble Dosing Matrix — Subcutaneous (SC) Implantable Device Summary

     
NOTES: 1)
  The allowable dose may not be exceeded without CyDex approval. These doses and
the 30% wlv 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® Doses by Duration of Study

                                          Example Volume2                      
(based on use of 30% w/v Captisol   Example   Daily Allowable Subcutaneous
Implantable Device   delivering indicated dose)   Concentration   Captisol®Dose1
Species   MiniPumps   Duration   (mL/dose)   (mL/kg)   (% w/v)   (mg/mL)  
(mg/kg)   mouse   1 pump @ 1 uL/hr = 0.024 mL/day
1 pump @ 0.5 uL/hr = 0.012 mL/day each
1 pump @ 0.25 uL/hr = 0.006 mL/day   7 days 14 days 1 month   0.024 0.012 0.006
  1.20
0.60
0.30   The highest concentration granted under this limited approval is 30% w/v
(300 mg/mL).1   360
180
 90
rat
  2 pumps @ 10 uL/hr = 0.24 mL/day each   7 days   0.480   1.92           576
 
  2 pumps @ 5 uL/hr = 0.12 mL/day each   14 days   0.240   0.96           288
 
  2 pumps @ 2.5 uL/hr = 0.06 mL/day each   1 month   0.120   0.48           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

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 
CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

Page 11
07/17/00

 

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(CYDEXLOGO) [f55044f5504402.gif]   Table 7
Captisol®: Allowble 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`)/0 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® Doses by Duration of Study

                                  Example Volume2                   (based on
use of 30% w/v Captisol           Daily Allowable Oral Solution (Gavage)  
delivering indicated dose)   Example Concentration   Captisol® Dose1 Species  
Duration   (mL/dose)   (mL/kg)   (% w/v)   (mg/mL)   (mg/kg)   mouse   single
dose
14 days   0.33
0.27   16.67 13.33   The highest concentration
granted under this limited   5000
4000
 
  1 month   0.13   6.67   approval is 30% w/v
(300 mg/mL).1   2000
rat
  single dose   4.17   16.67           5000
 
  14 days   3.33   13.33           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

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 
CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

Page 12
07/17/00

 

--------------------------------------------------------------------------------

 

      (CYDEX LOGO) [f55044f5504402.gif]   Table 8
Captisol®: Allowble 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®Doses by Duration of Study

                                          Daily Allowable Oral Solid   Example
Formulation   Example Dosage Forms   Captisol® Dose Species   Duration  
(mg/dose)   (Number of Doses)       (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 data exists for the oral   *
 
  14 days   *   *   dosing of solid Captisol.   *
 
  1 month   *   *   Please contact CyDex for approval of dosing conditions.   *
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
 

 

  [ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.   CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS
66213 • (913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion
1,

Page 13
07/17/00

--------------------------------------------------------------------------------

 

      (CYDEX LOGO) [f55044f5504402.gif]   Page 14
07/17/00

Appendix A
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

 

--------------------------------------------------------------------------------

 

      (CYDEX LOGO) [f55044f5504402.gif]   Page 15
07/17/00

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 Regine:
Vehicle:
Examination: (check all that apply)

         
o Clinical Observation
  o Body Weight   o Clinical Chemistry
o Food Consumption
  o Electrocardiograms   o Toxicokinetics
o Ophthalmology
  o Urinalysis   o Hematology
o Organ Weight
  o Necropsy   o Microscopy
o 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:
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

 

--------------------------------------------------------------------------------

 

      (CYDEX LOGO) [f55044f5504402.gif]   Page 16
07/17/00

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)

         
o Clinical Observation
  o Body Weight   o Clinical Chemistry
o Food Consumption
  o Electrocardiograms   o Toxicokinetics
o Ophthalmology
  o Urinalysis   o Hematology
o Organ Weight
  o Necropsy   o Microscopy
o 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:
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

 

--------------------------------------------------------------------------------

 

      (CYDEX LOGO) [f55044f5504402.gif]   Page 17
07/17/00

Oral Solid Formulation Protocol

     
CyDex Protocol Tracking form
  Protocol # _____
 
   
Title of Study:
   
