Document:

License Agreement

  
 Exhibit 10.1

  
 LICENSE AGREEMENT 
 BETWEEN 
 BIODELIVERY SCIENCES
INTERNATIONAL, INC. 
 AND 
 ACCENTIA, INC. 
  
 This License Agreement (this
“Agreement”) effective as of April 12, 2004, by and between BioDelivery Sciences International, Inc., a Delaware corporation, having its principal place of business at 185 South Orange Avenue, Administrative Building No. 4,
Newark, NJ 07103 (“BDSI”) and Accentia, Inc. having its principal place of business at 5310 Cypress Center Drive #101, Tampa, Florida 33609 (“ACCENTIA”) (collectively the “Parties”). 
  
 WITNESSETH: 
  
 Whereas, BDSI has rights to certain BDSI Licensed Technology (hereinafter defined) relating
to cochleates, geodes, nanocochleates, and liposomes; 
  
 Whereas, ACCENTIA
recognizes that the BDSI Licensed Technology represents a valuable means of delivering Licensed Products (hereinafter defined) for the use and/or sale in the treatment or prevention of human and/or animal diseases; 
  
 Whereas, ACCENTIA wishes to enter into an agreement to obtain exclusive licenses for specific
Licensed Products which utilize BDSI Licensed Technology in the Field (hereinafter defined) from BDSI in order to research, develop and commercialize therapeutic products made in accordance therewith; and 
  
 WHEREAS, BDSI is willing to grant such licenses to ACCENTIA under the terms and conditions
set forth in this Agreement. 
  
 NOW, THEREFORE, in consideration of the various
promises and undertakings set forth herein, the Parties agree as follows: 
  
 ARTICLE 1 - DEFINITIONS 
  
 As used herein,
capitalized terms shall have the following meanings: 
  
 1.1
“Affiliate”, with respect to any Party, shall mean any person or entity controlling, controlled by, or under common control with such Party. For these purposes, “control” shall refer to (i) the possession, directly or indirectly,
of the power to direct the management or policies of a person or entity, whether through the ownership of voting securities, by contract or otherwise or (ii) the ownership, directly or indirectly, of at least 50% of the voting securities or other
ownership interest of a person or entity. 
  

 1.2 “Antifungal Products” shall mean any and all products covered by the patent rights licensed to ACCENTIA by
MAYO under the ACCENTIA/MAYO Agreement that are not Licensed Products. “Antifungal Products” include, but are not limited to, topical antifungal products contemplated by the ACCENTIA/MAYO Agreement that do not require approval by the FDA
or appropriate regulatory authority in Europe. 
  
 1.3 “BDSI Licensed
Technology” shall mean any and all information, and all patentable and non-patentable inventions (including, without limitation, all Joint Inventions), improvements, discoveries, claims, formulae, processes, methods, trade secrets,
technologies, data and know-how owned, licensed or controlled by BDSI or to which BDSI has the right to grant licenses or sublicenses before or during the term of this Agreement: (i) related to the cochleate, geode, nanocochleate, or liposome
technology described in Exhibit C, or (ii) claimed, covered or disclosed in any patent or patent application listed in Exhibit B which relates to the cochleate, geode, nanocochleate, or liposome technology described in Exhibit C. 
  
 1.4 “Effective Date” shall mean the date first written above. 
  
 1.5 “Field” shall mean the field of any topical antifungal (including Amphotericin
B) for mucosal surface application for the indications of chronic sinusitis and asthma covered by patents licensed to ACCENTIA by the Mayo Clinic (“MAYO”), and transmucosal vaccine applications covered by a patent held by MAYO for the
indications of chronic sinusitis and asthma. 
  
 1.6 “Joint Invention”
shall mean any invention for which it is determined, in accordance with applicable law, that both: (i) employees or agents of ACCENTIA or any other persons obligated to assign such Invention to ACCENTIA, and (ii) employees or agents of BDSI or any
other persons obligated to assign such invention to BDSI, are joint inventors of such invention. 
  
 1.7 “Know-How” shall mean any and all know-how shared by the Parties under this Agreement. 
  
 1.8 “Licensed Patents” shall mean any current and future Patent, owned or controlled by BDSI, or any of the same jointly owned or controlled by BDSI and that
relate to the BDSI Licensed Technology, including Patents set forth on Exhibit B. 
  
 1.9 “Licensed Product” shall mean a Product in the form of (a) antifungal preparations (including Amphotericin B preparations) for mucosal surface application for the indications of chronic sinusitis and asthma; and (b)
transmucosal vaccine preparations for the indications of chronic sinusitis and asthma. 
  
 1.10 “Net Sales” shall mean the gross amount invoiced for all Antifungal Products or Licensed Products sold by ACCENTIA and/or its Affiliates in arm’s length sales or commercial transactions to a Third Party (excluding sales
to Sublicensees for their resale), less deductions for: 
  
 (a)
commissions, trade, quantity and cash discounts or rebates actually allowed or given; 
  
 (b) credits, allowances or refunds given or made for rejected, outdated or returned Licensed Products, if applicable; 
  

 2 

 (c) any tax or government charge (other than an income tax) levied on the sale, transportation or
delivery of a Licensed Product and borne by the seller thereof; and 
  
 (d) any prepaid or invoiced charges for freight, postage, shipping, import or export taxes, insurance or charges for returnable containers. 
  
 1.11 “Party” shall mean ACCENTIA or BDSI and, when used in the plural, shall mean ACCENTIA and BDSI. 
  
 1.12 “Patent” means (i) unexpired letters patent (including inventor’s
certificates) which have not been held invalid or unenforceable by a court of competent jurisdiction from which no appeal can be taken or has been taken within the required time period, including without limitation any substitution, extension,
registration, confirmation, reissue, re-examination, renewal or any like filing thereof and (ii) pending applications for letters patent, including without limitation any continuation, division or continuation-in-part thereof and any provisional
applications. 
  
 1.13 “Product” shall mean a cochleate, geode,
nanocochleate, or liposome preparation of an antifungal that is: (i) based upon, derived from, identified through or related to any BDSI Licensed Technology; and (ii) covered by one or more Licensed Patents and would infringe a Valid Claim thereof.

  
 1.14 “Sublicensee” shall mean any Third Party granted a sublicense
by ACCENTIA pursuant to Section 3.2 hereof. 
  
 1.15 “Sublicensee Net
Sales” shall mean the gross amount invoiced for all Licensed Products sold by a Sublicensee to a Third Party, less deductions for. 
  
 (a) commissions, trade, quantity and cash discounts or rebates actually allowed or given; 
  
 (b) credits, allowances or refunds given or made for rejected, outdated or returned Licensed Products, if applicable;

  
 (c) any tax or government charge (other than an income tax)
levied on the sale, transportation or delivery of a Licensed Product and borne by the seller thereof; and 
  
 (d) any prepaid or invoiced charges for freight, postage, shipping, import or export taxes, insurance or charges for returnable containers. 
  
 1.16 “Sublicensee Revenue” shall mean any and all revenue or other consideration
received by ACCENTIA from a Sublicensee for Licensed Products under this Agreement, including but not limited to, upfront revenue, milestone revenue, royalty income, and the market value at the time of transfer of all non-monetary consideration such
as barter or counter-trade in the country of disposition. 
  
 1.17
“Territory” shall mean the United States and the European Union. 
  
 1.18 “Third Party” means any person or entity other than ACCENTIA, BDSI or any Affiliate of either ACCENTIA or BDSI. 
  

 3 

 1.19 “Valid Claim” shall mean a claim of any issued or granted Licensed Patent which has not been held invalid
or unenforceable by final decision of a court or other governmental agency of competent jurisdiction, unappealable or unappealed within the time allowed for appeal, and which is not admitted to be invalid or unenforceable through reissue, disclaimer
or otherwise. 
  
 ARTICLE 2 - REPRESENTATIONS AND WARRANTIES

  
 2.1 Representations and Warranties of Both Parties. Each Party
represents and warrants to the other Party that: (i) it is free to enter into this Agreement; (ii) in so doing, it will not violate any other agreement to which it is a party; and (iii) it has taken all corporate action necessary to authorize the
execution and delivery of this Agreement and the performance of its obligations under this Agreement. 
  
 2.2 Representations and Warranties of BDSI. BDSI hereby represents and warrants that: 
  
 (a) BDSI either owns or licenses all of the Licensed Patents listed on Exhibit B, and has the exclusive right to grant licenses and sublicenses therefore
without the consent or approval of any Third Party, except as provided in Section 2.3; 
  
 (b) BDSI own or licenses all of the BDSI Licensed Technology in existence on the date of this Agreement, and has the right to grant licenses and sublicenses therefore without the consent or approval of any Third
Party; 
  
 (c) To the best of BDSI’s knowledge, all the
Licensed Patents listed on Exhibit B are in full force and effect and have been maintained to date; 
  
 (d) BDSI is not aware of any asserted or unasserted claim or demand against the BDSI Licensed Technology; 
  
 (e) To the best of BDSI’s knowledge, none of the BDSI Licensed
Technology infringes upon any patent or other proprietary rights of any other Third Party; and 
  
 (f) BDSI has not entered into any agreement with any Third Party which is in conflict with the rights granted to ACCENTIA pursuant to this Agreement. 
  
 2.3 Disclaimer. 
  
 (a) Government Rights; Research and Development. BDSI’s rights in the Licensed Patents is subject to the rights of the US Government, if any,
in the Patents and BDSI’s and its Affiliates’ reserved, irrevocable, royalty-free right to manufacture, have manufactured, and use any Products, including Licensed Products, for research and development purposes. 
  
 (b) Disclaimer of Other Warranties. EXCEPT AS PROVIDED HEREIN, THE
BDSI LICENSED TECHNOLOGY IS PROVIDED WITHOUT WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR ANY OTHER WARRANTY, EXPRESS OR IMPLIED. EXCEPT AS EXPRESSLY PROVIDED, NEITHER PARTY MAKES ANY 

  

 4 

 
REPRESENTATION OR WARRANTY THAT THE BDSI LICENSED TECHNOLOGY WILL NOT INFRINGE ANY PATENT OR OTHER PROPRIETARY RIGHT OF A THIRD PARTY. 
  
 2.4 Employee Agreements. Each Party warrants that it has, and covenants that it will
have, entered into a proprietary information and inventions agreement with each of its employees prior to the time that any such employee shall receive confidential information from a disclosing party or begin work related to this Agreement. Such
agreement shall minimally set forth employee obligations to assign inventions to the inventing Party and to maintain confidentiality of confidential information consistent with the terms of this Agreement. 
  
 ARTICLE 3 - LICENSE GRANT 
  
 3.1 Grant of License. 
  
 (a) Subject to the terms and conditions of this Agreement, BDSI hereby grants to ACCENTIA an exclusive license throughout
the Territory, with the right to grant sublicenses (subject to Sections 3.2 and 3.3), to make, use or sell Licensed Products in the Field. 
  
 (b) Subject to the terms and conditions of this Agreement, each Party hereby grants to the other Party a nonexclusive, perpetual license to use its
Know-How to develop, manufacture, use and sell Licensed Products in the Field. 
  
 For the avoidance of doubt, no rights are granted to MAYO under this Agreement including, but not limited to, license and sublicense rights, and rights in BDSI confidential information, trade secrets, data, and other information. No rights
are granted by MAYO to either Party under this Agreement. 
  
 3.2 Right to
Grant Sublicenses. 
  
 (a) United States. ACCENTIA
shall not have the right to sublicense the BDSI Licensed Technology in the United States. 
  
 (b) European Union. ACCENTIA shall have the right to sublicense the BDSI Licensed Technology in the European Union with the prior written approval of BDSI, which approval is not to be unreasonably withheld.
Each sublicense granted by ACCENTIA pursuant to this Agreement shall be consistent the provisions of this Agreement. Prior to the grant of each sublicense hereunder, ACCENTIA shall provide BDSI a copy of the sublicense. ACCENTIA shall not grant any
paid-up license or accept equity in consideration, directly or indirectly, for such sublicenses without BDSI’s written approval. 
  
 3.3 ACCENTIA Responsibility for Sublicenses. ACCENTIA shall be responsible for and guarantees the payment of all royalties to BDSI as provided in Article 4 as
though ACCENTIA itself had sold the Licensed Product and the provision of sales and other reports hereunder. 
  
 3.4 Intellectual Property. Any and all intellectual property developed by the Parties related to the BDSI Licensed Technology, including Joint Inventions and inventions developed solely by either BDSI or
ACCENTIA, shall be the sole and exclusive property of BDSI. Such intellectual property shall be considered BDSI Licensed Technology and therefore subject to the license rights granted to ACCENTIA in this Article 3. All intellectual property
developed by ACCENTIA (Joint Inventions and inventions developed solely by ACCENTIA), related to the Licensed Products but not related to the 

  

 5 

 
BDSI Licensed Technology shall be the sole and exclusive property of ACCENTIA. All intellectual property developed solely by BDSI related to the Licensed
Products but not related to the BDSI Licensed Technology shall be the sole and exclusive property of BDSI, subject to a nonexclusive license to such intellectual property to ACCENTIA. ACCENTIA shall have no rights in any intellectual property
related to Licensed Products developed jointly by BDSI with any third parties. 
  
 ARTICLE 4 - ROYALTY PAYMENTS AND REPORTS 
  
 4.1 License Fee. As consideration for entering into this Agreement, ACCENTIA shall pay to BDSI ten (10) dollars within thirty (30) days of the Effective Date. 
  
 4.2 Royalties. As consideration for the license rights granted ACCENTIA under this agreement, ACCENTIA will pay BDSI the following:

  
 (a) Antifungal Products. In lieu of any up front fees
and milestone payments, and as an inducement to BDSI to enter into this Agreement, ACCENTIA shall pay to BDSI a royalty equal to twelve percent (12%) of Net Sales of Antifungal Products in the Territory; 
  
 (b) Licensed Products. ACCENTIA shall pay to BDSI a royalty of
fourteen percent (14%) of Net Sales of any Licensed Products in the Territory; and 
  
 (c) Sublicensee Revenue. ACCENTIA shall pay to BDSI either: (i) an amount equal to fifty percent (50%) of Sublicensee Revenue to BDSI, after the prescribed royalty payment to MAYO; or (ii) a minimum royalty of
eight percent (8%) of Sublicensee Net Sales (regardless of the prescribed royalty to MAYO), whichever is greater, for Licensed Products. 
  
 4.3 Term of Royalty Obligations. The royalty obligations specified in Section 4.2 above shall continue as to each Licensed Product in the Territory for the term of
the last to expire of the Licensed Patent rights covering the Licensed Product. 
  
 4.4 Payments for Antifungal Products. Payments under Section 4.2(a) shall be made to BDSI no later than sixty (60) days following the end of the calendar quarter during which payment is received by ACCENTIA for Antifungal Products.

  
 4.5 Payments for Licensed Products. Payments under sections 4.2(b) and
4.2(c) shall be made to BDSI no later than sixty (60) days following the end of the calendar quarter during which Net Sales and Sublicensee Net Sales are invoiced and any other Sublicensee Revenue accrued for Licensed Products. 
  
 4.6 Place of Payment. All payments due shall be payable in United States dollars by
wire transfer to a bank account designated by each Party from time to time. ACCENTIA shall convert all non-U.S. dollar sales to U.S. dollars using the average exchange rates quoted in the Wall Street Journal for the final day of each month in the
relevant period for which the royalty is being paid. In the event payment of any royalties is restricted or prohibited by the laws or regulations of a particular country, then to the extent of such a restriction and prohibition, royalties shall be
paid to BDSI in that country and in the currency of said country into an account to be designated by BDSI. BDSI shall have the option of requesting payment in Euros upon notice under Section 10.7. 
  

 6 

 4.7 Taxation of Payments. 
  

(a) Insofar as any payment that is due under this Agreement is subject to any tax, duty, levy, or other government imposition, the Party receiving the
payment agrees to bear any and all such taxes, duties, levies or impositions. Each Party hereby authorizes the other Party to withhold such taxes, duties, levies or impositions from the payments in accordance with this Agreement if ACCENTIA or BDSI
is required to do so under the laws of the United States or any country in the Territory where such taxes, duties, levies or impositions are payable. Whenever a Party deducts such tax, duty, levy or imposition from any payments due, then it shall
furnish the other Party with a certificate showing the payment of thereof to the United States or any country in the Territory. 
  
 (b) In the event any payments which are due to under this Agreement are subject to value added taxation by any government, then the Party receiving the
payment shall bear such value added tax in full and the Party making the payment shall be reimbursed therefore. If appropriate, the Party receiving payment may add such value added taxes to its royalty accounts, provided such value added taxes are
credited against the other Party’s value added tax debt and the other Party is reimbursed in full with respect thereto. Notwithstanding anything herein to the contrary, the Party making the payment shall have no liability for any value added
tax directly or indirectly relating to thereto. 
  
 (c) In the
event any payment is subject to a withholding or other income tax in any country in the Territory, promptly following becoming aware of the applicability of any such tax, the Party making the payment shall so advise the other Party. The Party
receiving the payment shall have the right to contest with the appropriate governmental body any such proposed withholding and the other Party shall provide, at receiving Party’s expense, reasonable cooperation in any such contest. The Parties
shall provide each other with such receipts or other evidence of any tax withheld as is necessary to claim any credit or deduction available to it in other jurisdictions. Payments shall only be reduced for withholding taxes imposed by the
jurisdiction out of which the payment is directly made. 
  
 4.8 Interest.
All payments due hereunder that are not paid when due and payable as specified in this agreement shall bear interest at an annual rate equal to the prime rate (“Prime Rate”) for U.S. dollar deposits in effect from time to time, as
published daily in the Wall Street Journal plus 2%, compounded monthly from the date due until paid, or at such lower rate of interest as shall then be the maximum rate permitted by applicable law. 
  
 4.9 Right to Documentation. Upon request, BDSI shall have the right to request
reasonable documentation of ACCENTIA’s calculations to determine ACCENTIA’s Net Sales, Sublicensee Revenues and/or Sublicensee Net Sales for the Licensed Products and to request discussion of such calculations with appropriate
representatives of ACCENTIA. BDSI shall make all reasonable efforts to provide to ACCENTIA any existing data or other information owned by BDSI to support ACCENTIA’s efforts to obtain FDA approval. 
  
 4.10 Records Retention. ACCENTIA, its Sublicensee and Affiliates shall keep complete
and accurate records pertaining to the sale of Licensed Products in the Territory and covering all transactions which Net Sales are derived for a period of three (3) calendar years after the year in which such sales occurred, and in sufficient
detail to permit BDSI to confirm the accuracy of royalty calculations hereunder. Such records shall be available at all reasonable times for inspection by BDSI or its representatives for verification of royalty payments or compliance with other
aspects of this Agreement. 
  

 7 

 4.11 Audit Request. At the request of BDSI, ACCENTIA, its Affiliates and Sublicensees shall permit an independent,
certified public accountant appointed by BDSI acceptable to ACCENTIA or its Affiliates, at reasonable times and upon reasonable notice, to examine those records and all other material documents relating to or relevant to Net Sales, Sublicensee
Revenue, and Sublicensee Net Sales income in the possession or control of ACCENTIA, its Affiliates or Sublicensees, for a period of three (3) years after such royalties have accrued, as may be necessary to: (i) determine the correctness of any
report or payment made under this Agreement; or (ii) obtain information as to the royalties payable for any calendar quarter in the case of ACCENTIA’s or its Affiliate’s failure to report or pay pursuant to this Agreement. Said accountant
shall not disclose to BDSI any information other than information relating to said reports, royalties, and payments. Results of any such examination shall be made available to both Parties. BDSI shall bear the full cost of the performance of any
such audit, unless such audit demonstrates underpayment of royalties by ACCENTIA of more than ten percent (10%) from the amount of the original royalty payment made by ACCENTIA. In such event, ACCENTIA shall bear the full cost of the performance of
such audit 
  
 ARTICLE 5 - PATENT PROSECUTION; ENFORCEMENT;
INFRINGEMENT 
  
 5.1 Patent Prosecution and Maintenance. 
  
 (a) Responsibility. BDSI shall continue to have full responsibility
for and shall control the preparation and prosecution and maintenance of all Licensed Patents. 
  
 (b) Cooperation. Each Party agrees to cooperate with the other Party to execute any documents necessary or desirable to secure and perfect the other Party’s legal rights and worldwide ownership in the
other Party’s intellectual property, including, but not limited to documents relating to patent, trademark and copyright applications. Each Party agrees to take actions reasonably necessary to diligently prosecute and maintain its intellectual
property in major commercial markets where viable protection is available. Each party or its representatives shall be entitled to meet and confer with the other Party and their patent counsel at reasonable times and places. 
  
 5.2 Limitations on Publications. The Parties agree that no one Party shall publish the
results of any studies, whether conducted by its own employees or in conjunction with a Third Party, carried out pursuant to this Agreement or confidential information received from the other Party that is relating to a Licensed Product, without the
prior written approval of the other Party. Each Party agrees to provide the other Party with a copy of any proposed abstracts, presentations, manuscripts, or any other disclosure which discloses clinical study results pursuant to this Agreement or
confidential information received from the other Party at least one hundred twenty (120) days prior to their intended submission for publication and agrees not to submit or present such disclosure until the Party not seeking to disclose such
information provides its prior written approval. Such written approval will not be unreasonably withheld unless such proposed disclosure could reasonably harm or impair a Party’s intellectual property assets or may reasonably cause commercial
harm to a Party. 
  
 5.3 Notification of Infringement If either Party
learns of an infringement or threatened infringement by a Third Party of any Licensed Patent granted hereunder within the Territory, such Party shall promptly notify the other Party and shall provide such other Party with available evidence of such
infringement. Section 5.4 shall then be applicable. 
  

 8 

 5.4 Patent Enforcement. BDSI shall have the first right, but not the duty, to institute patent infringement
actions against third parties based on any Licensed Patent under this Agreement. If BDSI does not institute an infringement proceeding against an offending Third Party within ninety (90) days after receipt of notice from ACCENTIA, ACCENTIA shall
have the right, but not the duty, to institute such an action. The costs and expenses of any such action (including fees of attorneys and other professionals) shall be borne by the Party instituting the action, or, if the Parties elect to cooperate
in instituting and maintaining such action, such costs and expenses shall be borne by the Parties in such proportions as they may agree in writing. Each Party shall execute all necessary and proper documents and take such actions as shall be
appropriate to allow the other Party to institute and prosecute such infringement actions. Any award paid by third parties as a result of such an infringement action (whether by way of settlement or otherwise) shall be paid to the Party who
instituted and maintained such action, or, if both Parties instituted and maintained such action, such award shall be allocated among the Parties in proportion to their respective contributions to the costs and expenses incurred in such action.

  
 5.5 Infringement Action by Third Parties. 
  
 (a) Claim or Suit Against ACCENTIA. In the event of the institution of
any claim or suit by a Third Party against ACCENTIA for patent infringement involving the manufacture, use, lease or sale of any Licensed Product in the Territory, and related to BDSI Licensed Technology, ACCENTIA shall promptly notify BDSI in
writing of such claim or suit. ACCENTIA shall have the right to defend such claim or suit at its own expense and BDSI hereby agrees to assist and cooperate with ACCENTIA, at BDSI’s own expense, to the extent necessary in the defense of such
claim or suit During the pendency of such claim or suit, ACCENTIA shall continue to make all payments due under this Agreement, but shall have a credit against royalty payments otherwise payable hereunder for the full amount of all costs and
expenses incurred by ACCENTIA in defending against such claim or suit; provided, however, that in applying the credit against any royalty payments, the amount of such payment shall not be reduced by more than 50% and any remaining credit shall be
applied against subsequent royalty payments. 
  
 If as a result of
any judgment, award, decree or settlement resulting from a claim or action instituted by a Third Party, ACCENTIA is required to pay a royalty or other amounts to such Third Party (“Third Party Royalty”), ACCENTIA shall continue to pay
royalties for such Licensed Products in the country which is the subject of such action, but shall be entitled to a credit against such payments in an amount equal to the Third Party Royalty, but in no event shall such credit be more than the
royalties due hereunder for such Licensed Products in such country which is the subject of such action and any remaining credit shall be applied against subsequent royalty payments in the Territory. In addition, if ACCENTIA is required to pay
damages to such Third Party, and such damages are not otherwise reimbursed by BDSI, ACCENTIA shall be entitled to a credit against royalty payments in an amount equal to such damages, to the extent paid by ACCENTIA to such Third Party, but in no
event shall the total credit provided hereunder be more than such royalties due hereunder for such Licensed Products in such country which is the subject of such action. 
  
 (b) Claim or Suit Against BDSI. In the event of the institution of any claim or suit by a Third Party against BDSI
for patent infringement involving the manufacture, use, lease or sale of any Licensed Product in the Territory, BDSI shall promptly notify ACCENTIA in writing of such claim or suit. BDSI shall have the right to defend such claim or suit at its own
expense and ACCENTIA hereby 

  

 9 

 
agrees to assist and cooperate with BDSI, at ACCENTIA’s own expense, to the extent necessary in the defense of such claim or suit. 
  
 ARTICLE 6 - CONFIDENTIALITY 
  
 6.1 Use of Name. BDSI agrees not to use directly or indirectly ACCENTIA’s name
without ACCENTIA’s prior written consent. ACCENTIA agrees not to use directly or indirectly BDSI’s name or information without BDSI’s prior written consent. Notwithstanding the foregoing, ACCENTIA and BDSI may include an accurate
description of the terms of this Agreement to the extent required under federal or state securities or other disclosure; and ACCENTIA may use BDSI’s names in various documents used by ACCENTIA for capital raising and financing purposes.

  
 6.2 Confidentiality; Exceptions. Except to the extent expressly
authorized by this Agreement or otherwise agreed in writing, the Parties agree that, for the term of this Agreement and for three (3) years thereafter, the receiving Party shall keep completely confidential and shall not publish or otherwise
disclose and shall not use for any purpose other than proper performance hereunder any information furnished to it by the other Party pursuant to this Agreement, except to the extent that it can be established by the receiving Party by competent
proof that such information: 
  
 (a) was already known to the
receiving Party, other than under an obligation of confidentiality, at the time of disclosure by the other Party; 
  
 (b) was generally available to the public or otherwise part of the public domain at the time of its disclosure to the receiving Party; 
  
 (c) became generally available to the public or otherwise part of the public
domain after its disclosure and other than through any act or omission of the receiving Party in breach of this Agreement; 
  
 (d) was disclosed to the receiving Party, other than under an obligation of confidentiality, by a Third Party who had no obligation to the disclosing
Party not to disclose such information to others; or 
  
 (e) was
independently developed by or for the receiving Party by persons not having access to such information, as determined by the written records of such party. 
  
 6.3. Obligations of Employees and Consultants. The Parties each represent that all of its employees and the employees of its Affiliates, and any collaborators or
consultants to such Party or its Affiliates, who shall have access to confidential information of the Parties are bound by written obligations to maintain such information in confidence and not to use such information except as expressly permitted
herein. Each Party agrees to enforce confidentiality obligations to which its employees and consultants (and those of its Affiliates) are obligated. 
  
 6.4. Restrictions on Disclosure to MAYO. ACCENTIA agrees that it shall not disclose any BDSI confidential information to MAYO without the prior written consent of
BDSI, which consent is not to be unreasonably withheld. ACCENTIA agrees mat it shall not be unreasonable for BDSI to request that MAYO execute a confidentiality agreement with BDSI and/or ACCENTIA prior to disclosure of any such confidential
information. 
  

 10 

  
 ARTICLE 7 -
INDEMNIFICATION 
  
 7.1 Indemnification by ACCENTIA. ACCENTIA shall
defend, indemnify and hold BDSI, its officers, directors, employees and consultants harmless from and against any and all Third Party claims, suits or demands, threatened or filed, (“Claims”) for liability, damages, losses, costs and
expenses (including the costs and expenses of attorneys and other professionals), at both trial and appellate levels, relating to the distribution, testing, manufacture, use, lease, sale, consumption on or application of Licensed Products by
ACCENTIA, its Affiliates or its Sublicensees pursuant to this Agreement, including, without limitation, claims for any loss, damage, or injury to persons or property, or loss of life, relating to the promotion and advertising of Licensed Products
and/or interactions and communications with governmental authorities, physicians or other Third Parties relating to the Licensed Products. The foregoing indemnification shall not apply to any Third Party Claims to the extent are caused by the gross
negligence of BDSI. 
  
 7.2 Indemnification by BDSI. BDSI shall defend,
indemnify and hold ACCENTIA, its officers, directors, employees and consultants harmless from and against any and all Third Party Claims for liability, damages, losses, costs and expenses (including the costs and expenses of attorneys and other
professionals), at both trial and appellate levels, relating to BDSI’s activities contemplated under this Agreement, including, but not limited to, (a) breach of the representations, warranties and obligations of BDSI hereunder, or (b) any tax,
duty, levy or government imposition on any sums payable by ACCENTIA to BDSI hereunder. The foregoing indemnification shall not apply to any Claims to the extent caused by the gross negligence of ACCENTIA. 
  
 7.3 Notice. In the event that either Party seeks indemnification under Sections 7.1 or
7.2, the Party seeking indemnification agrees to (i) promptly inform the other Party of the Third Party Claim, (ii) permit the other Party to assume direction and control of the defense or claims resulting therefrom (including the right to settle it
at the sole discretion of that Party), and (iii) cooperate as reasonably requested (at the expense of that Party) in the defense of the Claim. 
  
 7.4 Insurance. 
  
 (a) Prior to the first human clinical trials of a Licensed Product under this Agreement, ACCENTIA shall obtain and maintain broad form comprehensive
general liability insurance and Licensed Products liability insurance with a reputable and financially secure insurance carrier, subject to approval by BDSI’s primary insurance broker, to cover such activities of ACCENTIA and ACCENTIA’s
contractual indemnity under this Agreement. Such insurance shall provide minimum annual limits of liability of $5,000,000 per occurrence and $5,000,000 in the aggregate with respect to all occurrences being indemnified under this Agreement. Such
insurance policy shall name BDSI as an additional insured and shall be purchased and kept in force for a time period sufficient to cover liability assumed by ACCENTIA associated with this Agreement. 
  
 (b) In the event that ACCENTIA chooses to rely on any strategic partners of
ACCENTIA to satisfy any of the requirements for insurance under this Section 7.4, then ACCENTIA shall provide details of such coverage to BDSI for its information. Any such coverage must substantially comply with the form, scope and amounts set
forth in this Section 7.4(a) which are applicable to such insurance. In the event that any such insurance is a self-insured plan, ACCENTIA shall determine that such strategic partner’s self-insured plan is adequate given the financial condition
of such strategic partner. At BDSI’s 

  

 11 

 
request, which shall not be more frequently than annually, ACCENTIA shall provide BDSI with a certificate of such insurance or written verification by such
strategic partner of such self-insurance. 
  
 (c) At BDSI’s
request, which shall not be more frequently than annually, ACCENTIA shall provide BDSI evidence of any insurance obtained pursuant to Section 7.4(a). ACCENTIA shall not, and shall not permit any strategic partner to, cancel or materially reduce the
coverage of any policy of insurance required under this Section 7.4(a) without giving BDSI thirty (30) days prior written notice thereof. 
  
 ARTICLE 8 – TERM; TERMINATION 
  
 8.1 Term. This Agreement shall commence as of the Effective Date and, unless sooner terminated as provided hereunder, shall terminate as to each Licensed Product
and as to each country in the Territory, upon the expiration of the last to expire Valid Claim of a Licensed Patent necessary for the manufacture, use or sale of such Licensed Product in such country. 
  
 8.2 Breach. Failure by either Party to comply with any of the material obligations
contained in this Agreement shall entitle the other Party to give to the Party in default notice specifying the nature of the default and requiring it to cure such default. If such default is not cured within sixty (60) days after the receipt of
such notice (or, if such default cannot be cured within such sixty (60) day period, if the Party in default does not commence and diligently continue actions to cure such default), the notifying Party shall be entitled, without prejudice to any of
its other rights conferred on it by this Agreement, in addition to any other remedies available to it by law or in equity, to terminate this Agreement by giving written notice to take effect within thirty (30) days after such notice unless the
defaulting Party shall cure such default within said thirty (30) days. The right of either Party to terminate this Agreement, as hereinabove provided, shall not be affected in any way by its waiver or failure to take action with respect to any
previous default. 
  
 8.3 Termination based on ACCENTIA actions or MAYO
Agreement. 
  
 (a) Failure to file an NDA. BDSI may, at
its option, terminate the entire license if ACCENTIA has not filed an NDA within 5 years of the Effective Date, or if the License Agreement between ACCENTIA and MAYO, dated February 10, 2004 (“ACCENTIA/MAYO Agreement”), is terminated.

  
 (b) Termination of Rights to MAYO Technology. BDSI may,
at its option, terminate exclusivity to BDSI Technology if ACCENTIA’s exclusive rights to MAYO technology terminate and ACCENTIA fails to regain exclusive rights to MAYO technology under the ACCENTIA/MAYO Agreement within sixty (60) days.
ACCENTIA is responsible for immediately notifying BDSI of any such above noted circumstances. 
  
 (c) Amendment or Termination of ACCENTIA/MAYO Agreement. Should a breach or default or any other event that can trigger amendment or termination of the ACCENTIA/MAYO Agreement occur, including an event that
triggers loss of exclusive rights or termination for Material Change under the ACCENTIA/MAYO Agreement, ACCENTIA shall immediately inform BDSI of such occurrence. ACCENTIA shall thereafter continue to keep BDSI informed of the status of the
ACCENTIA/MAYO Agreement. 
  

 12 

 (d) Assumption of Agreement by MAYO Under the ACCENTIA/MAYO Agreement. BDSI agrees that MAYO may
assume this Agreement under Section 7.03(c) of the ACCENTIA/MAYO Agreement, provided that: (i) BDSI is notified that MAYO will assume this Agreement by 17 March 2009; and (ii) MAYO agrees in writing to BDSI to accept this entire Agreement, including
all responsibilities and obligations to BDSI thereunder, by 17 April 2009. 
  
 (e) Access to IND. In the event that: (i) BDSI files and holds an IND for chronic rhinosinusitus; (ii) the ACCENTTA/MAYO License Agreement is terminated; and (iii) ACCENTIA has paid, in its entirety, for the
IND to the point of termination, BDSI agrees to give MAYO access to the IND as it relates to topical encochleated Amphotericin B for chronic rhinosinusitus. For the purpose of avoiding confusion, the Parties agree that no rights under this Agreement
(including rights under Article 3 of this Agreement and rights to BDSI Licensed Technology), will transfer to MAYO under this Section 8.3(e). 
  
 8.4 Termination by ACCENTIA. ACCENTIA shall have the right to terminate the licenses granted herein, in whole or as to any Licensed Product in the Territory, at
any time, and from time to time, by giving notice in writing to BDSI. Such termination shall be effective thirty (30) days from the date such notice is given, and all ACCENTIA’s rights associated therewith shall cease as of that date, subject
to Section 8.5. 
  
 8.5 Rights to Sell Stock on Hand. Upon the termination
of any license granted herein, in part or in whole or as to any Licensed Product, for any reason other than a failure to cure a material breach of the Agreement by ACCENTIA, ACCENTIA shall have the right for one (1) year or such longer period as the
Parties may reasonably agree to dispose of all Licensed Products or substantially completed Licensed Products then on hand to which such termination applies, and royalties shall be paid to BDSI with respect to such Licensed Products as though this
Agreement had not terminated. 
  
 8.6 Termination of Sublicenses. Upon any
termination of this Agreement, all sublicenses granted by ACCENTIA under this Agreement shall terminate simultaneously, subject, nevertheless, to Section 8.5. 
  

8.7 Effect of Termination. Upon the termination of any license granted herein as to any Licensed Product in the Territory other than pursuant to Section 8.1,
ACCENTIA and its Affiliates and Sublicensees shall promptly: (i) return to BDSI all relevant records, materials or confidential information of BDSI concerning the BDSI Licensed Technology relating to such Licensed Product in such country in the
possession or control of ACCENTIA or any of its Affiliates or Sublicensees; and (ii) assign to BDSI, or BDSI’s designee, its registrations with governmental health authorities, licensees, and approvals of such Licensed Product in such country.

  
 8.8 Surviving Rights. Termination of this Agreement shall not terminate
ACCENTIA’s obligation to pay all royalties which shall have accrued hereunder. The Parties’ obligations under Articles 6, 7 and 8, and Sections 10.6 and 10.10 also shall survive termination. 
  
 8.9 Accrued Rights, Surviving Obligations. Termination, relinquishtment or expiration
of this Agreement for any reason shall be without prejudice to any rights which shall have accrued to the benefit of either Party under this Agreement prior to such termination, relinquishment or expiration. Such termination, relinquishment or
expiration shall not relieve either Party from obligations which are expressly indicated to survive termination or expiration of this Agreement. 
  

 13 

  
 ARTICLE 9 — CLINICAL
TRIALS AND SUPPLIES OF MATERIAL 
  
 9.1 BDSI Supply Requirements. BDSI
shall provide all quantities of phospholipids ACCENTIA needs to develop and/or identify Licensed Products for ACCENTIA’s preclinical studies at BDSI’s fully absorbed cost. ACCENTIA shall identify the amounts of phospholipids needed.
Provision of phospholipids shall be accompanied by applicable quantity and quality information necessary to permit use of such Licensed Product in animal testing. If necessary, based on the stage of development, BDSI shall produce Licensed Product
in accordance with regulatory requirements to permit use of such Licensed Products in such pre-clinical testing. 
  
 9.2 Costs of Preclinical and Clinical Trials. ACCENTIA will be responsible, at its sole cost and expense, for all preclinical and clinical trial expenses under
this Agreement. ACCENTIA agrees to use its best efforts to meet the regulatory timelines set forth in Exhibit A. 
  
 9.3 Assistance in Third Party Contractor Identification. In the event that either Party desires to use a Third Party contractor for supply of phospholipids and/or
to manufacture of Licensed Product, it shall obtain the other Party’s prior written approval for use of such Third Party contractor, the approval of which shall not be unreasonably withheld. 
  
 ARTICLE 10 - MISCELLANEOUS PROVISIONS 
  
 10.1 Relationship of Parties. Nothing in this Agreement is or shall be deemed to
constitute a partnership, agency, employee or joint venture relationship between the Parties. No Party shall incur any debts or make any commitments for the other, except to the extent, if at all, specifically provided herein. 
  
 10.2 Assignment. Except as otherwise provided herein, neither this Agreement nor any
interest hereunder shall be assignable by any Party without the prior written consent of the other, which approval is not to be unreasonably withheld; provided, however, that either Party may assign this Agreement to any wholly-owned subsidiary or
to any successor by merger or sale of substantially all of its assets to which this Agreement relates in a manner such that the assignor shall remain liable and responsible for the performance and observance of all its duties and obligations
hereunder. This Agreement shall be binding upon the successors and permitted assigns of the parties and 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. Any assignment not in accordance with this Section 10.2 shall be void. 
  
 10.3 Further Actions. Each Party agrees to execute, acknowledge and deliver such further instructions, and to do all such other acts, as may be necessary or
appropriate in order to carry out the purposes and intent of this Agreement. 
  
 10.4 Force Majeure. Neither Party shall be liable to the other for loss or damages nor shall have any right to terminate this Agreement for any default or delay attributable to any act of God, flood, fire, explosion, strike, lockout,
labor dispute, shortage of raw materials, casualty, accident, war, revolution, civil commotion, act of public enemies, blockage or embargo, injunction, law, order, proclamation, 

  

 14 

 
regulation, ordinance, demand or requirement of any government or subdivision, authority or representative of any such government, or any other cause beyond
the reasonable control of such Party, if the Party affected shall give prompt notice of any such cause to the other Party. The Party giving such notice shall thereupon be excused from such of its obligations hereunder as it is thereby disabled from
performing for so long as it is so disabled and for thirty (30) days thereafter. Notwithstanding the foregoing, nothing in this Section 10.4 shall excuse or suspend the obligation to make any payment due hereunder in the manner and at the time
provided. 
  
 10.5 No Trademark Rights. Except as otherwise provided
herein, no right, express or implied, is granted by this Agreement to use in any manner the name “ACCENTIA” or “BDSI” or any other trade name or trademark of the other party in connection with the performance of this Agreement.

  
 10.6 Public Announcements. Except as required by law, neither Party
shall make any public announcement concerning this Agreement or the subject matter hereof without the prior written consent of the other. In the event of a required public announcement, the Party making such announcement shall provide the other with
a copy of the proposed text prior to such announcement. 
  
 10.7 Notices.
Any notice required or permitted to be given or delivered hereunder or by reason of the provisions of this Agreement shall be in writing and shall be deemed to have been properly served if: (a) delivered personally, (b) delivered by a recognized
overnight courier service instructed to provide next-day delivery, (c) sent by certified or registered mail, return receipt requested and first class postage prepaid, or (d) sent by facsimile transmission followed by confirmation copy delivered by a
recognized overnight courier service the next day. Such notices, demands and other communications shall be sent to the addresses set forth below, or to such other addresses or to the attention of such other person as the recipient Party has
specified by prior written notice to the sending Party. Date of service of such notice shall be: (i) the date such notice is personally delivered or sent by facsimile transmission (with issuance by the transmitting machine of confirmation of
successful transmission), (ii) three days after the date of mailing if sent by certified or registered mail, or (iii) one day after date of delivery to the overnight courier if sent by overnight courier. Unless otherwise specified in writing, the
mailing addresses of the Parties shall be as described below: 
  

	 	(a)	If to BDSI, addressed to: 

  
 Raphael J. Mannino, Ph.D. 
 Executive Vice
President and Chief Scientific Officer 
 BioDelivery Sciences International, Inc. 
 185 South Orange Avenue, Administrative Building No. 4 
 Newark, NJ 07103 
  

	 	(b)	If to ACCENTIA, addressed to: 

  
 Martin G. Baum 
 President 
 Accentia, Inc. 
 5310 Cypress Center Drive
#101 
 Tampa, Florida 33609 
  

 15 

 10.8 Amendment. No amendment, modification or supplement of any provision of this Agreement shall be valid or
effective unless made in writing and signed by a duly authorized officer of each Party. This Agreement may be executed in a series of counterparts, all of which, when taken together, shall constitute one and the same instrument. 
  
 10.9 Waiver. No provision of this Agreement shall be waived by any act, omission or
knowledge of a Party or its agents or employees except by an instrument in writing expressly waiving such provision and signed by the waiving Party. 
  