 
   
Purpose:
   
 
   
Animal: (include species, age, and weight)
   
 
   
Mean Weight Range:
   

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  
 
                                                                         
 
                                                                         
 
                                                                         

Dosing Regime:
Vehicle:
Examination: (check all that apply)

         
o Clinical Observation
  o Body Weight   o Clinical Chemistry
o Food Consumption
  o Electrocardiograms   o Toxicokinetics
o Ophthalmology
  o Urinalysis   o Hematology
o Organ Weight
  o Necropsy   o Microscopy
o 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:
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

 

--------------------------------------------------------------------------------

 

      (CYDEX LOGO) [f55044f5504402.gif]   Page 18
07/17/00

Appendix B
 

[ ** ] =   Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park, KS 66213 •
(913) 685-8850 • FAX (913) 685-8856 • E-mail: CDInfo@cydexinc,comVersion 1,

 

--------------------------------------------------------------------------------

 

      (CYDEX LOGO) [f55044f5504402.gif]   Page 1
07/17/00

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.
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.       CyDex Inc. 12980 Metcalf Ave., Suite 470, Overland Park,
KS 66213 • (913) 685-8850 • FAX (913) 685-8856 • E-mail:
CDInfo@cydexinc,comVersion 1,

 

--------------------------------------------------------------------------------

 

March 6, 2007
Dr. Susan Molineaux
CSO
Proteolix
230 East Grand Avenue, Suite A
South San Francisco, CA 94080
Dear Dr. Molineaux:
     Per section 4.2(a) of our license and supply agreement dated October 12th,
2005, the purchase price of clinical and research grades of Captisol is subject
to an annual increase equal to the average percentage indicated by the Producer
Price Index (Pharmaceutical Preparations) as reported by the Bureau of Labor
Statistics, U.S. Department of Labor, for the 12-month period ending October 31
of the prior year (http://data.bls.gov/cgi-bin/surveymost?wp).
     Said increase for the captioned period is 4.7%. This change is effective as
of January 1st, 2007 and for the remainder of the calendar year. Kindly reflect
price change on any purchases during 2007.
     This letter serves as an amendment to the supply agreement. Attached you
will find amendment to Exhibit C detailing the new price list.
     If you have any questions, please contact Allen Roberson at (913) 402-3536
or via email at aroberson@cydexinc.com.
With best regards,
/s/ Michelle Baragary
Michelle Baragary
Business Development Coordinator
enclosure

cc:   Jeff Stegall
Allen Roberson

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

AMENDMENT TO EXHIBIT C
PURCHASE PRICE FOR CAPTISOL
Effective January 1, 2007
1. Clinical Grade CAPTISOL: US$[ ** ] per kg, until such time as Proteolix
orders more than [ ** ] of Clinical Grade CAPTISOL, at which time the price of
Clinical Grade CAPTISOL will [ ** ] US$[ ** ] per kg.
2. Commercial Grade CAPTISOL: The price of Commercial Grade CAPTISOL shall be
determined pursuant to the following table, but subject to adjustment pursuant
to Section 4.2(a) of the Agreement.

      SUPPLIED CAPTISOL   COST (METRIC TONS PER YEAR)   (US$ PER KG) [ ** ]   [
** ] [ ** ]   [ ** ] [ ** ]   [ ** ] [ ** ]   [ ** ]

3. Research Grade CAPTISOL:

          Catalog No.   Package Size   Price (USD) NC-CAP-103   100 grams   [ **
] NC-CAP-105   500 grams   [ ** ] NC-CAP-106   1 kilogram   [ ** ] NC-CAP-107  
5 kilograms   [ ** ]     > 5 kilograms   [ ** ]