 10.10 Dispute Resolution. 
  
 (a) Senior Officials. The Parties recognize that a bona fide dispute as to certain matters may from time to time arise during the term of this
Agreement which relates to either Party’s rights and/or obligations hereunder. in the event of the occurrence of such a dispute, either Party may, by notice to the other Party, have such dispute referred to their respective senior officials
designated below or their successors, for attempted resolution by good faith negotiations within thirty (30) days after such notice is received. Said designated senior officials are as follows: 
  

					
	 For ACCENTIA:
	  	Martin G. Baum, President	  	 
	 For BDSI:
	  	Raphael J. Mannino, Ph.D., EVP & CSO	  	 

  
 In the event the designated senior
officials are not able to resolve such dispute within the thirty (30) day period, either Party may invoke the provisions of Section 10.10(b). 
  
 (b) Arbitration. In the event of any dispute, difference or question arising between the Parties in connection with this Agreement, the
construction thereof, or the rights, duties or liabilities of either Party, and which dispute cannot be amicably resolved by the good faith efforts of both Parties, then such dispute shall be resolved by binding arbitration in accordance with the
Commercial Arbitration Rules of the American Arbitration Association. The arbitration panel shall be composed of three arbitrators, one of whom shall be chosen by BDSI, one by ACCENTIA, and the third by the two so chosen. If both or either of
ACCENTIA or BDSI fails to choose an arbitrator or arbitrators within fourteen (14) days after receiving notice of commencement of arbitration or if the two arbitrators fail to choose a third arbitrator within fourteen (14) days after their
appointment, the then President of the American Arbitration Association shall, upon the request of both or either of the Parties to the arbitration, appoint the arbitrator or arbitrators required to complete the board or, if he shall decline or fail
to do so, such arbitrator or arbitrators shall be appointed by the New York office of the American Arbitration Association. The decision of the arbitrators shall be by majority vote and, at the request of either Party, the arbitrators shall issue a
written opinion of findings of fact and conclusions of law. Costs shall be borne as determined by the arbitrators. Unless the Parties to the arbitration shall otherwise agree to a place of arbitration, the place of arbitration shall be at New York,
New York, U.S.A. The arbitration award shall be final and binding upon the Parties to such arbitration and may be entered in any court having jurisdiction. 
  
 10.11 Governing Law. This Agreement shall be governed by and interpreted in accordance with the laws of the State of Delaware. 
  

 16 

 10.12 Severabilitv. Whenever possible, each provision of this Agreement will be interpreted in such manner as to
be effective and valid under applicable law, but if any provision of this Agreement is held to be prohibited by or invalid under applicable law, such provision will be ineffective only to the extent of such prohibition or invalidity, without
invalidating the remainder of this Agreement. 
  
 10.13 Entire Agreement of the
Parties. This Agreement constitutes and contains the entire understanding and agreement of the Parties and cancels and supersedes any and all prior negotiations, correspondence, understandings and agreements, whether oral or written, between the
Parties respecting the subject matter hereof. 
  
 [NEXT PAGE IS
THE SIGNATURE PAGE] 
  

 17 

 IN WITNESS WHEREOF, each of the Parties has caused this Agreement to be executed by its duly authorized
officer as of the day and year first above written. 
  

					
	 BIODELIVERY SCIENCES
 INTERNATIONAL, INC.

		
	By:	 	 /s/ Raphael J. Mannino

	 	 	 Name:
	 	 Raphael J. Mannino. Ph.D.

	 	 	 Title:
	 	Executive Vice President and Chief Scientific Officer

  

					
	ACCENTIA, INC.
		
	By:	 	 /s/ Martin G. Baum

	 	 	 Name:
	 	 Martin G. Baum

	 	 	 Title:
	 	 President

  

  
 EXHIBIT A 

 
 REGULATORY TIMELINES 
  

					
		
	 Meeting with the FDA
	  	Within three (3) months of the Effective Date
		
	 File IND
	  	Within six (6) months of the Effective Date1
		
	 Should FDA require Phase I or II studies
	  	 
			
	 	 	 Start Phase I
	  	Within six (6) months of approval of IND by FDA
			
	 	 	 Start Phase II
	  	Within six (6) months of clearance from FDA to proceed
			
	 	 	 Start Phase III
	  	Within six (6) months of clearance from FDA to proceed
			
	 	 	 File NDA
	  	Within 12 months of completing registration Phase III study, subject to Section 7.03(c) hereto
		
	Should FDA permit moving directly to Phase III studies	  	 
			
	 	 	 Start Phase III
	  	Within 6 months of approval of IND by FDA
			
	 	 	 File NDA
	  	Within 12 months of completing registration phase III study, subject to Section 7.03(c) hereto.

	1	The IND may be filled up to nine (9) months from the effective Date in the event that: (a) the FDA has agreed to initiate clinical trail under the IND with a Phase
III protocol, and (b) the FDA consequently requires chronic toxicology data to support the original IND. 

  

  
 EXHIBIT B 

 
 LICENSED PATENTS 
  

					
	 Docket No./Title/
Country

	  	Appln No./Patent No.

		
	 BSZ-005: Liposome Methods and Composition
	  	 
			
	 	 	US	  	4,663,161
		
	 BSZ-005DV: Reconstituting Viral Glycoproteins Into Large Phospholipid Vesicles
	  	 
			
	 	 	US	  	4,871,488
		
	 BSZ-006: Protein-or Peptide-Cochleate Vaccines and Methods of Immunizing Using the Same
	  	 
		
	 BSZ-006CP: Stabilizing Delivery Means of Biological Molecules
	  	 

  

			
	 US
	  	5,643,574
	 Int’I (PC)
	  	US94/10913
	 Canada
	  	2,169,297
	 Australia
	  	689505
	 Europe (incl.)
	  	0 722 338
	 Great Britain
	  	94930484.4
	 Sweden
	  	0 722 338
	 Austria
	  	0 722 338
	 Switzerland
	  	E 20 3413
	 Ireland
	  	0 722 338
	 Italy
	  	0 722 338
	 France
	  	0 722 338
	 Germany
	  	0 722 338
	 US (CN)
	  	08/629,923
	 US (CP)
	  	5,840,707
	 Int’I (CP2PC)
	  	US96/01704
	 Australia (CP2AUl)
	  	49748/96
	 Australia (CP2AU2)
	  	32599/00
	 Australia (CP2AU3)
	  	2002300615
	 Canada (CP2CA)
	  	2,212,238
	 Europe (CP2EP)
	  	96906334.6
	 Japan (CP2JP)
	  	8-525713
	 US (CP3)
	  	5,994,318
	 Int’I (CP3PC)
	  	US97/02632
	 Canada (CP3CA)
	  	2,246,754

  

			
	 Docket No./Title/
 Country

	  	 Appln No./ Patent No.

  

			
	BSZ-007: Protein-Lipid Vesicles And Autogenous Vaccine Comprising The Same	  	 

  

			
	 US
	  	5,834,015
	 US (CP)
	  	6,165,502
	 Int’l (PC)
	  	US97/08422
	 Australia
	  	722647
	 Canada
	  	2,264,646
	 Europe
	  	97940721.0
	 Japan
	  	10-513692

  

			
	BSZ-009: Nanocochleate Formulations, Process Of Preparation And Method Of Delivery of Pharmaceutical Agents

  

			
	 US
	  	6,153,217
	 Int’l (PC)
	  	US00/01684
	 Australia
	  	3213/00
	 Canada
	  	2,358,505
	 Europe
	  	00 909 961.5
	 Japan
	  	2000-594446
	 US (CP)
	  	09/613,840
	 US (CPCN)
	  	10/421,358
	 Int’l (CPPC)
	  	US01/02299
	 Australia (CPAU)
	  	31114/01
	 Canada (CPCA)
	  	2,397,792
	 Europe (CPEP)
	  	01 903 273.9
	 Japan (CPJP)
	  	2001-552865

  

			
	BSZ-010: Cochleates From Purified Soy Phosphatidylserine	  	 

  

			
	 US
	  	10/105,314
	 US (CN)
	  	10/304,567
	 Int’l (PC)
	  	PCT/US03/09562

  

			
	BSZ-014: Geodate Delivery Vehicles	  	 

  

			
	 US (PR)
	  	60/422,989
	 US (PR)
	  	60/440,284
	 US
	  	10/701,364
	 PCT
	  	PCT/US03/35136

  

			
	BSZ-016: Rigid Liposomal Compositions	  	 

  

			
	 US (PR)
	  	60/531,546

  

			
	 Docket No./Title/
 Country

	  	Appln No./ Patent No.

	BSZ-017: Cochleate Preparations of Fragile Nutrients
		
	 US (PR)
	  	60/440,120
	 US (PR)
	  	60/465,754
	 US
	  	10/759,381
	 PCT
	  	PCT/US04/01236
		
	BSZ-018: Antisense Cochleates	  	 
		
	 US (PR)
	  	60/461,483
	 US (PR)
	  	60/463,076
	
	BSZ-020: Cochleates Including Aggregation Inhibitors
		
	 US (PR)
	  	60/502,557
	 US(PR)
	  	60/537,252
	
	BSZ-023: Novel Encochleation Methods, Cochleates and Methods of Use
		
	 US (PR)
	  	60/499,247
	 US(PR)
	  	60/532,755
	
	BSZ-038: Replacement Enzyme Cochleates
		
	 US (PR)
	  	60/541,707
	
	BSZ-039 Apoprotein Cochleate Compositions
		
	 US (PR)
	  	60/540,269

  

  
 EXHIBIT C 

 
 BDSI LICENSED TECHNOLOGY 
  

	I.	COCHLEATE TECHNOLOGY 

  
 Origin of cochleates 
  
 Over the years,
biochemists and biophysicists have studied artificial membrane systems to understand their properties and potential applications. In studying this topic, Demetrios Papahadjopoulos and coworkers began investigating the interactions of divalent
cations with negatively charged lipid bilayers. They reported that the addition of calcium ions to small phosphatidylserine vesicles induced their collapse into discs which fused into large sheets of lipid. In order to minimize their interaction
with water, these lipid sheets rolled up into jellyroll-like structures, termed “cochleate” cylinders, after the Greek name for a snail with spiral shell. 
  
 The Cochleate Advantage 
  
 Cochleate delivery vehicles represent a new technology platform for oral, mucosal and systemic delivery of clinically important drugs that possess poor bioavailability.
For example, oral cochleates have been successfully used in animal models for the delivery of drugs that previously were only available given by injection. 
  
 High stability: Cochleate delivery vehicles are stable phospholipids-divalent cation precipitates composed of simple, naturally occurring materials, for example,
phosphatidylserine and calcium. They have a unique multilayered structure consisting of a large, continuous, solid, lipid bilayer sheet rolled up in a spiral, with no internal aqueous space. Cochleates can be stored in a cation-containing buffer, or
lyophilized to a powder and stored at room temperature. Lyophilized cochleates can be placed in capsules and given orally, or reconstituted with liquid prior to in vitro use or in vivo administration. Lyophilization has no adverse
effects on cochleate morphology or functions. Cochleate preparations have been shown to be stable for more than two years at 4°C in a cation-containing buffer, and at least one year as a lyophilized powder at room temperature. Encochleation imparts increased stability to drugs, proteins and polynucleotides. 
  
 Encapsulation: Cochleate delivery vehicles “wrap-up” or encapsulate the
drug, rather than chemically bond with the included drug. 
  
 Target delivery:
Cochleates carry the encapsulated drug within the interior of the formulation and delivery the drug to the target cell. This results in low blood levels of free drug and high efficiency delivery to the target cell. Once at the target cell,
cochleates can be envisioned as membrane fusion intermediates. When a cochleate comes into close approximation to a target membrane, a fusion event between the outer layer of the cochleate and the cell membrane occurs. This fusion results in the
delivery of a small amount of the encochleated material into the cytoplasm of the target cell. The cochleate may slowly fuse or break free of the cell and be available for another fusion event, either with this or another cell. Cochleates may also
be taken up by endocytosis, and fuse from within endocytic vesicles. 
  
 Resistance to environmental attack: The unique structure of the cochleate provides protection from degradation for associated “encochleated” molecules. Traditionally, many drugs can be damaged from exposure to adverse
environmental conditions such as sunlight, oxygen, water and temperature. Since the entire cochleate structure is a series of solid layers, components within the interior of the cochleate structure remain intact, even though the outer layers of the
cochleate may be exposed to harsh environmental conditions or enzymes. 
  
 Oral
availability: The drug delivery technology is being developed to enable oral availability of a broad spectrum of compounds, such as those with poor water solubility, as well as polynucleotides, and protein and peptide biopharmaceuticals, which
have been difficult to formulate and administer. 
  

 Release characteristics: The cochleate technology offers the potential to be tailored to control the release of
the drug depending on the desired application. 
  
 Formulation of Cochleates

  
 BDSI scientists have investigated various aspects of the manufacturing
process, including pH, agitation method and rate, type of cation, ratio of lipid to material, and other parameters, in order to optimize the formulation and manufacturing process for a given material. In one typical manufacturing process, the
materials to be formulated (chemical drugs, proteins, peptides, DNA, antigens, nutrients) are added to a suspension of liposomes comprised mainly of negatively charged lipids. The addition of divalent metal ions such as calcium, (although other
multivalent cations can be used) induces the collapse and fusion of the liposomes into large sheets composed of lipid bilayers, which spontaneously roll up or stack into cochleates. If desired, the cochleates can be purified to remove unencochleated
material, and then resuspended in a buffer containing divalent metal ions. 
  
 Various processes have been developed by BDSI scientists to prepare cochleate formulations of a wide variety of drugs, peptides and proteins, with molecular weights ranging from 1 to greater than 200KD, and oligonucleotides or DNA of 20 to
greater than 10,000 base pairs. The percentage of encochleation of material ranges from 40-95%, depending on the material and the manufacturing conditions. 
  
 Biocompatibiliry of Cochleate Vehicles 
  
 The fundamental components of the cochleate delivery vehicle are phosphatidylserine (PS) and calcium. Phosphatidylserine is a natural component of all biologic membranes,
and is most concentrated in the brain. Clinical studies by other investigators, (more than 30 have been published), to evaluate the potential of phosphatidylserine as a nutrient supplement indicate that PS is very safe and may play a role in the
support of mental functions in the aging brain. Indeed, phosphatidylserine isolated from soy beans is sold in health food stores as a nutritional supplement. 
  
 In mice, BDSI has evaluated the in vivo safety of multiple administrations of cochleates by various routes, including intravenous, intraperitoneal, intranasal and
oral. Multiple administrations of cochleate formulations to the same animal do not result in either the development of an immune response to the cochleate matrix, or to any side effects relating to the cochleate vehicle. 
  
 Mechanism of Delivery 
  
 The interaction of calcium with negatively charged lipids has been extensively studied. Many naturally occurring membrane fusion events
involve the interaction of calcium with negatively charged phospholipids (generally phosphatidylserine and phosphatidylglycerol). Calcium induced perturbations of membranes containing negatively charged lipids, and the subsequent membrane fusion
events, are important mechanisms in many natural membrane fusion processes. Hence, cochleates can be envisioned as membrane fusion intermediates. 
  
 During the past several years substantial research by BDSI scientists has demonstrated that cochleate formulations are simple, safe and highly efficacious mediators of
the in vivo delivery of proteins, peptides and polynucleotides for the induction of antigen specific immune responses following oral, intranasal and intramuscular administration. Significantly, the ability of cochleates to mediate the
induction of antigen specific, CD8+ cytotoxic lymphocytes, as well as the efficient induction of immune responses to plasmid encoded antigens, supports the hypothesis that cochleates facilitate the cytoplasmic delivery of cochleate associated
bioactive molecules. 
  
 The observations indicate that, as the calcium rich,
highly ordered membrane of a cochleate first comes into close approximation to a natural membrane, a perturbation and reordering of the cell membrane is induced. This results 

  

 
in a fusion event between the outer layer of the cochleate and the cell membrane. This fusion also results in the delivery of a small amount of the
encochleated material into the cytoplasm of the target cell. The cochleate may slowly fuse or break free of the cell and be available for another fusion event, either with this or another cell. Cochleates may also be taken up by endocytosis, and
fuse from within endocytic vesicles. 
  
 Uptake of Cochleates by Macrophage

  
 An important observation relative to the interaction of cochleates with
cells is their uptake by macrophage. For example, in vivo, fluorescent cochleates are accumulated by macrophage. Macrophages are on the first line of defense against microbial infections. Many human pathogens cause diseases because they have
developed the capacity to survive within macrophage. Examples include viruses such as HIV, bacteria such as staphylococcus and Mycobacterium tuberculosis, fungi such as Candida and parasites such as Leishmania. 
  
 Cochleate Mediated Oral Delivery of Drugs 
  
 Cochleate formulation technology is particularly applicable to macromolecules as well as
small molecule drugs that are hydrophobic, positively, or negatively charged, and possess poor oral bioavailability. Proof-of-principle studies for cochleate mediated oral delivery of macromolecules as well as small molecule drugs is being carried
out in appropriate animal models with a well established, clinically important drug which currently can only be effectively delivered by injection, amphotericin B, a potent antifungal agent. 
  
 II. PROTEOLIPOSOME TECHNOLOGY 
  
 Proteoliposome Technology (PLT), relates to novel liposome compositions and methods for
their preparation. Utilization of PLT provides an efficient reconstitution of membrane proteins into large (0.1 to 2 micron diameter) phospholipid vesicles with a large, internal aqueous space. The method has been exemplified with the use of
glycoproteins of influenza (A/PR8/34) and Sendai (parainfluenza type I) viruses. The method comprises (A) extracting out the desired membrane protein from a source biological material with an extraction buffer comprising a detergent; (B) mixing the
extract with a phospholipid solution and deriving a cochleate intermediate; and (C) forming large phospholipid vesicles with integrated membrane protein in a biologically active state. 
  
 PLT has been used to produce liposome structures with improved delivery capabilities for drug delivery and gene therapy as well as enhanced
immune responses. In addition, BDSI PLT can be used to formulate and stabilize biologically important but structurally fragile hydrophobic proteins. 
  
 The PLT is protected by US Patent Nos. 4,663,161 and 4,871,488. 
  
 III. GEODATE TECHNOLOGY 
  
 Geodate technology generally relates to a novel delivery vehicle that encapsulates agents in a stable emulsion, slurry, or powder. Geodate technology is particularly attractive for use with hydrophobic agents, as it
can incorporate them at a high yield. It also is particularly attractive for delivery of fragile or unstable agents as the “geodes” remain intact and protect the fragile core molecules, such as beta-carotene, under environmental conditions
that normally will result in destruction or inactivation of the molecules. 
  
 It
has been discovered by BDSI scientists that a monolayer of lipid can form about a hydrophobic core, and that this monolayer can further be encrusted in a lipid/cation matrix, further protecting the hydrophobic core. The resulting “geode”
is highly stable and protects of the core from degradation or inactivation, even at elevated pressures and temperatures, such as those encountered in food processing technology. 
  

 ASSET PURCHASE AGREEMENT 
  
 This ASSET PURCHASE AGREEMENT (the “Agreement”) is entered into and effective as of the 7th day of
September 2004 (the “Effective Date”), by and between BioDelivery Sciences International, Inc., a Delaware corporation (“BDSI”) and Accentia, Inc., a Florida corporation (“Accentia”). 
  
 WHEREAS, BDSI and Accentia have heretofore entered into that certain
License Agreement, dated April 12,2004 (as amended, the “License Agreement”); 
  
 WHEREAS, the License Agreement calls for certain royalty payments to be made from Accentia to BDSI (the “Royalty Payments”); and 
  
 WHEREAS, Accentia desires to purchase from BDSI an asset consisting of a portion of the Royalty Payments (such
portion of the Royalty Payments, as further defined in Section I(e) hereof, the “Royalty Stream”) that will be based on sales of the Products. 
  

NOW, THEREFORE, in consideration of the foregoing and the representations, warranties, covenants and agreements herein contained, the parties
hereto agree as follows. 
  
 1. Definitions. In addition to
capitalized terms defined elsewhere in this Agreement, the following capitalized terms shall have the meanings set forth below: 
  
 (a) “Affiliate” means with respect to any Person, any Person directly or indirectly controlling, controlled by or under common control
with such other Person. For purposes of this definition, a Person shall be deemed to control another entity if it owns or controls, directly or indirectly, at least fifty percent (50%) of the voting securities of another entity (or other comparable
ownership interest for an entity other than a corporation) or if it has management control of the other entity. For purposes of this Agreement, BDSI and Accentia shall not be deemed Affiliates for any purpose. 
  
 (b) “Lien” means, with respect to any agreement or other
asset, any mortgage, lien, pledge, charge, security interest or encumbrance of any kind in respect of such asset. 
  
 (c) “Mayo Agreement” means that certain Mayo Foundation For Medical Education and Research License Agreement, with an effective date of
February 10,2004, between Accentia and Mayo Foundation For Medical Education and Research (“Mayo”). 
  
 (d) “Person” means an individual, corporation, partnership, limited liability company, association, trust or other entity or
organization, but not including a government or political subdivision or any agency or instrumentality of such government or political subdivision. 
  
 (e) “Royalty Stream” means fifty percent (50%) of all Royalty Payments required to be paid by Accentia under the License Agreement.
Notwithstanding the forgoing, Royalty Stream shall not include Royalty Payments that are payable by Accentia under the License Agreement that are based on the sale of products exclusively intended to treat asthma. 

 2. Purchase and Sale of the Royalty Stream. 
  
 (a) Purchase and Sale. Upon the terms and subject to the conditions of
this Agreement, on and as of the Effective Date, Accentia shall purchase from BDSI, and BDSI shall sell to Accentia, free and clear of all Liens, all rights title and interest in and to the Royalty Stream for a one-time, irrevocable payment of Two
Million Five Hundred Thousand Dollars ($2,500,000) in cash (the “Purchase Price”). 
  