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

2 January 2008
Dr. Susan Molineaux
CSO
Proteolix
230 East Grand Avenue, Suite A
South San Francisco, CA 94080
Dear Dr. Molineaux,
Per section 4.2(a) of our License and Supply Agreement dated October 12, 2005,
the purchase price of research, clinical and commercial grades of Captisol is
subject to an annual increase equal to the average percentage indicated by the
Producer Price Index (Pharmaceutical Preparations) as reported by the Bureau of
Labor Statistics, U.S. Department of Labor, for the 12-month period ending
October 31 of the prior year (http://data.bls.gov/cgi-bin/surveymost?wp).
Said increase for the captioned period is 5.0%. However, CyDex has made the
decision to increase only the clinical grade of Captisol by [ ** ]%. This change
is effective as of January 1, 2008 and for the remainder of the calendar year.
Kindly reflect price change on future purchase orders.
This letter serves as an amendment to the license and supply agreement. Attached
you will find the 2nd Amendment to Exhibit C detailing the new price list.
If you have any questions, please contact Allen Roberson at (913) 402-3536 or
via email at aroberson@cydexinc.com.
With best regards,

 
/s/ Michelle Baragary
 
Michelle Baragary
Business Development Coordinator
Enclosure

cc:   Jeff Stegall
Leon Ku
Allen Roberson

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

2nd AMENDMENT TO EXHIBIT C
PURCHASE PRICE FOR CAPTISOL
Effective January 1, 2008
1. Clinical Grade CAPTISOL: US$[ ** ] per kg, until such time as Proteolix
orders more than [ ** ] of Clinical Grade CAPTISOL, at which time the price of
Clinical Grade CAPTISOL will [ ** ] US$[ ** ] per kg.
2. Commercial Grade CAPTISOL: The price of Commercial Grade CAPTISOL shall be
determined pursuant to the following table, but subject to adjustment pursuant
to Section 4.2(a) of the Agreement.

      Supplied CAPTISOL   Cost (Metric Tons Per Year)   (US$ per kg)
[ ** ]
  [ ** ] [ ** ]   [ ** ] [ ** ]   [ ** ] [ ** ]   [ ** ]

3. Research Grade CAPTISOL:

          Catalog No.   Package Size   Price (USD) NC-CAP-103   100 grams   [ **
] NC-CAP-105   500 grams   [ ** ] NC-CAP-106   1 kilogram   [ ** ] NC-CAP-107  
5 kilograms   [ ** ]     > 5 kilograms   [ ** ]

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

February 9, 2009
Dr. Susan Molineaux
CSO
Proteolix
230 East Grand Avenue, Suite A
South San Francisco, CA 94080
Dear Dr. Molineaux,
Per section 4.2(a) of our License and Supply Agreement dated October 12, 2005,
the purchase price of research, clinical and commercial grades of Captisol is
subject to an annual increase equal to the average percentage indicated by the
Producer Price Index (Pharmaceutical Preparations) as reported by the Bureau of
Labor Statistics, U.S. Department of Labor, for the 12-month period ending
October 31 of the prior year (http://data.bls.gov/cgi-bin/surveymost?wp).
Said increase for the captioned period is 6.2%. However, CyDex has made the
decision to increase only clinical grade of Captisol by [ ** ]% and research
grade of Captisol by [ ** ]%. This change is effective as of March 1, 2009 and
for the remainder of the calendar year. Kindly reflect price change on future
purchase orders.
This letter serves as an amendment to the license and supply agreement. Attached
you will find the 3rd Amendment to Exhibit C detailing the new price list.
If you have any questions, please contact Allen Roberson at (913) 402-3536 or
via email at aroberson@cydexinc.com.
With best regards,
/s/ Marylyn Rives
Marylyn Rives
Business Development Coordinator

Enclosure

cc:   Jeff Stegall
Leon Ku
Allen Roberson

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

3rd AMENDMENT TO EXHIBIT C
PURCHASE PRICE FOR CAPTISOL
Effective March 1, 2009
1. Clinical Grade CAPTISOL: US$[ ** ] per kg, until such time as Proteolix
orders more than [ ** ] of Clinical Grade CAPTISOL, at which time the price of
Clinical Grade CAPTISOL will [ ** ] US$[ ** ] per kg.
2. Commercial Grade CAPTISOL: The price of Commercial Grade CAPTISOL shall be
determined pursuant to the following table, but subject to adjustment pursuant
to Section 4.2(a) of the Agreement.