 (b) Payment. The Purchase Price shall be due and payable to BDSI not later than September 30,2004. 
  
 (c) No Assumed Obligations. Notwithstanding any provision in this
Agreement, and except as already provided for under the Mayo Agreement or the License Agreement or otherwise, Accentia is acquiring only the Royalty Stream and is not assuming any liability or obligation of BDSI of whatever nature, whether presently
in existence or arising or asserted hereafter. All such liabilities and obligations shall be retained by and remain obligations and liabilities of BDSI. 
  
 (d) Net Payments. For the avoidance of doubt, the parties acknowledge that, as of the Effective Date, and by reason of the purchase and sale of the
Royalty Stream affected hereby, all Royalty Payments required to be made by Accentia under the License Agreement shall be automatically reduced by the amount of such purchased Royalty Stream. 
  
 (e) Definition of Territory. For all purposes under the License
Agreement, including but not limited to Article 3, the term “Territory” as defined in Section 1.17 of the License Agreement shall be amended to mean “world-wide”. Accentia shall have the right to Grant Sublicenses in all
areas of the Territory which are outside of the United States and European Union. 
  
 3. Representations and Warranties of BDSI. Except in each case as disclosed on or prior to the date hereof in BDSI’s filings with the US. Securities and Exchange Commission (including the exhibits
thereto), BDSI hereby represents and warrants to Accentia as follows. 
  
 (a) Corporate Existence and Power. BDSI is a corporation duly incorporated, validly existing and in good standing under the laws of its jurisdiction of incorporation and has all corporate powers and all material licenses,
authorizations, consents and approvals required to carry on its business as now conducted. 
  
 (b) Corporate Authorization. The execution, delivery and performance by BDSI of this Agreement, and the consummation by BDSI of the transactions contemplated hereby are within BDSI’s corporate powers and
have been duly authorized by all necessary corporate action on the part of BDSI. 
  

 27 

 (c) Governmental Authorization. The execution, delivery and performance by BDSI of this Agreement
does not require any notice to, action or consent by or in respect of, or filing with, any governmental authority. 
  
 (d) Non-Contravention. The execution, delivery and performance by BDSI of this Agreement does not and will not: (i) contravene or conflict with the
corporate charter or bylaws of BDSI; (ii) contravene or conflict with or constitute a violation of any provision of any law or regulation binding upon or applicable to BDSI, which contravention, conflict or violation could reasonably be expected to
have a material adverse effect on BDSI or the Royalty Stream; (iii) contravene or conflict with or constitute a violation of any judgment, injunction, order or decree binding upon or applicable to BDSI, which contravention, conflict or violation
could reasonably be expected to have a material adverse effect on BDSI or the Royalty Stream; (iv) constitute a default under any agreement or give rise to any right of termination, cancellation or acceleration of any right or obligation of BDSI or
to a loss of any benefit relating to the Royalty Stream; or (v) result in the creation or imposition of any Lien on the Royalty Stream or other assets of BDSI (except for any Lien in favor of Accentia). 
  
 (e) No Liens. BDSI has not granted, and there does not currently
exist, any Lien on the Royalty Stream or the License Agreement or on any receivables therefrom. BDSI will not grant any Liens on the Royalty Stream, the License Agreement or any receivables therefrom without the prior consent of Accentia. The
Royalty Stream is not subject to any claim of off-set for any other liability or obligation of BDSI. 
  
 (f) Litigation. Except as disclosed in BDSI’s public filings with the Securities and Exchange Commission or its public press releases, there
is no action, suit, investigation or proceeding (or any basis therefor), of which BDSI has received notice, pending or, to the knowledge of BDSI, threatened, before any governmental authority or arbitrator, which has or could materially affect the
Royalty Stream or the business of BDSI. There have been no claims made by any Person with respect to, and no actions, suits or other proceedings relating to BDSI or the conduct of its business, which could reasonably be expected to have a material
adverse effect thereon. 
  
 (g) Compliance with Laws.
Except as disclosed in BDSI’s public filings with the Securities and Exchange Commission or its public press releases, BDSI is not in violation of, has not violated, and to the knowledge of BDSI, is not under investigation with respect to and
has not been threatened to be charged with or given notice of any violation of, any material law, rule, ordinance or regulation, or judgment, order or decree entered by any governmental authority, which could reasonably be expected to have a
material adverse effect thereon. 
  
 (h) No Brokers. There
is no investment banker, broker, finder or other intermediary which has been retained by or is authorized to act on behalf of BDSI who might be entitled to any fee or commission from Accentia or any of its Affiliates upon consummation of the
transactions contemplated by this Agreement. 
  
 (i) Other
Information. This Agreement does not contain any untrue statement of a material fact regarding BDSI or omit to state a material fact relating to BDSI necessary in order to make the statements contained herein not misleading. 
  

 28 

 4. Representations and Warranties of Accentia. Accentia hereby represents and warrants to BDSI as
follows: 
  
 (a) Organization and Existence. Accentia is
duly organized, validly existing and in good standing under the laws of its jurisdiction of organization and has all applicable powers and all material governmental licenses, authorizations, consents and approvals required to carry on its business
as now conducted. 
  
 (b) Corporate Authorization. The
execution, delivery and performance by Accentia of this Agreement and the consummation by Accentia of the transactions contemplated hereby are within the powers of Accentia and have been duly authorized by all necessary action on the part of
Accentia. 
  
 (c) Governmental Authorization. The
execution, delivery and performance by Accentia of this Agreement does not require any action by or in respect of, or filing with, any governmental authority. 
  

(d) Mayo Agreement. The Mayo Agreement is in full force and effect and Accentia has all rights under the Mayo Agreement to develop and
commercialize the Products and receive payments from Mayo as contemplated by the Mayo Agreement. The copy of the Mayo Agreement as provided by Accentia to BDSI is true, correct and complete. There have been no amendments or modifications to the Mayo
Agreements, with the exception of that certain Consent and Agreement, dated June 24, 2004, between Accentia and Mayo. Accentia is in compliance the Mayo Agreement and is not in breach of its obligations with respect thereto. To Accentia’s
knowledge, Mayo is in compliance with the Mayo Agreement, and Accentia has no reason to believe that Mayo does not intend to comply with its obligations pursuant to the Mayo Agreement. 
  
 (e) No Brokers. There is no investment banker, broker, finder or other intermediary that has been retained by or is
authorized to act on behalf of Accentia who might be entitled to any fee or commission from BDSI or any of its Affiliates upon consummation of the transactions contemplated by this Agreement. 
  
 5. Covenants. Accentia and BDSI agree as follows. 
  
 (a) Confidential Treatment. Accentia and BDSI will hold, and will use
reasonable commercial efforts to cause their officers, directors, employees, accountants, counsel, consultants, advisors and agents to hold, in confidence, unless compelled to disclose by judicial or administrative process or unless required by law
or the rules and regulations of the US. Securities and Exchange Commission or any securities exchange or trading system, all confidential documents and information concerning Accentia, BDSI, this Agreement and the Royalty Stream. 
  

 29 

 (b) Public Announcement. Except as required by law or the rules and regulations of the U.S.
Securities and Exchange Commission or any securities exchange or trading system, the parties agree to consult with each other before issuing any press release or making any public statement with respect to Accentia’s acquisition of the Royalty
Stream. 
  
 6. Indemnification. 
  
 (a) Indemnification by BDSI. BDSI hereby indemnifies Accentia and its
Affiliates against and agrees to hold each of them harmless from any and all damage, loss, liability and expense (including, without limitation, reasonable expenses of investigation and reasonable attorneys’ fees and expenses in connection with
any action, suit or proceeding) (collectively, ‘Loss”) incurred or suffered by Accentia or any of its Affiliates arising out of any misrepresentation or breach of warranty, covenant or agreement made or to be performed by BDSI
pursuant to this Agreement. Accentia agrees to give prompt notice to BDSI of the assertion of any claim, or the commencement of any suit, action or proceeding in respect of which indemnity may be sought under this Section 6(a); provided that the
failure to give such notice shall not affect Accentia’s rights hereunder except to the extent BDSI is materially prejudiced by such failure. BDSI may, and at the request of Accentia shall, participate in and control the defense of any such
third party suit, action or proceeding at its own expense. BDSI shall not be liable under this Section 6(a) for any settlement effected without its prior consent of any claim, litigation or proceeding in respect of which indemnity may be sought
hereunder; provided that such consent may not be unreasonably withheld. No investigation or knowledge by Accentia of BDSI shall limit Accentia’s rights to indemnification hereunder. Nothing in this Agreement shall limit any remedies available
to Accentia at law or in equity for any claims under this Agreement. 
  
 (b) Indemnification by Accentia. Accentia hereby indemnifies BDSI and its Affiliates against and agrees to hold each of them harmless from any and all Losses incurred or suffered by BDSI or any of its Affiliates arising out of any
misrepresentation or breach of warranty, covenant or agreement made or to be performed by Accentia pursuant to this Agreement. BDSI agrees to give prompt notice to Accentia of the assertion of any claim, or the commencement of any suit, action or
proceeding in respect of which indemnity may be sought under such Section 6(b); provided that the failure to give such notice shall not affect BDSI’s rights hereunder except to the extent Accentia is materially prejudiced by such failure.
Accentia may, and at the request of BDSI shall, participate in and control the defense of any such third party suit, action or proceeding at its own expense. Accentia shall not be liable under this Section 6(b) for any settlement effected without
its prior consent of any claim, litigation or proceeding in respect of which indemnity may be sought hereunder; provided that such consent may not be unreasonably withheld. No investigation or knowledge by BDSI of Accentia shall limit BDSI’s
rights to indemnification hereunder. Nothing in this Agreement shall limit any remedies available to BDSI at law or in equity for any claims under this Agreement. 
  
 (c) Survival. The representations, warranties, covenants and agreements, including without limitation the agreements
set forth in (a) above, contained herein shall survive for twelve (12) months from the Effective Date. 
  

 30 

 7. Miscellaneous. 
  
 (a) Amendment to License Amendment. Except as provided in Section 2(d) hereof or expressly provided elsewhere in this
Agreement, the License Agreement shall remain unchanged and in full force and effect. 
  
 (b) Waiver. The failure of either party to complain of any default by the other party or to enforce any of such party’s rights, no matter how long such failure may continue, will not constitute a waiver of
the party’s rights under this Agreement. The waiver by either party of any breach of any provision of this Agreement shall not be construed as a waiver of any subsequent breach of the same or any other provision. No part of this Agreement may
be waived except by the further written agreement of the parties. 
  
 (c) Governing Law. This Agreement shall be construed and governed in accordance with the laws of the State of New Jersey, without regard to its conflicts of laws principles. 
  
 (d) Headings. The headings of paragraphs and sections used in this
Agreement are for convenience of reference only, and shall not affect the meaning or interpretation of this Agreement unless the context requires otherwise. 
  
 (e) Notices. All notices and other business communications between the parties related to this Agreement shall be in writing, sent by certified
mail or facsimile, addressed as follows: 
  

			
	 If to Accentia:
	  	Accentia, Inc.
	 	  	2501 Aerial Center Parkway, Suite 100
	 	  	Morrisville, NC 27560
	 	  	Attn: Martin G. Baum
	 	  	Fax: (919) 481-9311
		
	 If to BDSI:
	  	BioDelivery Sciences International, Inc.
	 	  	UMDNJ-New Jersey Medical School
	 	  	185 South Orange Avenue,
Administrative Building 4
	 	  	Newark, NJ 07103
	 	  	Attn: Dr, Raphael J. Mannino
	 	  	Fax: (973) 972-0323

  
 Notices sent by certified mail shall
be deemed given and received on the third day following the date of mailing. Notices sent by facsimile shall be deemed given and received on the date transmitted as evidenced by the transmission report generated by the sender’s facsimile
machine. Either party may change its address or facsimile number by giving written notice in compliance with this paragraph. 
  
 (f) Relationship. Neither party is the agent, employee, or servant of the other. Except as specifically set forth herein, neither party shall have
nor exercise any control or direction over the methods by which the other party performs work or obligations under this 
  

 31 

 
Agreement. Further, nothing in this Agreement is intended to create any partnership, joint venture, lease, or equity relationship, expressly or by
implication, between the parties with the respect to the subject matter herein. 
  
 (g) Entire Agreement. This Agreement constitutes the final, complete and exclusive agreement between the parties with respect to its subject matter and supercedes all past and contemporaneous agreements,
promises, and understandings, whether oral or written, between the parties. 
  
 (h) Binding Effect. This Agreement shall be binding upon and inure to the benefit of the parties and their respective successors and assigns. 
  
 (i) Severability. In the event any provision of this Agreement is held to be invalid or unenforceable, the remainder
of this Agreement shall remain in full force and effect as if the invalid or unenforceable provision had never been a part of the Agreement. 
  
 (j) Amendments. This Agreement may not be amended or modified except by a writing signed by both parties and identified as an amendment to this
Agreement. 
  
 (k) Expenses. All costs and expenses
incurred in connection with this Agreement shall be paid by the party incurring such cost or expense. 
  
 (1) Counterparts; Effectiveness. This Agreement may be signed in any number of counterparts, each of which may be delivered by facsimile
transmission and which shall be deemed an original, with the same effect as if the signatures thereto and hereto were upon the same instrument. This Agreement shall become effective when each party hereto shall have received a counterpart hereof
signed by the other party hereto. 
  
 [The remainder of this page
is intentionally left blank] 
  

 32 

 IN WITNESS WHEREOF, the parties have executed this Asset Purchase Agreement as of the Effective Date.

  

			
	BIODELIVERY SCIENCES INTERNATIONAL, INC.
		
	By:	 	 /s/ Raphael J. Mannino

	 	 	 Name: Raphael J. Mannino
 Title: Executive Vice
President and Chief
           Scientific Officer

  

			
	ACCENTIA, INC.
		
	By:	 	 /s/ Martin G. Baum

	 	 	 Name: Martin G. Baum
 Title:
President

  

 33 

 

 
  
 March 28, 2005 
  
 BioDelivery Sciences International, Inc. 
 2501 Aerial Center Parkway, Suite 205 
 Morrisville, North Carolina 27560

  
 Gentlemen: 
  
 Reference is made to that certain License Agreement, dated effective as of April 12, 2004, as amended (the “License
Agreement”), by and between BioDelivery Sciences International, Inc. (“BDSI”) and Accentia Biopharmaceuticals, Inc. f/k/a Accentia, Inc. (“Accentia”). All capitalized terms used but not defined herein shall have the meanings
ascribed to such terms in the License Agreement. 
  
 Pursuant to
Section 10.8 of the License Agreement, BDSI and Accentia desire to, for good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, and hereby do, amend the License Agreement as follows: 
  
 1. Section 1.2 of the License Agreement is deleted in its entirety and
replaced with the following: 
  
 “1.2 “Antifungal
Products” shall mean any and all products (but specifically excluding any product to treat asthma) covered by the patent rights licensed to ACCENTIA by MAYO under the ACCENTIA/MAYO Agreement that are not Licensed Products.” 
  
 2. In order to clarify the effects of the June 4, 2004 amendment to License
Agreement and the September 8, 2004 Asset Purchase Agreement between BDSI and Accentia, BDSI and Accentia hereby amend the License Agreement to delete Sections 4.2(a) and 4.2(b) in their entirety and replace such Sections with a new Section 4.2(a),
as follows: 
  
 “(a) BDSI shall be entitled to the following
royalty payments: 
  
 (i) In lieu of any up front
fees and milestone payments, and as an inducement to BDSI to enter into this Agreement, ACCENTIA shall pay to BDSI a 6% royalty on Net Sales in the Territory (i.e., anywhere in the world) of any Antifungal Products which have not received marketing
approval by the U.S. Food and Drug Administration (such approval, “FDA Approval”), it being agreed that, with respect to any of such Antifungal Products individually, the obligation of Accentia to make such royalty payments shall
automatically terminate with respect to sales made on or after, but not prior to, the date that the license to ACCENTIA under Section 3.01(b) the ACCENTIA/MAYO Agreement is terminated by function of the ACCENTIA/MAYO Agreement; 
  
 (ii) A 7% royalty on Net Sales in the Territory (i.e.,
anywhere in the world) of any Licensed Products for the treatment of chronic sinusitis which have received FDA Approval for such indication; 
  
 (iii) A 14% royalty on Net Sales in the Territory (i.e., anywhere in the world) of any Licensed Products for the treatment of asthma which
have received FDA Approval for such indication; 
  

 5310 Cypress Center Drive, Suite 101, Tampa, FL 33609 
 PH: (813) 864-2562 FAX: (813) 288-8757 

 

 
  
 (iv) For the
avoidance of doubt, no royalty on any sales of any products for the treatment of asthma that are not Licensed Products; and 
  
 (v) For the avoidance of doubt, no royalty on any sales of products for the treatment of chronic sinusitis that: (i) have received FDA
Approval and (ii) are not Licensed Products.” 
  
 2. The
parties agree that the terms “chronic rhinosinusitis” as used in the ACCENTIA/MAYO Agreement and the term “chronic sinusitis” as used in the License Agreement shall be interpreted to mean the same indication. 
  
 3. Except as modified hereby, the License Agreement shall remain unmodified,
unchanged and in full force and effect. Upon execution of this letter agreement by both BDSI and Accentia, this letter agreement shall become a binding amendment to the License Agreement. 
  

			
	 Sincerely,

	
	 ACCENTIA BIOPHARMACEUTICALS, INC.

		
	By:	 	 /s/ Martin Baum

	 	 	Martin Baum, President and Chief Operating Officer of Commercial Operations and Business Development

  
 Accepted and Agreed to:

  

			
	BIODELIVERY SCIENCES INTERNATIONAL, INC.
		
	By:	 	 /s/ Raphael Mannino

	 	 	 Raphael Mannino, EVP and CSO

  

 5310 Cypress Center Drive, Suite 101, Tampa, FL 33609 
 PH: (813) 864-2562 FAX: (813) 288-8757 

 [LOGO OF ACCENTIA BIOPHARMACEUTICALS] 
  
 April 25, 2005 
  
 BioDelivery Sciences International, Inc. 
 2501 Aerial Center Parkway, Suite
205 
 Morrisville, North Carolina 27560 
  
 Gentlemen: 
  
 Reference is made to that certain License Agreement, dated effective as of April 12, 2004 (as amended by the agreements referred to below, the “License Agreement”), by and between BioDelivery Sciences
International, Inc. (“BDSI”) and Accentia Biopharmaceuticals, Inc. f/k/s, Accentia, Inc. (“Accentia”), as amended and modified by: (i) an Amendment to the License Agreement, dated effective June 1, 2004, (ii) an Asset Purchase
Agreement, dated September 8, 2004, and (iii) a letter amendment to the License Agreement, dated March 28, 2005, each by and between BDSI and Accentia. All capitalized terms used but not defined herein shall have the meanings ascribed to such terms
in the License Agreement. Pursuant to Section 10.8 of the License Agreement, BDSI and Accentia desire to, for good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, and hereby do, amend the License Agreement as
follows: 
  
 1. Section 9.1 of the License Agreement is deleted in
its entirety and replaced with the following: 
  
 “9.1
BDSI Supply Requirements. BDSI shall provide, at ACCENTIA’S sole cost and expense, all quantities of phospholipids ACCENTIA needs to develop and/or identify Licensed Products for ACCENTIA’s preclinical and clinical studies and for
any other purpose hereunder. ACCENTIA shall identify the amounts of phospholipids needed. Provision of phospholipids shall be accompanied by applicable quantity and quality information necessary to permit use of such Licensed Product in animal or
human testing. If necessary, based on the stage of development, BDSI shall produce at ACCENTIA’s sole cost and expense, Licensed Product in accordance with regulatory requirements to permit use of such Licensed Products in such pre-clinical or
clinical testing or other purpose.” 
  
 2. Except as modified
hereby, the License Agreement shall remain unmodified, unchanged and in full force and effect. Upon execution of this letter agreement by both BDSI and Accentia, this letter agreement shall become a binding amendment to the License Agreement.

  

	
	Sincerely,
	
	ACCENTIA BIOPHARMACEUTICALS, INC.
	
	/s/ Martin Baum
	By: Martin Baum, President and Chief Operating Officer of Commercial Operations and Business Development

  
 Accepted and Agreed to:

  

	
	BIODELIVERY SCIENCES INTERNATIONAL, INC.
	
	/s/ Raphael Mannino
	By: Raphael Mannino, EVP and CSO

  
 324 Hyde Park Avenue,
Suite 350, Tampa FL 33606 
 PH: (813) 864-2562 FAX: (813) 288-8757Cooperative Research & Developement Agree

  
 Exhibit 10.12

  
 PUBLIC HEALTH SERVICE 
  
 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT 
  
 This Cooperative Research and Development Agreement, hereinafter referred to as the
“CRADA,” consists of this Cover Page, an attached Agreement, and various Appendices referenced in the Agreement. This Cover Page serves to identify the Parties to this CRADA: 
  
 (1) the following Bureau(s), Institute(s), Center(s) or Division(s) of the National Institutes of Health (“NIH”),
the Food and Drug Administration (“FDA”), and the Centers for Disease Control and Prevention (“CDC”): 
  
 The National Cancer Institute (“NCI”), hereinafter singly or collectively referred to as the Public Health Service (“PHS”); and

  
 (2) Biovest International, which has offices at 540 Sylvan
Avenue, Englewood Cliffs, NJ 07632-3022, hereinafter referred to as the “Collaborator.” 
  