      Supplied CAPTISOL   Cost (Metric Tons Per Year)   (US$ per kg) [ ** ]   [
** ] [ ** ]   [ ** ] [ ** ]   [ ** ] [ ** ]   [ ** ]

3. Research Grade CAPTISOL:

          Catalog No.   Package Size   Price (USD) NC-CAP-103   100 grams   [ **
] NC-CAP-105   500 grams   [ ** ] NC-CAP-106   1 kilogram   [ ** ] NC-CAP-107  
5 kilograms   [ ** ]     > 5 kilograms   [ ** ]

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

(CYDEX LOGO) [f55044f5504403.gif]
10513 W. 84th Terrace
Lenexa, KS 65214
P 913.685.8850
F: 913.685.8856
www.cydexpharma.com
January 20, 2010
Leon Ku
Director, Supply Chain Management
Onyx Pharmaceuticals
333 Allerton Avenue
South San Francisco, CA 94080
Dear Mr. Ku,
Per section 4.2(a) of our License and Supply Agreement dated October 12, 2005,
the purchase price of research, clinical and commercial grades of Captisol is
subject to an annual increase equal to the average percentage indicated by the
Producer Price Index (Pharmaceutical Preparations) as reported by the Bureau of
Labor Statistics, U.S. Department of Labor, for the 12-month period ending
October 31 of the prior year (http://data.bls.gov/cgi-bin/surveymost?wp).
Said increase for the captioned period is 6.3%. However, CyDex has made the
decision to increase the price of clinical grade of Captisol by [ ** ]% and
research grade of Captisol by [ ** ]%. This change is effective as of
February 15, 2010 and for the remainder of the calendar year. Kindly reflect
price change on future purchase orders.
This letter serves as an amendment to the license and supply agreement. Attached
you will find the 4th Amendment to Exhibit C detailing the new price list.
If you have any questions, please contact Marylyn Rives at (913) 685-8850 or via
email at mrives@cydexpharma.com.
With best regards,
/s/ Jessica Smith
Jessica Smith
Business Development & Marketing Assistant
Enclosure
 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

(CYNDEX LOGO) [f55044f5504403.gif]
10513 W. 84th Terrace
Lenexa, KS 65214
P 913.685.8850
F: 913.685.8856
www.cydexpharma.com

cc:   Jeff Stegall
Evan Lewis
Allen Roberson

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.

 

--------------------------------------------------------------------------------

 

(CYNDEX LOGO) [f55044f5504403.gif]
10513 W. 84th Terrace
Lenexa, KS 65214
P 913.685.8850
F: 913.685.8856
www.cydexpharma.com
4th AMENDMENT TO EXHIBIT C
PURCHASE PRICE FOR CAPTISOL
Effective February 15, 2010
1. Clinical Grade CAPTISOL: US$[ ** ] per kg, until such time as Proteolix
orders more than [ ** ] of Clinical Grade CAPTISOL, at which time the price of
Clinical Grade CAPTISOL will [ ** ] US$[ ** ] per kg.
2. Commercial Grade CAPTISOL: The price of Commercial Grade CAPTISOL shall be
determined pursuant to the following table, but subject to adjustment pursuant
to Section 4.2(a) of the Agreement.

      Supplied CAPTISOL   Cost (metric tons per year)   (US$ per kg) [ ** ]   [
** ] [ ** ]   [ ** ] [ ** ]   [ ** ] [ ** ]   [ ** ]

3. Research Grade CAPTISOL:

          Catalog No.   Package Size   Price (USD) NC-CAP-103   100 grams   [ **
] NC-CAP-105   500 grams   [ ** ] NC-CAP-106   1 kilogram   [ ** ] NC-CAP-107  
5 kilograms   [ ** ]     > 5 kilograms   [ ** ]

 

[ ** ]  =  Certain confidential information contained in this document, marked
by brackets, has been omitted and filed separately with the Securities and
Exchange Commission pursuant to Rule 24b-2 of the Securities Exchange Act of
1934, as amended.