					
	 	  	Page 1 of 11	  	CONFIDENTIAL

 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT 
  
 Article 1. Introduction 
  
 This Cooperative Research and Development Agreement (CRADA) between PHS and the Collaborator will be effective when signed
by all Parties. The research and development activities which will be undertaken by each of the Parties in the course of this CRADA are detailed in the Research Plan (RP) which is attached as Appendix A. The funding and staffing commitments of the
Parties are set forth in Appendix B. Any exceptions or changes to the CRADA are set forth in Appendix C. This CRADA is made under the authority of the Federal Technology Transfer Act, 15 U.S.C. 3710a and is governed by its terms. 
  
 Article 2. Definitions 
  
 As used in this CRADA, the following terms shall have the indicated meanings: 
  

	2.1	“Affiliate” means any corporation or other business entity controlled by, controlling, or under common control with Collaborator. For this purpose,
“control” means direct or indirect beneficial ownership of at least fifty (50) percent of the voting stock or at least fifty (50) percent interest in the income of such corporation or other business. 

  

	2.2	“Cooperative Research and Development Agreement” or “CRADA” means this Agreement, entered into by PHS pursuant to the Federal Technology Transfer Act of
1986, as amended, 15 U.S.C. 3710a et seq. and Executive Order 12591 of October 10. 1987. 

  

	2.3	“Government” means the Government of the United States as represented through the PHS agency that is a Party to this agreement. 

  

	2.4	“IP” means intellectual property. 

  

	2.5	“Invention” means any invention or discovery which is or may be patentable or otherwise protected under title 35, United States Code, or any novel variety or plant
which is or may be protectable under the Plant Variety Protection Act (7 U.S.C. 2321 et seq.). 

  

	2.6	“Principal Investigator(s)” or “PIs” means the persons designated respectively by the Parties to this CRADA who will be responsible for the
scientific and technical conduct of the RP. 

  

	2.7	“Proprietary/Confidential Information” means confidential scientific, business, or financial information provided that such information does not include:

  

	 	2.7.1	  information that is publicly known or available from other sources who are not under a confidentiality obligation to the source of the information; 

 

	 	2.7.2 	information which has been made available by its owners to others without a confidentiality obligation; 

  

	 	2.7.3 	information which is already known by or available to the receiving Party without a confidentiality obligation; or 

  

					
	 	 	Page 2 of 11	 	CONFIDENTIAL

	 	2.7.4 	information which relates to potential hazards or cautionary warnings associated with the production, handling or use of the subject matter of the Research Plan of this CRADA.

  

	2.8	“Research Materials” means all tangible materials other than Subject Data first produced in the performance of this CRADA. 

 

	2.9	“Research Plan” or “RP” means the statement in Appendix A of the respective research and development commitments of the Parties to this CRADA.

  

	2.10	“Subject Invention” means any Invention of the Parties, conceived or first actually reduced to practice in the performance of the Research Plan of this
CRADA. 

  

	2.11	“Subject Data” means all recorded information first produced in the performance of this CRADA by the Parties. 

  
 Article 3. Cooperative Research 
  

	3.1	Principal Investigators. PHS research work under this CRADA will be performed by the PHS laboratory identified in the RP, and the PHS Principal Investigator (PI) designated
in the RP will be responsible for the scientific and technical conduct of this project on behalf of PHS. Also designated in the RP is the Collaborator PI who will be responsible for the scientific and technical conduct of this project on behalf of
the Collaborator. 

  

	3.2	Research Plan Change. The RP may be modified by mutual written consent of the Principal Investigators. Substantial changes in the scope of the RP will be treated as
amendments under Article 13.6. 

  
 Article 4. Reports

  

	4.1	Interim Reports. The Parties shall exchange formal written interim progress reports on a schedule agreed to by the PIs, but at least within twelve (12) months after this
CRADA becomes effective and at least within every twelve (12) months thereafter. Such reports shall set forth the technical progress made, identifying such problems as may have been encountered and establishing goals and objectives requiring further
effort, any modifications to the Research Plan pursuant to Article 3.2, and identify Subject Inventions pursuant to Article 6.1. 

  

	4.2	Final Reports. The Parties shall exchange final reports of their results within four (4) months after completing the projects described in the RP or after the expiration or
termination of this CRADA. 

  
 Article 5. Financial and Staffing
Obligations 
  

	5.1	PHS and Collaborator Contributions. The contributions of the Parties, including payment schedules, if applicable, are set forth in Appendix B. PHS shall not be obligated to
perform any of the research specified herein or to take any other action required by this CRADA if the funding is not provided as set forth in Appendix B. PHS shall return excess funds to the Collaborator when it sends its final fiscal report
pursuant to Article 5.2, except for staffing support pursuant to Article 10.3. Collaborator acknowledges that the U.S. Government will have the authority to retain and expend any excess funds for up to one (1) year subsequent to the expiration or
termination of the CRADA to cover any costs incurred during the term of the CRADA in undertaking the work set forth in the RP. 

  

					
	 	 	Page 3 of 11	 	CONFIDENTIAL

	5.2	Accounting Records. PHS shall maintain separate and distinct current accounts, records, and other evidence supporting all its obligations under this CRADA. and shall provide
the Collaborator a final fiscal report pursuant to Article 4.2. 

  

	5.3	Capital Equipment. Equipment purchased by PHS with funds provided by the Collaborator shall be the property of PHS. All capital equipment provided under this CRADA by one
party for the use of another Party remains the property of the providing Party unless other disposition is mutually agreed upon by in writing by the Parties. If title to this equipment remains with the providing Party, that Party is responsible for
maintenance of the equipment and the costs of its transportation to and from the site where it will be used. 

  
 Article 6. Patent Applications 
  

	6.1	Reporting. The Parties shall promptly report to each other in writing each Subject Invention and any patent applications filed thereon resulting from the research conducted
under this CRADA that is reported to them by their respective employees. Each Party shall report all Subject Inventions to the other Party in sufficient detail to determine inventorship. Such reports shall be treated as Proprietary/Confidential
Information in accordance with Article 8.4. 

  

	6.2	Filing of Patent Applications. Each party shall be responsible for filing patent or other IP applications in a timely manner and at its own expense and after consultation
with the other Party. The Parties will consult and mutually determine a filing strategy for jointly-owned subject inventions. 

  

	6.3	Patent Expenses. The expenses attendant to the filing of patent or other IP applications generally shall be paid by the Parly filing such application. If an exclusive license
to any Subject Invention is granted to the Collaborator, the Collaborator shall be responsible for all past and future out-of-pocket expenses in connection with the preparation, filing, prosecution and maintenance of any applications claiming such
exclusively-licensed inventions and any patents or other IP grants that may issue on such applications. The Collaborator may waive its exclusive license rights on any application, patent or other IP grant at any time, and incur no subsequent
compensation obligation for that application, patent or IP grant. 

  

	6.4	Prosecution of Intellectual Property Applications. Within one month of receipt or filing, each Party shall provide the other Party with copies of the applications and all
documents received from or filed with the relevant patent or other IP office in connection with the prosecution of such applications. Each Party shall also provide the other Party with the power to inspect and make copies of all documents retained
in the patent or other IP application files by the applicable patent or other IP office. Where licensing is contemplated by Collaborator, the Parties agree to consult with each other with respect to the prosecution of applications for PHS Subject
Inventions and joint Subject Inventions. If the Parties agree that Collaborator shall file and prosecute IP applications on joint Subject Inventions, then Collaborator agrees to grant PHS an associate power of attorney (or its equivalent) on such IP
applications. 

  
 Article 7. Licensing 
  

	7.1	 Option for Commercialization License. With respect to Government IP rights to any Subject Invention not made solely by the Collaborator’s employees for
which a patent or other IP application is filed, PHS hereby grants to the Collaborator an exclusive option to elect an exclusive or nonexclusive commercialization license, which is substantially in the form of the appropriate model PHS
license agreement. This option does not apply to Subject Inventions conceived prior to the effective date of this CRADA that are reduced to practice under this CRADA, if prior to that reduction to practice, PHS has 

  

					
	 	 	Page 4 of 11	 	CONFIDENTIAL

	 	 
filed a patent application on the invention and has licensed it or offered to license it to a third party. The terms of the license will fairly reflect the
nature of the invention, the relative contributions of the Parties to the invention and the CRADA, the risks incurred by the Collaborator and the costs of subsequent research and development needed to bring the invention to the marketplace. The
field of use of the license will be commensurate with the scope of the RP. 

  

	7.2	Exercise of License Option. The option of Article 7.1 must be exercised by written notice mailed within three (3) months after either (I) Collaborator receives written notice from
PHS that the patent or other IP application has been filed; or (ii) the date Collaborator files such IP application. Exercise of this option by the Collaborator initiates a negotiation period that expires nine (9) months after the exercise of the
option. If the last proposal by the Collaborator has not been responded to in writing by PHS within this nine (9) month period, the negotiation period shall be extended to expire one (1) month after PHS so responds, during which month the
Collaborator may accept in writing the final license proposal of PHS. In the absence of such acceptance, or an extension of the time limits by PHS, PHS will be free to license such IP rights to others. In the event that the Collaborator elects the
option for an exclusive license, but no such license is executed during the negotiation period, PHS agrees not to make an offer for an exclusive license on more favorable terms to a third party for a period of six (6) months without first offering
Collaborator those more favorable terms. These times may be extended at the sole discretion of PHS upon good cause shown in writing by the Collaborator. 

  

	7.3	License for PHS Employee Inventions and Joint Inventions. Pursuant to 15 U.S.C.’ 3710a(b)(l)(A), for Subject Inventions made under this CRADA by a PHS employee(s) or jointly by
such employee(s) and employees of the Collaborator and licensed pursuant to the option of Article 7.1, the Collaborator grants to the Government a nonexclusive, nontransferable, irrevocable, paid-up license to practice the invention or have the
invention practiced throughout the world by or on behalf of the Government. In the exercise of such license, the Government shall not publicly disclose trade secrets or commercial or financial information that is privileged or confidential within
the meaning of 5 U.S.C. 552(b)(4) or which would be considered as such if it had been obtained from a non-Federal party. 

  

	7.4	License in Collaborator Inventions. Pursuant to 15 U.S.C.’ 3710a(b)(2), for inventions made solely by Collaborator employees under this CRADA, the Collaborator grants to the
Government a nonexclusive, nontransferable, irrevocable, paid-up license to practice the invention or have the invention practiced throughout the world by or on behalf of the Government for research or other Government purposes.

  

	7.5	Third Party License. Pursuant to 15 U.S.C.’ 3710a(b)(l)(B), if PHS grants an exclusive license to a Subject Invention made wholly by PHS employees or jointly with a
Collaborator under this CRADA, the Government shall retain the right to require the Collaborator to grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense to use the invention in Collaborator=s licensed field
of use on terms that are reasonable under the circumstances; or if the Collaborator fails to grant such a license, to grant the license itself. The exercise of such rights by the Government shall only be in exceptional circumstances and only if the
Government determines (I) the action is necessary to meet health or safety needs that are not reasonably satisfied by Collaborator, (ii) the action is necessary to meet requirements for public use specified by Federal regulations, and such
requirements are not reasonably satisfied by the Collaborator; or (iii) the Collaborator has failed to comply with an agreement containing provisions described in 15 U.S.C. 3710a(c)(4)(B). The determination made by the Government under this Article
is subject to administrative appeal and judicial review under 35 U.S.C. 203(2). 

  

	7.6	 Joint Inventions Not Exclusively Licensed. In the event that the Collaborator does not acquire an exclusive commercialization license to IP rights in all fields in
joint Subject Inventions then each Party 

  

					
	 	 	Page 5 of 11	 	CONFIDENTIAL

	 	 
shall have the right to use the joint Subject Invention and to license its use to others in all fields not exclusively licensed to Collaborator. The Parties
may agree to a joint licensing approach for such IP rights. 

  
 Article 8. Proprietary Rights and Publication 
  

	8.1	Right of Access. PHS and the Collaborator agree to exchange all Subject Data produced in the course of research under this CRADA. Research Materials will be shared equally by
the Parties to the CRADA unless other disposition is agreed to by the Parties. All Parties to this CRADA will be free to utilize Subject Data and Research Materials for their own purposes, consistent with their obligations under this CRADA.

  

	8.2	Ownership of Subject Data and Research Materials. Subject to the sharing requirements of Paragraph 8.1 and the regulatory filing requirements of Paragraph 8.3, the producing
Party will retain ownership of and title to all Subject Inventions, all Subject Data and all Research Materials produced solely by their investigators. Jointly developed Subject Inventions, Subject Data and Research Materials will be jointly owned.

  

	8.3	Dissemination of Subject Data and Research Materials. To the extent permitted by law, the Collaborator and PHS agree to use reasonable efforts to keep Subject Data and
Research Materials confidential until published or until corresponding patent applications are filed. Any information that would identify human subjects of research or patients will always be maintained confidentially. To the extent permitted by
law, the Collaborator shall have the exclusive right to use any and all CRADA Subject Data in and for any regulatory filing by or on behalf of Collaborator, except that PHS shall have the exclusive right to use Subject Data for that purpose, and
authorize others to do so, if the CRADA is terminated or if Collaborator abandons its commercialization efforts. Collaborator acknowledges the basic research mission of the PHS, and agrees that after publication, PHS may make unpatented research
materials arising out of this CRADA available to third parties for further research. 

  

	8.4	Proprietary/Confidential Information. Each Party agrees to limit its disclosure of Proprietary/Confidential Information to the amount necessary to carry out the Research Plan
of this CRADA, and shall place a confidentiality notice on all such information. Confidential oral communications shall be reduced to writing within 30 days by the disclosing Party. Each Party receiving Proprietary/Confidential Information agrees
that any information so designated shall be used by it only for the purposes described in the attached Research Plan. Any Party may object to the designation of information as Proprietary/Confidential Information by another Party. Subject Data and
Research Materials developed solely by the Collaborator may be designated as Proprietary/Confidential Information when they are wholly separable from the Subject Data and Research Materials developed jointly with PHS investigators, and advance
designation of such data and material categories is set forth in the RP. The exchange of other confidential information, e.g., patient-identifying data, should be similarly limited and treated. Jointly developed Subject Data and Research Material
derived from the Research Plan may be disclosed by Collaborator to a third party under a confidentiality agreement for the purpose of possible sublicensing pursuant to the Licensing Agreement and subject to Article 8.7. 

  

	8.5	 Protection of Proprietary/Confidential Information. Proprietary/Confidential Information shall not be disclosed, copied, reproduced or otherwise made
available to any other person or entity without the consent of the owning Party except as required under court order or the Freedom of Information Act (5 U.S.C. ‘ 552). Each Party agrees to use its best efforts to maintain the
confidentiality of Proprietary/Confidential Information. Each Party agrees that the other Party is not liable for the disclosure of Proprietary/Confidential Information which, after notice to and consultation with the concerned Party, the 

  

					
	 	 	Page 6 of 11	 	CONFIDENTIAL

	 	 
other Party in possession of the Proprietary/Confidential Information determines may not be lawfully withheld, provided the concerned Party has been given an
opportunity to seek a court order to enjoin disclosure. 

  

	8.6	Duration of Confidentiality Obligation. The obligation to maintain the confidentiality of Proprietary/Confidential Information shall expire at the earlier of the date when
the information is no longer Proprietary Information as defined in Article 2.7 or three (3) years after the expiration or termination date of this CRADA. The Collaborator may request an extension to this term when necessary to protect
Proprietary/Confidential Information relating to products not yet commercialized. 

  

	8.7	Publication. The Parties are encouraged to make publicly available the results of their research. Before either Party submits a paper or abstract for publication or otherwise
intends to publicly disclose information about a Subject Invention, Subject Data or Research Materials, the other Party shall be provided thirty (30) days to review the proposed publication or disclosure to assure that Proprietary/Confidential
Information is protected. The publication or other disclosure shall be delayed for up to thirty (30) additional days upon written request by any Party as necessary to preserve U.S. or foreign patent or other IP rights. 

  
 Article 9. Representations and Warranties 
  

	9.1	Representations and Warranties of PHS. PHS hereby represents and warrants to the Collaborator that the official signing this CRADA has authority to do so.

  

	9.2	Representations and Warranties of the Collaborator. 

  
 (a) The Collaborator hereby represents and warrants to PHS that the Collaborator has the requisite power and authority to enter into this CRADA and to
perform according to its terms, and that the Collaborator’s official signing this CRADA has authority to do so. The Collaborator further represents that it is financially able to satisfy any funding commitments made in Appendix B. 

 
 (b) The Collaborator certifies that the statements herein are true,
complete, and accurate to the best of its knowledge. The Collaborator is aware that any false, fictitious, or fraudulent statements or claims may subject it to criminal, civil, or administrative penalties. 
  
 Article 10. Termination 
  

	10.1	Termination By Mutual Consent. PHS and the Collaborator may terminate this CRADA, or portions thereof, at any time by mutual written consent. In such event the Parties shall
specify the disposition of all property, inventions, patent or other IP applications and other results of work accomplished or in progress, arising from or performed under this CRADA, all in accordance with the rights granted to the Parties under
the terms of this Agreement. 

  

	10.2	Unilateral Termination. Either PHS or the Collaborator may unilaterally terminate this entire CRADA at any time by giving written notice at least thirty (30) days prior to
the desired termination date, and any rights accrued in property, patents or other IP rights shall be disposed of as provided in paragraph 10.1, except that PHS may, at its option, retain funds transferred to PHS prior to unilateral termination by
Collaborator for use in completing the Research Plan solely or with another partner. 

  

					
	 	 	Page 7 of 11	 	CONFIDENTIAL

	10.3	Staffing. If this CRADA is mutually or unilaterally terminated prior to its expiration, funds will nevertheless remain available to PHS for continuing any staffing commitment
made by the Collaborator pursuant to Article 5.1 above and Appendix B, if applicable, for a period of six (6) months after such termination. If there are insufficient funds to cover this expense, the Collaborator agrees to pay the difference.

  

	10.4	New Commitments. No Party shall make new commitments related to this CRADA after a mutual termination or notice of a unilateral termination and shall, to the extent
feasible, cancel all outstanding commitments and contracts by the termination date. 

  

	10.5	Termination Costs. Concurrently with the exchange of final reports pursuant to Articles 4.2 and 5.2, PHS shall submit to the Collaborator for payment a statement of all costs
incurred prior to the date of termination and for all reasonable termination costs including the cost of returning Collaborator property or removal of abandoned property, for which Collaborator shall be responsible. 

  
 Article 11. Disputes 
  

	11.1	Settlement. Any dispute arising under this CRADA which is not disposed of by agreement of the Principal Investigators shall be submitted jointly to the signatories of this
CRADA. If the signatories are unable to jointly resolve the dispute within thirty (30) days after notification thereof, the Assistant Secretary for Health (or his/her designee or successor) shall propose a resolution. Nothing in this Article shall
prevent any Party from pursuing any additional administrative remedies that may be available and, after exhaustion of such administrative remedies, pursuing all available judicial remedies. 

  

	11.2	Continuation of Work. Pending the resolution of any dispute or claim pursuant to this Article, the Parties agree that performance of all obligations shall be pursued
diligently in accordance with the direction of the PHS signatory. 

  
 Article 12. Liability 
  

	12.1	Property. The U.S. Government shall not be responsible for damages to any Collaborator property provided to PHS, where Collaborator retains title to the property, or any
property acquired by Collaborator for its own use pursuant to this CRADA. 

  

	12.2	NO WARRANTIES. EXCEPT AS SPECIFICALLY STATED IN ARTICLE 9, THE PARTIES MAKE NO EXPRESS OR IMPLIED WARRANTY AS TO ANY MATTER WHATSOEVER, INCLUDING THE CONDITIONS OF THE
RESEARCH OR ANY INVENTION OR PRODUCT, WHETHER TANGIBLE OR INTANGIBLE, MADE, OR DEVELOPED UNDER THIS CRADA, OR THE OWNERSHIP, MERCHANTABILITY, OR FITNESS FOR A PARTICULAR PURPOSE OF THE RESEARCH OR ANY INVENTION OR PRODUCT. 

 

	12.3	Indemnification. The Collaborator agrees to hold the U.S. Government harmless and to indemnify the Government for all liabilities, demands, damages, expenses and losses
arising out of the use by the Collaborator for any purpose of the Subject Data, Research Materials and/or Subject Inventions produced in whole or part by PHS employees under this CRADA, unless due to the negligence or willful misconduct of PHS, its
employees, or agents. The Collaborator shall be liable for any claims or damages it incurs in connection with this CRADA. PHS has no authority to indemnify the Collaborator. 

  

					
	 	 	Page 8 of 11	 	CONFIDENTIAL

	12.4	Force Majeure. Neither Party shall be liable for any unforeseeable event beyond its reasonable control not caused by the fault or negligence of such Party, which causes such
Party to be unable to perform its obligations under this CRADA, and which it has been unable to overcome by the exercise of due diligence. In the event of the occurrence of such a force majeure event, the Party unable to perform shall
promptly notify the other Party. It shall further use its best efforts to resume performance as quickly as possible and shall suspend performance only for such period of time as is necessary as a result of the force majeure event.

  
 Article 13. Miscellaneous 
  

	13.1	Governing Law. The construction, validity, performance and effect of this CRADA shall be governed by Federal law, as applied by the Federal Courts in the District of
Columbia. Federal law and regulations will preempt any conflicting or inconsistent provisions in this CRADA. 

  

	13.2	Entire Agreement. This CRADA constitutes the entire agreement between the Parties concerning the subject matter of this CRADA and supersedes any prior understanding or
written or oral agreement. 

  

	13.3	Headings. Titles and headings of the articles and subarticles of this CRADA are for convenient reference only, do not form a part of this CRADA, and shall in no way affect
its interpretation. The PHS component that is the Party for all purposes of this CRADA is the Bureau(s), Institute(s), Center(s) or Division(s) listed on the Cover Page herein. 

  

	13.4	Waivers. None of the provisions of this CRADA shall be considered waived by any Party unless such waiver is given in writing to the other Party. The failure of a Party to
insist upon strict performance of any of the terms and conditions hereof, or failure or delay to exercise any rights provided herein or by law, shall not be deemed a waiver of any rights of any Party. 

  

	13.5	Severability. The illegality or invalidity of any provisions of this CRADA shall not impair, affect, or invalidate the other provisions of this CRADA.

  

	13.6	Amendments. If either Party desires a modification to this CRADA, the Parties shall, upon reasonable notice of the proposed modification or extension by the Party desiring
the change, confer in good faith to determine the desirability of such modification or extension. Such modification shall not be effective until a written amendment is signed by the signatories to this CRADA or by their representatives duly
authorized to execute such amendment. 

  

	13.7	Assignment. Neither this CRADA nor any rights or obligations of any Party hereunder shall be assigned or otherwise transferred by either Party without the prior written
consent of the other Party. 

  

	13.8	Notices. All notices pertaining to or required by this CRADA shall be in writing and shall be signed by an authorized representative and shall be delivered by hand or sent by
certified mail, return receipt requested, with postage prepaid, to the addresses indicated on the signature page for each Party. Notices regarding the exercise of license options shall be made pursuant to Article 7.2. Any Party may change such
address by notice given to the other Party in the manner set forth above. 

  

	13.9	Independent Contractors. The relationship of the Parties to this CRADA is that of independent contractors and not agents of each other or joint venturers or partners. Each
Party shall maintain sole and exclusive control over its personnel and operations. Collaborator employees who will be working at PHS facilities may be asked to sign a Guest Researcher or Special Volunteer Agreement appropriately modified in view of
the terms of this CRADA. 

  

					
	 	 	Page 9 of 11	 	CONFIDENTIAL

	13.10 	Use of Name or Endorsements. By entering into this CRADA. PHS does not directly or indirectly endorse any product or service provided, or to be provided, whether directly or
indirectly related to either this CRADA or to any patent or other IP license or agreement which implements this CRADA by its successors, assignees, or licensees. The Collaborator shall not in any way state or imply that this CRADA is an endorsement
of any such product or service by the U.S. Government or any of its organizational units or employees. Collaborator issued press releases that reference or rely upon the work of PHS under this CRADA shall be made available to PHS at least 7 days
prior to publication for review and comment. 

  

	13.11 	Exceptions to this CRADA. Any exceptions or modifications to this CRADA that are agreed to by the Panics prior to their execution of this CRADA are set forth in Appendix
C. 

  

	13.12 	Reasonable Consent. Whenever a Party’s consent or permission is required under this CRADA, such consent or permission shall not be unreasonably withheld.

  
 Article 14. Duration of Agreement 
  

	14.1	Duration. It is mutually recognized that the duration of this project cannot be rigidly defined in advance, and that the contemplated time periods for various phases of the
RP are only good faith guidelines subject to adjustment by mutual agreement to fit circumstances as the RP proceeds. In no case will the term of this CRADA extend beyond the term indicated in the RP unless it is revised in accordance with Article
13.6. 

  

	14.2	Survivability. The provisions of Articles 4.2, 5-8, 10.3-10.5, 11.1, 12.2-12.4, 13.1, 13.10 and 14.2 shall survive the termination of this CRADA. 

  
 SIGNATURES BEGIN ON THE NEXT PAGE 
  

					
	 	 	Page 10 of 11	 	CONFIDENTIAL

					
	 FOR PHS:
	 	 	 	 
			
	 /s/ Alan Ralsor
	 	 	 	 8/30/01

	 Alan Ralsor, M.D.
	 	 	 	 Date

	 Deputy Director, NCI
	 	 	 	 

  
 Mailing Address for Notices:

  
 National Cancer Institute-Frederick 
 Technology Transfer Branch 
 1003 West Seventh Street, Suite 502 

Frederick MD 21701 
 Phone: 301-846-5465 
 FAX: 301-846-6820 
  

					
	 FOR THE COLLABORATOR:
	 	 	 	 
			
	 /s/ Christopher Kyriakides
	 	 	 	  
	 	 	 	 	 Date

	 	 	 	 

  
 Mailing Address for Notices:

  
 Biovest International, Inc. 
 8500 Evergreen Boulevard 
 Minneapolis MN 55433 
 763-786-0302 
 763-786-0915 
  

					
	 	 	Page 11 of 11	 	CONFIDENTIAL

 APPENDIX A 
  

RESEARCH PLAN 
  
 Clinical Development of Hybridoma-Based Idiotypic Vaccines for 
 Treatment of Follicular B-Cell Lymphoma 
  
 NCI Principal Investigator(s) 
 Barry L. Gause, M.D. 
 Center for Cancer Research (CCR) 
 National Cancer Institute (NCI) 
  
 Collaborator Principal Investigator(s) 
 Stephane E. Allard, M.D. 
 Medical Director

 Biovest International, Inc. 
  
 Term of CRADA 
 Eight (8) years from the date of
the final CRADA signature. 
  
 A Letter of Intent (LOI) for this
CRADA was executed 
 by and between the Parties on January 9, 2001. 
 An Extension to the LOI was executed by and between 
 the Parties on June 25, 2001

  

	
	CONFIDENTIAL
	A - 1

 GOALS OF THIS CRADA 
  
 The goal of this project is to develop an efficacious hybridoma-based idiotype vaccine to produce long-term disease-free survival in follicular B-cell lymphoma patients
who have attained a complete clinical response from chemotherapy and to compile data required to support a Biological License Application (BLA) to the U.S. Food and Drug Administration (FDA) for hybridoma-based idiotype follicular B-cell lymphoma
vaccine. 
  
 The Center for Cancer Research (CCR), National Cancer Institute (NCI)
and Collaborator shall work together toward the successful development of the hybridoma-based idiotype vaccine as a safe and effective novel anti-cancer treatment for follicular B-cell lymphoma. The CCR will work closely with Collaborator to obtain
and evaluate the clinical data that may be required to allow Collaborator to obtain regulatory approval by the FDA. Collaborator will provide expertise in the development, formulation and Good Manufacturing Practice (GMP) production of the vaccine.
Additionally, CCR will work with Collaborator in the ongoing clinical trial planned under this CRADA as well as all regulatory aspects and the BLA filings necessary for Collaborator to obtain marketing approval. 
  
 The scope of this CRADA includes the development of the processes required for large-scale
GMP production of adequate numbers of GMP-produced and formulated idiotype vaccines to complete the clinical development of this treatment for follicular B-Cell lymphoma. This vaccine strategy involves the use of an immunological adjuvant,
granulocyte-macrophage colony-stimulating factor (GM-CSF), which is being provided for this study under an agreement between Biovest and Immunex/Berlex. 
  
 BACKGROUND 
  
 INTRODUCTION 
  
 Current Treatment of Indolent Follicular Lymphomas 
  
 The indolent follicular lymphomas (FL) are follicular small-cleaved cell (FSC) and follicular mixed lymphoma (FM). Stage I and II patients comprise only 10% to 15% of all cases of follicular lymphomas and are best
managed with radiation therapy. Eighty-five percent of patients with follicular lymphomas present with stage III or IV disease. The optimal management of these patients remains controversial and has generally followed two divergent approaches (1,
2). An aggressive approach, which has included radiation therapy, combination chemotherapy, or combined modality therapy; and a conservative approach that involves no initial treatment followed by a single-agent chemotherapy or involved-field
radiotherapy when required (3, 4). Most forms of systemic therapy have the capacity to produce high complete response rates. However, they have failed to produce long-term disease-free survival or to prolong overall survival; thus, it has become
clear that the vast majority of patients with this disease will relapse and die of their lymphoma, despite its usually indolent course. 
  
 Technology Summary 
  
 The development of a vaccine against human malignancies has been a long-sought goal, which has yet to be achieved. Many of the efforts toward this end have been
frustrated by the lack of identification of a tumor-specific antigen which would allow tumor cells to be distinguished from normal cells. Conceptually, such an antigen could be used as a vaccine to induce the host’s immune system to reject
cells bearing that antigen. 
  

	
	CONFIDENTIAL
	A - 2

 Immunoglobulin (Ig) molecules are composed of heavy and light chains, which possess highly specific variable regions at
their amino termini. The variable regions of heavy and light chains combine to form the unique antigen-recognition site of the Ig protein. These variable regions contain determinants that can themselves be recognized as antigens, or
idiotypes. B-cell malignancies are composed of clonal proliferations of cells synthesizing a single antibody molecule with unique variable regions in the heavy and light chains. B-cell lymphomas are neoplasms of mature resting and reactive
lymphocytes, which generally express synthesized Ig on the cell surface. The idiotypic determinants of the surface Ig of a B-cell lymphoma can thus serve as a tumor-specific marker for the malignant clone. 
  
 Studies in experimental animals, as well as in man, have demonstrated the utility of the Ig
idiotype as a tumor-specific antigen (5, 6). Lynch and Eisen were the first to demonstrate that active immunization against idiotypic determinants on malignant B cells could produce resistance to tumor growth, and this phenomenon of idiotype tumor
resistance has been reproduced subsequently in a number of syngeneic experimental tumor models, as well as specific anti-tumor therapy against established tumors (7-16). These results, taken together, provided the rationale for testing autologous
tumor-derived idiotypic surface Ig (Id) as a therapeutic “vaccine” against human B-cell lymphoma. 
  
 Summary of Previous Clinical Studies Sponsored by NCI 
  
 Phase 1 Clinical Trial. 
  
 Kwak et al. first immunized human patients with B-cell lymphoma with autologous Id protein (17). The Id-keyhole limpet hemocyanin (Id-KLH) was emulsified
in a Pluronic polymer-based adjuvant vehicle formulation. Ultimately, approximately 40 patients were treated on this protocol. Because the study population was heterogeneous, it was not designed to answer the question of anti-tumor efficacy. Rather,
this first study assessed the question of immunogenicity; i.e., is it even possible to immunize a patient against a self-tumor antigen? In this context, this study was important, because it demonstrated that patients with B-cell lymphoma could be
induced to make primarily idiotype-specific antibody responses, but with little evidence for T-cell immunity. 
  
 Improving the potency of the Id-KLH Vaccine. 
  
 At the NCI, the objective of Id vaccine development has been to further optimize the immunogenicity of this vaccine. To this end, NCI focused on the use
of novel immunological adjuvants, which were 1), more potent and 2) more effective in the induction of cell-mediated immune responses, particularly CD8+ T-cells, compared with the pluronic polymer-based adjuvant used in the pilot study. 

 
 As a preclinical aim, Kwak et al. utilized a murine B cell tumor as a
model system in which to screen promising immunological adjuvants. A number of these included cytokines, and among these, GM-CSF emerged as a promising adjuvant for idiotypic Ig antigen (18). 
  
 The results demonstrated that the augmented survival benefit afforded by
immunization with relevant Id-KLH alone could be significantly enhanced by the addition of GM-CSF at either the 100 or 10,000 unit dose. A curious but reproducible observation was the loss of this protective effect at a higher dose of GM-CSF of
50,000 units. These data suggest that GM-CSF may have a 

  

	
	CONFIDENTIAL
	A - 3

 
potent adjuvant effect in vivo for Id-KLH antigen, especially at relatively low doses. Furthermore, T-cell subset depletion experiments demonstrated
that effector CD8+ T-cells were required for anti-tumor immunity. 
  
 Phase 2 Clinical Trial. 
  
 Based on the findings
of this preclinical study, the NCI sponsored a Phase 2 clinical study to evaluate the ability of this new idiotype vaccine to elicit tumor-specific T-cell immunity, as measured by the ability of patient T cells to specifically lyse their own tumor
cells in vitro, and to exert antitumor effects as measured by the elimination of t(14;18)-bearing cells from the peripheral blood of uniformly treated FL patients in first CR (complete remission). Patients in this study were previously
untreated and received a uniform chemotherapy regimen, PACE; Prednisone, Adriamycin, Cytoxan, and Etoposide. (modified ProMACE without methotrexate). By design, therefore, they comprised a very homogeneous patient
population in a minimal residual disease state. Of 35 patients, 23 (66%) achieved CR by standard clinical criteria. One of the patients was lost to analysis because of early relapse within six months, and two were excluded because a vaccine could
not be made. This left a total study group of 20 patients in CR. Six to 15 months after completion of chemotherapy, these 20 patients were treated with a series of five monthly vaccinations with autologous FL Ig protein (0.5 mg) conjugated to KLH,
together with local granulocyte-macrophage colony-stimulating factor (GM-CSF, 100 or 500 mcg/m2) subcutaneously (19). 
  
 Eighteen of 20 patients remain in continuous, first complete remission (median: 42+ months from completion of chemotherapy, range: 28+ to 53+). UPN 9 and
14 relapsed at 15 and 7 months after completion of vaccine therapy, respectively. UPN 9 had never cleared the t(14;18)-bearing cells from the peripheral blood; UPN 14 did not have the MBR rearrangement and thus, molecular CR status could not be
established. 
  
 The rationale for a pivotal, randomized trial,
which is the subject of this CRADA is thus based on three independent results from this completed Phase 2 study: (1) tumor-specific CD8+ T-cell responses (cytotoxicity against autologous FL targets and cytokine production) were seen in 17 of 20
(85%) vaccinated patients, (2) 8 of 11 (73%) patients sampled after completion of vaccination converted to PCR negative and have maintained both PCR negativity and clinical CR, and (3) with a median follow-up of 36+ months after completion of
chemotherapy (range 22+ to 47+ months), 18 of 20 (90%) patients remain in continuous clinical CR. 
  
 Taken together, these data suggest that idiotype vaccination can elicit a tumor-specific response that is associated with clearance of residual tumor
cells from the blood in the majority of patients with FL. It remains to be determined whether molecular CR is associated with prolonged disease-free survival. However, this systematic analysis of molecular response rate provides the first evidence
for an anti-tumor effect of vaccination. Finally, this study established GM-CSF as an essential component of the vaccine strategy, particularly for induction of CD8+ T-cell responses. 
  
 CCR, NCI 
  
 Dr. Kwak and his group pioneered the first human studies of vaccines for B-cell malignancies. Dr Kwak’s group has a broad range of scientific and clinical interests
spanning tumor immunology, adoptive T cell therapy, and management of lymphomas and myelomas. 
  

	
	CONFIDENTIAL
	A - 4

 Specific work in his laboratory is focused on studies of immunobiology and immunotherapy of hematological malignancies.
The laboratory’s principal objective is to obtain conclusive proof for the cancer vaccine concept; i.e., simply that it is possible to induce an immune response against a self protein, which is inherently poorly immunogenic, in human cancer
patients. The goals for vaccine development are: (1) to increase the potency of vaccine formulations, and (2) to develop formulations which are more effective in activating the cellular arm of the immune response. The working hypothesis is that
achieving the eventual goal of demonstrating clinical efficacy will depend on the ability of vaccines to elicit sustained, potent cell-mediated responses. 
  
 The current clinical trial of Id vaccination in previously untreated patients with follicular lymphomas initiated by the laboratory, which is the subject of this CRADA,
features a new formulation of the prototype Id-KLH conjugate vaccine using GM-CSF as a potent immunological adjuvant. CD8+ T cell responses, capable of lysing autologous tumor targets, and molecular remissions have been observed in the vast majority
of vaccinated patients. 
  
 BIOVEST INTERNATIONAL INC.

  
 INTRODUCTION 
  
 The proprietary technology of Biovest (hollow fiber bioreactor instrumentation) that will be
applied under this CRADA utilizes a patented process that optimizes fluid flow dynamics within perfused bioreactors to maintain high cell densities and continuously harvest secreted protein for extended periods of time. An experienced team of
mechanical, electrical, software and biochemical engineers was established at Biovest to develop this technology. As a result of these efforts, the company gained significant expertise in the large-scale application of cGMP mammalian cell culture,
which has subsequently been applied to a wide variety of cell lines for hollow fiber bioreactor production of recombinant or fusion based proteins. Combined with this existing expertise, a cGMP process will be developed that will be designed to
facilitate commercial application of patient-specific vaccines. 
  
 Biovest’s
cell culture expertise was recognized when the National Center for Research Resources, NIH, awarded the National Cell Culture Center to Biovest. This research resource facility was awarded to Biovest in 1990 through a competitive five-year
Cooperative Agreement Award, which has been renewed twice, currently funded through September 2005. This resource was created to provide the biomedical research community with subsidized access to professional large-scale cell culture services.
During that time, Biovest has received hundreds of cell lines from academic investigators within many major research institutions in the United States, for the purpose of large-scale production. The majority of these lines are hybridoma, transfected
or chimeric lines, created for the production of immunoglobulin. 
  
 In addition,
for the past ten years, Biovest has provided contract services to biotechnology and pharmaceutical companies for use in clinical (cGMP) applications, produced in isolation suites within Biovest’s manufacturing facility. For the vast majority of
these cell lines, automated hollow fiber bioreactor instrumentation is utilized for protein production. Biovest instrumentation, combined with years of process development experience for high-cell density perfusion culture, is one principal
advantage of Biovest’s contract laboratory. This ability to modify hardware and understand the biochemical aspects of high-density culture has allowed us to develop successfully many processes unique to large-scale culture, which are typically
incorporated into cGMP manufacture of the final 

  

	
	CONFIDENTIAL
	A - 5

 
product. Currently, a documentation system exists that addresses cGMP production requirements for numerous specialized cell lines and processes with hollow
fiber bioreactor technology in a multi-use facility. 
  
 Similar to cGMP cell
culture procedures, the existing instrumentation was developed as a Class I medical device, suitable for clinical application. This experience will be an important asset to the development and large-scale manufacture of instrumentation that can be
applied to vaccine production. 
  
 Biovest International, Inc. (formerly Cellex
Biosciences) is a leading manufacturer of hollow fiber bioreactor instrumentation and contract production services worldwide. In 1984, the corporation began development of instrumentation that automated the culture of mammalian cells on a large
scale. Subsequently, the company utilized this hollow fiber bioreactor technology to create a cGMP production process that accommodates economic production of large amounts of specific cell-secreted protein (e.g. monoclonal antibodies) from numerous
cell lines within one facility. During the past two decades, Biovest has developed a range of hollow fiber bioreactor instruments to address production at the research level through large-scale pharmaceutical needs. This patented technology is now
widely accepted by numerous biotechnology and pharmaceutical companies throughout the world. As a result, Biovest, with perfusion cell culture methodology (hollow fiber bioreactor), offers a well-defined cGMP approach to large-scale commercial
production of clinical and pharmaceutical grade proteins. 
  
 In December 1999,
Biovest was awarded a contract with NCI to produce idiotype (antibody) as crude supernatant from heteromyeloma patient cell lines, created in Dr. Kwak’s laboratory. This idiotype was subsequently used to create the Id-keyhole limpet hemocyanin
(Id-KLH) lymphoma vaccine for study in an ongoing Phase 3 clinical trial, which is the subject of this CRADA. Creation of this vaccine is extremely labor intensive and Biovest, along with Dr. Kwak, recognized that commercial application would
ultimately be dependent on research and development of a simplified or automated process. As such, Biovest responded to an NCI CRADA announcement and proposed a collaboration toward this end. Biovest will leverage its cell culture, purification, and
clinical instrument expertise to facilitate production and commercialization of the idiotype tumor vaccine for B-cell lymphoma. Under the CRADA, a process and accompanying automated technology will be designed to produce and purify idiotype from
each patient-specific cell line, both rapidly and cost effectively in a cGMP environment. Biovest recognizes that this patient-specific approach is dependent on technology designed to address these needs. Unlike conventional biologicals or drugs,
which benefit from mass production or economy of scale, this new technology will be designed with the aim of allowing thousands of patient-specific vaccines to be manufactured efficiently each year. 
  
 Work Under this CRADA: The Phase 3 Clinical Trial. 
  
 To definitively answer the question of clinical efficacy, the NCI opened a
multi-institutional, controlled, randomized Phase 3 clinical trial in January 2000 under the auspices of the NCI Vaccine Working Group and with support from the Office of the Director. Given the fact that no cancer vaccine has been licensed for use
in the United States, designing this trial as a scientifically rigorous test of the cancer vaccine hypothesis, with scientific proof of principle as the primary objective, was felt to be paramount. Therefore, no changes in the key variables were (or
will be) considered. Specifically, the design of the study remains identical to that of the Phase 2 study. Specifically, only patients with previously untreated lymphoma of follicular types are eligible, all patients receive uniform PACE
chemotherapy, and vaccination is therefore administered to a homogeneous group of patients in first complete remission. Importantly, the vaccine formulation is also identical to that used in the Phase 2 trial, using the same 

  

	
	CONFIDENTIAL
	A - 6

 
hybridoma fusion technology to generate the vaccine, and using the same dose, schedule, and route of vaccine administration. A multi-center consortium of
clinical sites has been assembled, including Northwestern University, University of Pennsylvania, Duke University, Moffitt Cancer Center, and the NIH Clinical Center with additional sites under consideration. 
  
 The trial is anticipated to enroll a total of 563 patients, approximately 2/3 of whom are
expected to achieve a clinical complete remission from PACE chemotherapy. Patients achieving a complete remission are randomized to begin treatment with either a specific vaccine consisting of Id-KLH + GM-CSF, or non-specific vaccine consisting of
KLH + GM-CSF, in a 2:1 ratio (in favor of specific vaccine) starting six months after completion of chemotherapy. 
  
 This trial anticipates accrual over five years, and because of the long natural history of follicular lymphoma, an additional three years of follow-up time is projected
to observe at least a 20% improvement in disease-free survival (study endpoint) for the experimental group. 
  
 The achievement of scientific proof of concept remains the primary objective of this Phase 3 trial. The addition of a CRADA partner will allow the data from this trial to be put together in support of a BLA with the
FDA, which is necessary to help bring this vaccine to market. Furthermore, the CRADA partner’s contribution of intellectual property will allow for development of an automated system for the practical production of a vaccine to be brought to
market and fulfill a currently unmet public health need. Finally, the addition of a corporate partner may make it possible to accelerate patient accrual in order to complete the trial and provide data necessary to support a BLA with the FDA in a
shorter period of time. 
  
 Production of Id
Vaccines. 
  
 Since Id is a clonal marker unique to each lymphoma,
vaccines must be produced on an individualized basis for each patient. The strategy used to isolate immunogloblin from the surfaces of human B-cell lymphomas consists of performing a hybridization between the lymphoma cell and a modified mouse/human
heteromyeloma cell that grows in vitro and that has the cellular machinery to synthesize and secrete large quantities of immunoglobulin. Such myeloma fusion partners have been engineered not to secrete any immunoglobulin of their own;
therefore, the immunoglobulin that is secreted following fusion is derived purely from the human tumor. 
  
 The production of Id protein begins with the isolation of malignant cells from tumor biopsy specimens, most commonly involved lymph nodes, although tumor cells isolated from peripheral blood, bone marrow or spleen can
be used. The minimal starting material consists of about 75 million tumor cells. These cells are then fused with a hypoxanthine-aminopterin-thymidine (HAT) – sensitive fusion partner, and hybridomas selected in HAT medium that secrete
immuoglobulin with the type of heavy and light chains corresponding to the known immunophenotype of the tumor specimen are identified. This is vaccine production process step 1. 
  
 Polymerase chain reaction (PCR) amplification of the immunoglobulin variable region genes
from both the hybridoma and the primary tumor specimen are performed, and the sequences are compared to establish the identify of the secreted immunoglobulin. This is vaccine production step 2. 
  
 Heterohybridomas identified in this way are expanded. This is vaccine production process
step 3. 
  
 Id protein is the purified from collected culture
supernatants by affinity chromatography depending on the 

  

	
	CONFIDENTIAL
	A - 7

 
isotype of the lymphoma immunoglobulin. Each idiotype protein is then conjugated to KLH. These two processes are collectively referred to as vaccine
production process step 4. 
  
 This Id-conjugate is then used to
immunize the patient from whose tumor it was originally isolated.Vaccine production process Steps 1-2 were performed in Dr. Kwak’s laboratory at NCI-Frederick until April 29, 2004. Effective April 29, 2004, Biovest International assumed
responsibility for vaccine production process steps 1-4. The technology for heterohybridoma fusion and selection and PCR sequencing will continue to be optimized for GMP production at Biovest International. As noted above, the ultimate goal of this
CRADA is to fully develop the technology allowing optimized Id vaccine production under GMP conditions that would be necessary for FDA approval for human clinical use. As part of that goal, NCI and Biovest will investigate the automation of this
stepwise production of Id vaccines using Biovest’s proprietary instrument. 
  
 Under optimal conditions, approximately three months are required for production of the final product. This time period does not constitute a limitation, as the vaccine administration occurs following six to eight months of cytoreduction
with conventional chemotherapy and an additional six month rest period. 
  
 Overall, the CRADA is an extension and combination of existing NCI and Biovest systems and procedures for cell culture, purification and clinical instrument development. NCI and Biovest staff will undertake the cell fusion, gene sequencing,
and purification/conjugation procedures. Combined with Biovest’s existing intellectual property and instrument manufacturing experience, these procedures will be incorporated into a single instrument that can be applied to production and
purification of personalized cancer vaccines in a clinical setting. It is envisioned that several principle steps required to create this vaccine can be incorporated into an affordable, user-friendly technology, designed specifically for commercial
production of this vaccine. 
  
 Ultimately, successful commercialization will
depend on the capability to service large numbers of patients economically. The autologous nature of this therapy places significant emphasis on creating an automated, yet individualized, manufacturing process for each patient. This
“personalized” approach precludes the efficiencies or economies of scale typically observed in commercial antibody production. It is estimated that a minimum of 15,000 patients (US only) per annum will seek vaccination. To realize that
number (200 to 300 per week), an efficient and affordable patient-specific Current Good Manufacturing Process (cGMP) is required. As such, an automated process for antibody production and purification becomes a key to the success of this approach.

  
 Biovest is committed to expanding its technological capabilities in parallel
with the first two years of the Phase 3 clinical trial. Based on past experience, this is a reasonable timeline and will allow for equivalency studies, initial validation testing, and instrument manufacture suitable for FDA approval. Biovest
laboratories also contain cGMP space, as well as build-out capacity, if required, that can be dedicated to commercialization efforts. Beyond that space, an additional 12,000 square feet of FDA validated cGMP space is available for production and
purification as the Phase 3 clinical trial expands. Biovest has utilized hollow fiber technology for over 3 years and successfully operated isolation suites that parallel the needs for personal vaccine production. 
  
 The goal is to transfer to Biovest the B-cell isolation techniques and the unique cell
fusion, molecular sequencing and conjugation expertise developed at NCI, and the transfer took place in June 2004. Biovest and NCI will work together to train skilled cellular immunologists and protein biochemists at Biovest, The ultimate
objective is to establish material duplication of these procedures in other 

  

	
	CONFIDENTIAL
	A - 8

 
laboratories. Based on 15,000 vaccinations per year (U.S.), the ability to set up at least one cGMP production facility for cell fusion, screening and
molecular sequencing is essential. This will be done in parallel with the ongoing Phase 3 clinical trial to expedite the commercialization process. 
  
 Enhancing Patient Accrual. 
  
 Additionally, Biovest intends to enhance patient accrual for the Phase 3 clinical trial by providing access to patients through the New York University (NYU) hospitals.
NCI and Biovest intend to further participate in patient accrual and shorten the time required to complete this study. 
  
 Further, Biovest will enhance national physician and patient awareness of this clinical trial by assuming responsibility for the marketing strategy. To do this, Biovest
is prepared to take several actions designed to increase patient accrual for the Phase 3 clinical trial. Biovest’s marketing firm has represented that these actions will include both direct and indirect promotional and marketing efforts.
Biovest’s promotional and marketing efforts related to and during the term of this CRADA will be reviewed and approved by NCI. It is anticipated that this promotional campaign will greatly accelerate patient accrual for this clinical trial.

  
 As set forth in the preceding sections, Biovest is equipped scientifically and
financially to collaborate with NCI to successfully perform all aspects of bringing this idiotype tumor vaccine through the final clinical trial and into commercial production. Because of their expertise in the field of hollow fiber perfusion
technology, they possess the necessary team of experienced engineers and scientific personnel to develop the cGMP process crucial to therapeutic application of this vaccine. It is anticipated that this vaccine production process will be complete and
a broadly accessible therapy prior to conclusion of this Phase 3 study. Associated with instrumentation, and following FDA approval, the hollow fiber bioreactor manufacturing will be implemented to fulfill the large number of anticipated vaccines.
The objective is to incorporate automated technology with cGMP production processes, such that this personalized approach to the treatment of lymphoma can be brought to market to answer an unmet public health need. 
  
 WORK SCOPE OF PROPOSED CRADA

  
 The scope of this CRADA includes the development of the processes
required for large-scale GMP production of adequate numbers of GMP-produced and formulated idiotype vaccines to complete the clinical development of this treatment for follicular B-Cell lymphoma. This vaccine strategy involves the use of an
immunological adjuvant, GM-CSF, which is being provided for this study under an agreement between Biovest and Immunex/Berlex. Such processes may include, but are not limited to refinement of GMP process and automation of the vaccine production.
 
  

	
	CONFIDENTIAL
	A - 9

 RESPECTIVE CONTRIBUTIONS OF THE PARTIES

  

	A.	Joint Responsibilities 

  

	1.	Steering Committee- Effective April 29, 2004, the Parties agree to establish a joint clinical development team whose responsibility will be the oversight of the ongoing Phase 3
Clinical Trials performed under the Collaborators IND related to this CRADA. The Steering Committee will comprise the following NCI staff: the Principal Investigator, the Project Officer for Vaccine Production, the Protocol Coordinator, the Protocol
Chairman, and the following Collaborator staff: Principal Investigator, and appropriate Collaborator staff in the areas of clinical monitoring, pharmacy, statistics, manufacturing and publicity. Although the members of the Steering Committee shall
be considered as having been delegated to the Steering Committee, they shall continue to remain employed by their respective employers under their respective terms of employment. 

  

	2.	Both parties to the CRADA will provide independent statistical expertise and work closely together to ensure that the CRADA clinical trial moves forward expeditiously. Activities
conducted in support of this obligation include providing public notice and promotion of the clinical trial to foster patient accrual. 

  

	3.	Both parties to the CRADA shall collaborate in the collection and analysis of data from the clinical trial. 

  

	4.	Both parties to the CRADA will evaluate the study as it progresses to ensure that the appropriate questions are being addressed and to ensure that the study is modified as required
based on the developing data. The DCTD will utilize its existing procedures and mechanisms to follow the clinical study to ensure that the study meets the pertinent FDA regulations until Biovest receives an approved IND for this technology.

  

	5.	Both parties to the CRADA will meet with the FDA jointly to discuss protocol and requirements necessary for the study to support a Biologic License Application with the FDA

  

	6.	Both parties to the CRADA will work closely together to develop processes for commercial cGMP production of Id-KLH follicular B-cell lymphoma vaccine with GM-CSF as adjuvant.

  

	B.	NCI Responsibilities 

  
 The National Cancer Institute contribution to the collaborative research and clinical development of Id-KLH indolent follicular lymphoma vaccine includes the following: 
  

	1.	Effective March 1, 2004, Dr. Barry Gause will serve as the NCI Principal Investigator for this CRADA. Authorship of publications concerning research performed under this CRADA shall
be in accordance with scientific customs and subject to the terms of Article 8. Proprietary Rights and Publication hereunder. 

  

	2.	Subject to the provisions of Articles 8.3 and 10.6 hereunder, the CCR will collaborate solely with Collaborator for development of Agent under Biovest’s Protocol #BV 301 and
NCI’s protocol #00-C-0050 (P-92). 

  

	
	CONFIDENTIAL
	A - 10

	3.	The CCR Data Safety and Monitoring Board will be responsible for reviewing, at least annually, the accumulated toxicity and efficacy data of Biovest Protocol #BV 301/ NCI protocol
#00-C-0050 (P-92) and providing a report summarizing its recommendations to Collaborator. 

  

	4.	The CCR will work with Biovest in development of processes necessary for Collaborator to perform vaccine production steps 1- 4 in the production of Id-KLH indolent follicular
lymphoma vaccine in support of Biovest Protocol #BV 301/ NCI Protocol #00-C-0050 (P-92). 

  

	5.	Using NCI immunologic assays currently under development, the CCR will examine these surrogate endpoints in support of Biovest Protocol #BV 301/ NCI protocol #00-C-0050 (P-92).

  

	6.	Biovest will have access to the follicular lymphoma vaccine clinical data and results and raw data in NIH’s possession and control as defined in Article 2.16 as needed to
support the registration of the Agent by the FDA in this disease. Furthermore, Biovest will be provided safety data generated from the use of the Agent that is in the possession and control of NIH as needed to support the FDA registration.
Collaborator’s access to and use of said data is subject to the terms of Article 8 hereunder and limited to use for regulatory filings only. 

  

	C.	Biovest Responsibilities 

  

	1.	Subject to the provisions of Articles 8.4, 8.10 and 13.1 hereunder, effective April 29, 2004, the Collaborator will be responsible for: adverse event monitoring and reporting, drug
distribution, clinical data collection, and protocol amendments for NCI Protocol #00-C-0050 (P-92). 

  

	2.	Upon execution of the CRADA, Collaborator will perform vaccine production step 3 and provide hybridoma supernatants in the production of Id-KLH indolent follicular lymphoma vaccine
in support of NCI Protocol #00-C-0050 (P-92). 

  

	3.	Effective April 29, 2004, Collaborator will be responsible for supply of Immunex/Berlex GM-CSF for NCI Protocol #00-C-0050 (P-92). 

  

	4.	Effective April 29, 2004, Collaborator will perform vaccine production steps 1, 2, 3 and 4 in the production of Id-KLH indolent follicular lymphoma vaccine in support of NCI
Protocol #00-C-0050 (P-92). 

  

	5.	Collaborator will conduct studies as necessary with the goal of optimizing and automating vaccine production and refining and validating production procedures as required by the
FDA. 

  

	6.	Subject to the provisions of Articles 8.4, 8.10 and 13.1 hereunder, Collaborator will develop an electronic archive for storage and retrieval of study-related data as required by
the FDA for submission of data in support of a BLA. 

  

	7.	Effective April 29, 2004, Collaborator will be responsible for conduct of data monitoring activities related to NCI Protocol #00-C-0050 (P-92). 

  

	
	CONFIDENTIAL
	A - 11

	8.	Collaborator will provide long-term patient monitoring to determine overall survival outcomes. 

  

	9.	Collaborator will arrange, host and provide support for: meetings associated with the Protocol Steering Committee and the Oversight Committee and; quarterly site visits by
appropriate NCI and Biovest staff to each clinical consortium site and; clinical investigators meetings as needed (anticipated every 6-12 months). 

  

	12.	For activities conducted pursuant to this CRADA in the United States of America, Collaborator, to the extent it engages in applicable conduct, agrees to comply with all appropriate
DHHS regulations relating to Human Subjects Use, all U.S. Department of Agriculture regulations, the decisions of the NCI Data Safety and Monitoring Board, and all Public Health Service policies relating to the use and care of laboratory animals.
For activities conducted pursuant to this CRADA outside of the United States of America, Collaborator shall conduct such in accordance with Good Laboratory Practices (GLPs) and all applicable rules, regulations and statutes, both local and national,
governing such activity in that country. 

  

	13.	Collaborator agrees to provide the NCI a redacted version of this CRADA suggested for release under Freedom of Information Act (FOIA) requests. 

  

	14.	Biovest will seek, with NCI approval, to accelerate patient accrual to NCI Protocol #00-C-0050 (P-92) by: 

  

	 	(1)	supporting protocol-related patient care and personnel costs at extramural consortium sites and; 

  

	 	(2)	by providing aggressive promotional and marketing efforts subject to NCI approval. These efforts will be comprehensive, including, at a minimum, engaging a professional marketing
firm, nationwide direct marketing to referring doctors, organizing and sponsoring seminars in each of the geographic areas represented by current and future clinical consortium centers nationwide, and developing an interactive website.

  

	15.	Biovest will assume responsibility for storage, maintenance, and recordkeeping of any phase 3 biopsy samples, including any phase 3 biopsy samples transferred from NCI to Biovest,
in accordance with FDA rules and regulations and subject to the terms of Article 8 as modified in Appendix C of this Agreement. This responsibility will survive termination of the CRADA. 

  
 References: 
  
 Longo DL, Young RC, DeVita VT. What is so good about the “good prognosis” lymphoma? in Williams CG, Whithouse JMA (eds.):
Recent Advances in Clinical Oncol Edinburgh, Churchill-Livingstone, pp. 223-231, 1982. 
  
 Portlock CS. “Good risk” non-Hodgkin’s lymphomas: Approaches to management. Sem Hematol, 1980, 20:25-34. 
  

	
	CONFIDENTIAL
	A - 12

 Portlock CS, Rosenberg SA. No initial therapy for stage 3 and IV non-Hodgkin’s lymphomas of favorable histologic
types. Ann Intern Med, 1979, 90:10-13. 
  
 Horning SJ,
Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin’s lymphomas. N Engl J Med, 1984, 311:147-5. 
  
 Stevenson GT, Stevenson FK. Antibody to molecularly defined antigen confined to a tumor cell surface. Nature, 1975, 254:714-6. 
  
 Stevenson GT, Elliott EV, Stevenson FK. Idiotypic determinants on the surface immunoglobulin
of neoplastic lymphocytes: a therapeutic target. Fed Proc, 1977, 36:2268-71. 
  
 Sirisinha S, Eisen HN. Autoimmune-like antibodies to the ligand-binding sites of myeloma proteins. Proc Natl Acad Sci USA, 1971, 68:3130-5. 
  
 Lynch, R. G., R. J. Graff, S. Sirisinha, E. S. Simms, and H. N. Eisen. Myeloma proteins as
tumor-specific transplantation antigens. Proc. Natl.Acad. Sci. USA, 1972, 69:1540. 
  
 Jorgensen T, Gaudernack G, Hannestad K. Immunization with the light Chain and the VL domain of the isologous myeloma protein 315 inhibits growth of mouse plasmacytoma MOPC-315. Scand J Immunol, 1980, 11:29-35.

  
 Daley MJ, Gebel HM, Lynch RG. Idiotype-specific transplantation resistance to
MOPC-315: Abrogation by post-immunization thymectomy. J Immunol, 1978, 120:1620-4. 
  
 Bridges SH. Participation of the humoral immune system in the myeloma-specific transplantation resistance. J Immunol, 1978, 121:479-83. 
  
 Freedman PM, Autry JR, Tokuda S, Williams RC, Jr. Tumor immunity Induced by preimmunization with BALB/c mouse myeloma protein. J
Natl Cancer Inst 1976, 56:735-740. 
  
 Sugai S, Palmer DW,
Talal N, Witz IP. Protective and cellular immune responses to idiotypic determinants on cells from a spontaneous lymphoma of NZB/NZWF1 mice. J Exp Med, 1974, 140:1547-58. 
  
 Stevenson FK, Gordon J. Immunization with idiotypic immunoglobulin Protects against
development of B lymphocytic leukemia, but emerging tumor cells can evade antibody attack by modulation. J Immunol, 1983, 130:970-973. 
  
 George AJT, Tutt AL, Stevenson FK. Anti-idiotypic mechanisms involved in the suppression of a mouse B cell lymphoma, BCL. J Immunol, 1987, 138:628-634.

  
 Kaminski MS, Kitamura K, Maloney DG, Levy R. Idiotype vaccination Against
murine B cell lymphoma. Inhibition of tumor immunity by free idiotype protein. J Immunol, 1987, 138:1289-1296. 
  
 Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R. Induction of immune responses in patients with B cell lymphoma against the surface immunoglobulin idiotype
expressed by their tumors. N Engl J Med, 1992, 327:1209-1215. 
  

	
	CONFIDENTIAL
	A - 13

 Kwak LW, Young HA, Pennington RW, Weeks SD, Vaccination with syngeneic, lymphoma-derived immunoglobulin idiotype combined
with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell response. Proc Natl Acad Sci USA 1996 Oct 1;93(20):10972-7. 
  
 Bendandi MB, Gocke C, Kobrin C, Benko F, Sternas L, Pennington R, Watson T, Reynolds C, Gause B, Duffey P, Jaffe E, Creekmore S, Longo D,
and Kwak LW. Complete molecular remissions induced by patient-specific vaccination plus GM-CSF against lymphoma. Nat Med, 5:1171-1177, 1999. 
  

	
	CONFIDENTIAL
	A - 14

 DESCRIPTION OF
OTHER NCI-BIOVEST INTERNATIONAL, INC. AGREEMENTS AND
INTELLECTUAL PROPERTY OF THE PARTIES 
  

			
	CRADAs:	  	None
		
	MTAs:	  	None
		
	CTAs:	  	None
		
	CDAs:	  	2-02244-01; “Discussions for the entering into of a Cooperative Research & Development Agreement (‘CRADA’) for the development and production of idiotype vaccines against
B-cell lymphoma “; Executed November 20, 2000.

  
 PATENTS/PATENT
APPLICATIONS: 
  
 Biovest International 
  
 Patents 
  
 US Patent 4,804,628, Hollow Fiber Cell Culture Device and Method of
Operation. 
  
 US Patent 5,079,168. Cell Culture Apparatus.

  
 US Patent 5,416,022. Cell Culture Apparatus. 
  
 US Patent 5,330,915. Pressure Control System for a Bioreactor 
  
 US Patent 4,629,686. Apparatus for Delivering a Controlled Dosage of a
Chemical Substance. 
  
 US Patent 4,618,586. Apparatus for
Delivering a Controlled Dosage of a Chemical Substance Having an Improved Culture Chamber. 
  
 US Patent 4,650,766. Culturing Apparatus 
  
 US Patent 297,620. Multi-Port Fitting for a Flask 
  
 US Patent 5,202,254. Process for Improving Mass Transfer in a Membrane Bioreactor Providing a More Homogeneous Culture Environment. 
  
 US Patent 4,722,902. Apparatus and Method for Culturing Cells, Removing Waste, and Concentrating Product. 
  
 US Patent 4,973,558. Method of Culturing Cells Using Highly Gas Saturated
Media 
  
 US Patent 6,001,585 Micro Hollow Fiber Bioreactor.

  
 US Patent 4,889,812. Bioreactor Apparatus 
  
 US Patent 4,894,342 Bioreactor System 
  
 US Patent 5,656,421 Multi-Bioreactor Hollow Fiber Cell Propagation System
and Method 
  
 US Patent 5,998,184 Basket-Type Bioreactor

  

	
	CONFIDENTIAL
	A - 15

 Non-Patented Intellectual Property 
  
 Biovest has been a leader in developing the hollow fiber bioreactor market. In the process,
Biovest has developed a number of preferred and alternate methods, vendors, and customers. This knowledge base is proprietary and is not the subject of this CRADA. 
  
 Abstract of the Research Plan of the CRADA 
  
 The National Cancer Institute (NCI) has initiated an FDA-approved, multi-institutional Phase
3 clinical trial of protein-based immunoglobulin idiotype vaccines for the treatment of low-grade follicular B-cell lymphoma. B-cell tumors are composed of clonally-expanded cells synthesizing a single antibody molecule containing unique variable
regions known as idiotypic determinants. The idiotypic determinants of B-cell derived tumors comprise tumor-specific antigens that can serve as a target for immunotherapy. Based on success of earlier clinical trials (Nature Medicine 5: 1171-1177,
Oct. 1999), NCI has decided to partner with Biovest International, Inc. (Biovest) in furtherance of the clinical study and scale-up work necessary for further vaccine production and eventual FDA product commercialization. A specific goal of this
CRADA will be development of the processes required for automated large-scale GMP production of adequate numbers of GMP produced and formulated idiotype vaccines as needed to complete the clinical development of this agent for the treatment of
follicular B-cell lymphoma. 
  

	
	CONFIDENTIAL
	A - 16

 APPENDIX B 
  
 FINANCIAL AND STAFFING CONTRIBUTIONS OF THE PARTIES 
  
 National Cancer Institute 
  
 Personnel 
  
 The NCI estimates that 0.85 professional person years/year of effort will be dedicated to its participation in the clinical study, Steering
Committee Meetings, compiling data, data management and monitoring in support of the clinical trial, and pathology. Such estimate of PHS staff includes its Principal Investigator (0.25 person years/year) and sufficient staffing to execute and
fulfill the obligations of the CRADA, including a Protocol Chairman (0.5 person years/year), and a Central Pathologist (0.1 person years/year). NCI will provide no funding to the Collaborator for collaborative research and development pursuant to
this CRADA inasmuch as financial contributions by the U.S. government to non-federal parties under a CRADA are not authorized under the Federal Technology Transfer Act (15 U.S.C. §3710(d)(1)). 
  
 Biovest International 
  
 Personnel: 
  
 Biovest intends to commit 50 to 60 person years per year of effort to permit the timely execution of the study implemented under this CRADA.
More specifically, this staffing shall include Biovest full-time employees, consultants to the company, external contract agencies and contract research organizations and personnel. 
  
 Funding: 
  
 NCI-CCR Costs 
  
 Beginning October 1, 2004, Collaborator shall provide $45,170.00 dollars quarterly for reasonable and necessary expenses incurred by NCI in carrying out its responsibilities associated with conduct of the clinical
trial under this CRADA and are to be deposited to an NCI CAN account established for the administration of this CRADA. No full-time tenured employees will be supported under this CRADA by Biovest International, Inc. These expenses include, but are
not limited to, costs associated with cGMP lymph node biopsy processing, molecular and immunologic monitoring, publication of clinical trial, supplementation of support services contracts and shipment of samples, associated administration support
and professional meetings support related to the CRADA, transportation and lodging costs to support the participation of NCI staff at semi-annual Principal Investigator meetings and for quarterly site visits to consortium centers. The first payment
will be due within thirty days of the execution of the CRADA Amendment with future payments due on the quarterly anniversary date of the execution of the CRADA. Travel costs are limited by the Federal Travel Rules and Regulations for all government
staff whether paid for by government funds or private Collaborators. Collaborator may provide direct support, under the 348 travel mechanism, for the travel and associated costs for attendance of NCI staff at selected scientific or development
meetings. 
  

	
	CONFIDENTIAL
	A - 17

 A check in the amount of $90,340.00 will be provided to the NCI by Biovest within thirty (30) days of the execution of
the CRADA Amendment. Checks should be made payable to the “National Cancer Institute”, should reference the CRADA #01030 and be sent to: CRADA Funds Coordinator, Technology Transfer Branch, EPS-450, 6120 Executive Blvd., Rockville, MD
20852. 
  
 Any adjustments will be made by amendment pursuant to Article 13.6
hereunder. Adjustments to the above-noted costs will be made on a yearly basis as mutually agreed upon by both parties, taking into account the level of control Biovest assumes for these responsibilities, the rate of patient accrual, and the
overhead costs associated with, but not limited to, increase in cost of living. 
  

	
	CONFIDENTIAL
	A - 18

 APPENDIX C 
  
 EXCEPTIONS OR MODIFICATIONS TO THIS CRADA 
  
 Modify Article 1 to read as follows: 
  
 Article 1. Introduction 
  
 This Cooperative Research and Development Agreement (CRADA) between PHS and the Collaborator will be effective when signed by all Parties. The research and development
activities which will be undertaken by each of the Parties in the course of this CRADA are detailed in the Research Plan (RP) which is attached as Appendix A. The funding and staffing commitments of the Parties are set forth in Appendix B. Any
exceptions or changes to the CRADA are set forth in Appendix C. A copy of the Letter of Intent and Extension to the Letter of Intent are included as Appendix D for informational purposes. This Cooperative Research and Development Agreement (CRADA)
between PHS and the Collaborator will be fully executed when signed by all Parties and effective retroactively with regard to intellectual property and confidentiality to January 09, 2001, which is the date of the execution of the Letter of Intent
(LOI). This CRADA is made under the authority of the Federal Technology Transfer Act, 15 U.S.C. 3710a and is governed by its terms. 
  
 Modify Article 2.11 as follows: 
  

	2.11	“Subject Data” means all recorded information first produced in the performance of this CRADA by the parties. “Subject Data” shall specifically exclude
“Identifiable Private Information.” 

  
 Add the following
new sections to the Article 2. Definitions: 
  

	2.12	“Adverse Drug Experience” means an adverse clinical experience as defined under 21 C.F.R. 312.32. 

  

	2.13	“Agent” means Id-KLH follicular B-cell lymphoma vaccine administered in combination with GM-CSF adjuvant. 

  

	2.14	“Annual Report” means the brief report of the progress of an IND associated investigation which the IND sponsor is required to submit to the FDA within 60 days of
the anniversary date that the IND went into effect (pursuant to 21 C.F.R. 312.33). 

  

	2.15	“Clinical Data and Results” means all information, data and results developed or obtained in connection with clinical trials conducted within the scope of the CRADA
Research Plan whether by intramural research scientists or extramural grantee or contract investigators. 

  

	2.16	 “Clinical Data and Results and Raw Data in NIH’s Possession and Control” means all 

  

	
	 CONFIDENTIAL

	1

	 	 
information collected from NIH intramural preclinical or clinical studies performed pursuant to the Research Plan, all data obtained by NIH under contracts
with extramural contract investigators for completion of studies within the scope of the CRADA Research Plan, and all information and data in the NCI-sponsored IND for Agent. 

  

	2.17	“Contract” means a funding agreement that is a research and development contract that provides that the contractor perform for the benefit of the Government, with
an expectation of completion of the stated research goals and the delivery of a report, data, materials or other product. Generally, Contracts are administered under the Federal Acquisition Regulations (FAR) codified at Title 48 C.F.R., Chapter 1 or
the Health Services Acquisition Regulations (HSAR) codified at Title 48 C.F.R., Chapter 3. 

  

	2.18	“Cooperative Agreement” means a Funding Agreement that is a species of a grant, whereby the funding Federal agency intends to be substantially involved in carrying
out the research program. Cooperative Agreements may be used where the Federal agency intends for its scientists to directly collaborate with the researchers of the funded institution on a joint research project. The Federal agency may then pay for
the research of both its employees and those of the funded institution (see 45 C.F.R. Part 74). 

  

	2.19	“CTA” means Clinical Trial Agreement. 

  

	2.20	“CTEP” means the Cancer Therapy Evaluation Program, DCTD, NCI, the program within NCI which plans, assesses and coordinates all aspects of clinical trials including
extramural clinical research programs, internal resources, treatment methods and effectiveness, and compilation and exchange of data. 

  

	2.21	“DCTD” means Division of Cancer Treatment and Diagnosis, NCI. 

  

	2.22	“FDA” means US Food and Drug Administration. 

  

	2.23	“Funding Agreement” means a Contract, Grant or Cooperative Agreement entered into between a Federal agency and another party for the performance of experimental,
developmental, or research work funded in whole or in part by the Federal Government. 

  

	2.24	“Grant” means a funding agreement that is an award of financial assistance which may be provided for support of basic research in a specific field of interest to
the funding Federal agency. 

  

	2.25	“IND” means an Investigational New Drug Application submitted to the FDA to receive approval to conduct experimental clinical trials. 

  

	2.26	“Multi-Party Data” means clinical data from clinical studies sponsored by NCI pursuant to CTAs or CRADAs, where such data are collected under protocol involving
combinations of investigational agents from more than one CTA or CRADA collaborator. 

  

	2.27	“NCI” means the National Cancer Institute, NIH, PHS, DHHS. 

  

	
	 CONFIDENTIAL

	2

	2.28	“Protocol Review Committee” (or “PRC”) means the CTEP/DCTD committee that reviews and approves studies involving NCI investigational agents and/or
activities supported by NCI. 

  

	2.29	“Raw Data” means the primary quantitative and empirical data first collected by the intramural and extramural investigators from experiments and clinical trials
conducted within the scope of the Research Plan of this CRADA . 

  

	2.30	“Steering Committee” means a joint clinical development team (hereinafter referred to as the “Steering Committee”) the Parties agree to establish once
Biovest establishes its own IND whose responsibility will be the oversight of the ongoing Phase 3 Clinical Trials performed under the Collaborators IND related to this CRADA The Steering Committee will comprise the following NCI staff: the Principal
Investigator, the Project Officer for Vaccine Production, the Protocol Coordinator, the Protocol Chairman, and the following Collaborator staff: Principal Investigator, and appropriate Collaborator staff in the areas of clinical monitoring,
pharmacy, statistics, manufacturing and publicity. Although the members of the Steering Committee shall be considered as having been delegated to the Steering Committee, they shall continue to remain employed by their respective employers under
their respective terms of employment. 

  

	2.31	“Oversight Committee” means the joint NCI Collaborator research and development team to be established upon execution of this CRADA and whose composition shall
include, but not be limited to: The NCI PI, the Collaborator P.I. the Project Officer for Vaccine Production, and the Vice-President of the Collaborator. The responsibilities of the Oversight Committee will include oversight of the fiscal
expenditures under the CRADA and review and approval of any possible third party involvement in any aspect of the CRADA Research Plan. Others may be added to this committee as mutually agreed upon by both parties. Although the members of the
Oversight Committee shall be considered as having been delegated to the Oversight Committee, they shall continue to remain employed by their respective employers under their respective terms of employment. 

  

	2.32	“Identifiable Private Information” means patient-identifying data from medical records or attached to patient specimens, to be obtained prospectively or from stored
medical records or specimens, that can be linked to individual human subjects, either directly or indirectly through codes. 

  
 Add the following new sections to the Article 3. Cooperative Research: 
  

	3.3	Review of Work. Periodic conferences shall be held by the Steering Committee to review work progress. It is understood that the nature of this cooperative research precludes
a guarantee of its completion within the specified period of performance or limits of allocated financial or staffing support. Accordingly, research under this CRADA is to be performed on a best efforts basis. 

  

	3.4	Clinical Protocol. Effective April 29, 2004, NCI protocol #00-C-0050 (P-92), entitled ‘Phase 3 Randomized Study of Autologous Lymphoma Derived Idiotype Specific
Vaccination Plus Sargramostim (GM-CSF) in Patients with Indolent Follicular Lymphoma in First Complete Remission’ will be conducted under Collaborator’s IND application # 5427. 

  

	
	 CONFIDENTIAL

	3

	3.6	Investigational New Drug Application. Collaborator’s IND #5427 cross-references NCI’s IND #5427. If Collaborator abandons its commercialization efforts, and NCI
decides to continue its development of the Agent that is the subject of this CRADA, Collaborator will supply information in support of NCI’s IND in the form of a Drug Master File directly to the FDA and Collaborator grants NIH a right to
cross-reference such information in its IND filing. In the event that Collaborator supplies CONFIDENTIAL information directly to NCI in support of an NCI IND, such information will be protected in accordance with the corresponding Confidentiality
provisions of Article 8 of this Agreement. 

  

	3.7	Biologics License Application. Collaborator will submit a Biologics License Application to the FDA within six (6) months of the date the NIH Data Safety and Monitoring
Board’s final analysis of results of the clinical trial or be considered to have abandoned its commercialization efforts. Collaborator shall have the right to file an application for “fast-track” licensing of Agent at any time during
the term of this CRADA once Collaborator has an approved IND on file with the FDA. Biovest will have access to the follicular lymphoma vaccine clinical data and results and raw data in NIH’s possession and control as defined in Article 2.16 as
needed to support the registration of the Agent by the FDA in this disease. Furthermore, Biovest will be provided safety data generated from the use of the Agent that is in the possession and control of NIH as needed to support the FDA registration.
Collaborator’s access to and use of said data is subject to the terms of Article 8 hereunder and limited to use for regulatory filings only. 

  

	3.8	Drug Information and Supply. Collaborator agrees to provide NCI without charge formulated and acceptably-labeled clinical-grade Agent in sufficient quantity to complete the
preclinical studies and clinical trial protocol sponsored by NCI within the scope of the CRADA Research Plan. It is understood that NCI shall take responsibility for and reasonable steps to maintain appropriate records and assure appropriate supply,
handling, storage, distribution and usage of these materials in accordance with the terms of this Agreement, the protocol and any applicable laws and regulations relating thereto. 

  
 Effective April 29, 2004, Collaborator agrees to take responsibility and
shall arrange directly with Immunex/Berlex for provision and distribution of adjuvant GM-CSF necessary to complete the clinical trial performed under this CRADA Changes in the composition or manufacture of the Agent for the studies performed under
this CRADA will be mutually agreed upon by both parties. 
  
 The
Collaborator contact will be Dr. Beverly Norris, Biovest (Telephone Number 508-793-0001). 
  

	3.9	Protection of Human Subjects and Appropriate Care of Laboratory Animals. All human clinical trials performed under this CRADA shall conform to the appropriate Federal law,
including, but not limited to all applicable FDA regulations and DHHS regulations relating to the protection of human subjects (see 45 C.F.R. Part 46, 21 C.F.R. Parts 50 and 56). NCI and Collaborator also agree to comply with all applicable Federal
statutes and Public Health Service policies relating to the use and care of laboratory animals (see 7 U.S.C. 2131 et seq.) Additional information is available from the Office for Human Research Protections, Telephone: 301-496-7163. In accordance
with the HHS Office for Human Research Protections guidelines, private patient identifiable information shall only be used by Collaborator for licensing applications to the FDA, if required. All other uses of information under this Agreement shall
assure that no private patient identifiable information is disclosed. 

  

	
	 CONFIDENTIAL

	4

 Amend Article 4.1 “Interim Reports” to read as follows: 
  

	4.1	Interim Reports. The Parties shall exchange formal written interim progress reports on a schedule agreed to by the PIs, but at least within six (6) months after this CRADA
becomes effective and at least within every six (6) months thereafter. Such reports shall set forth the technical progress made, identifying such problems as may have been encountered and establishing goals and objectives requiring further effort,
any modifications to the Research Plan pursuant to Article 3.2, and identify Subject Inventions pursuant to Article 6.1. Oversight Committee reports or copies of CRADA Annual Reports updating the progress of the CRADA research shall satisfy the
reporting requirements under this Article 4.1. In addition, copies of the Annual Reports and other pertinent IND data related to NCI protocol # 00-C-0050 (P-92) (including, but not limited to, clinical brochure data, and formulation and preclinical
data, including toxicology findings) shall be exchanged by the Parties as they become available. 

  
 Add a new Article 4.3 as follows: 
  

	4.3	Adverse Drug Experience Reporting. Effective April 29, 2004, Collaborator shall report all serious or unexpected adverse events to FDA in accordance with the reporting
obligations of 21 CFR 312.32 and will, concurrently, forward all such reports to CCR, NCI . All other adverse event reports received by Collaborator shall be reported to the FDA consistent with 21 CFR 312.32 and 312.33. In addition, copies of the
Annual Reports and other pertinent IND data (including, but not limited to, Clinical Brochure data, formulation and preclinical data, including toxicology findings) will be provided to CCR, NCI as they become available. 

  
 The Collaborator will then notify the investigator(s) conducting studies
under the Collaborator -sponsored protocol. 
  
 Amend Article 5
“Financial and Staffing Obligations” as follows: 
  

	5.1	PHS and Collaborator Contributions. The contributions of the Parties, including personnel, services, property and payment schedules, if applicable, are set forth in Appendix
B. PHS shall not be obligated to perform any of the research specified herein or to take any other action required by this CRADA if the funding is not provided as set forth in Appendix B. PHS shall return excess funds to the Collaborator when it
sends its final fiscal report pursuant to Article 5.2, except for staffing support pursuant to Article 10.3. Collaborator acknowledges that the U.S. Government will have the authority to retain and expend any excess funds for up to one (1) year
subsequent to the expiration or unilateral termination of the CRADA to cover any costs incurred during the term of the CRADA in undertaking the work set forth in the RP. 

  

	5.2	Accounting Records. PHS shall maintain separate and distinct current accounts, records, and other evidence supporting all its obligations under this CRADA, and shall provide
the Collaborator a final fiscal report reflecting the use of Collaborator funds, technical progress, established goals and objectives pursuant to Article 4.2. 

  

	
	 CONFIDENTIAL

	5

 Amend Article 6 “Patent Applications” as
follows: 
  

	6.2	Filing of Patent Applications. Each party shall be responsible for filing patent or other IP applications in a timely manner and at its own expense and after consultation
with the other Party. The Parties will consult and mutually determine a filing strategy for jointly-owned subject inventions. If either Party decides to abandon a patent or patent application covering a jointly owned subject invention it will
provide written notice to the other Party of this intention at least thirty (30) days prior to the date of any applicable deadline by which the patent or patent application would be deemed abandoned. If the non-abandoning Party elects to continue
the patent or patent application, the abandoning Party will cooperate in providing the other Party with needed information to continue the patent or patent application. The Party deciding to continue the patent or patent application will bear all
costs associated therewith. If trade secret information or Collaborator Confidential/Proprietary is essential to file a properly enabled patent application, Collaborator will cooperate to provide equivalent information to file such application.

  

	6.3	Patent Expenses. The expenses attendant to the filing or maintaining of jointly-owned patent or other IP applications generally shall be paid by the Party filing such
application. If Collaborator elects to take an exclusive license to any Subject Invention under paragraph 7.1, the Collaborator shall be responsible for all reasonable past and future out-of-pocket expenses in connection with the preparation,
filing, prosecution and maintenance of any applications claiming such exclusively-licensed inventions and any patents or other IP grants that may issue on such applications. The Collaborator may waive its exclusive license rights on any application,
patent or other IP grant at any time, and incur no subsequent compensation obligation for that application, patent or IP grant. 

  

	6.4	 Prosecution of Intellectual Property Applications. In connection with any patent or IP application relating to a subject invention filed pursuant to the
CRADA, within one month of receipt or filing, each Party shall provide the other Party with copies of the applications and all documents received from or filed with the relevant patent or other IP office in connection with the prosecution of such
applications. Each Party shall also provide the other Party with the power to inspect and make copies of all documents retained in the patent or other IP application files by the applicable patent or other IP office. Each Subject Invention made
solely by PHS employees shall be solely owned by PHS. PHS agrees to exclude from any patent application Collaborator trade secret information or Collaborator Proprietary/Confidential Information. If such trade secret information or Collaborator
Confidential/Proprietary is essential to file a properly enabled patent application, Collaborator will cooperate to provide equivalent information to file such application. Each Subject Invention made solely by Collaborator employees shall be solely
owned by Collaborator. Collaborator agrees to exclude from any patent application PHS trade secret information or PHS Proprietary/Confidential Information. If such trade secret information or PHS Confidential/Proprietary is essential to file a
properly enabled patent application, PHS will cooperate to provide equivalent information to file such application. The Parties agree to consult with each other with respect to the prosecution of applications for PHS Subject Inventions and joint
Subject Inventions. If the Parties agree that Collaborator shall file and prosecute IP applications on joint Subject Inventions, then Collaborator agrees to all Customer Number Practice and/or granting of power(s) of attorney (or its equivalent)
necessary to assure PHS 

  

	
	 CONFIDENTIAL

	6

	 	 
access to its United States, International, and Foreign intellectual property rights on said applications. 

  
 Amend Article 7 “Licensing” to read as follows: 
  

	7.1	Option for Commercialization License. With respect to Government IP rights to any Subject Invention not made solely by the Collaborator’s employees for which a patent or
other IP application is filed, PHS hereby grants to the Collaborator an exclusive option to elect an exclusive or nonexclusive commercialization license, which is substantially in the form of the appropriate model PHS license agreement. This option
does not apply to Subject Inventions conceived prior to the effective date of this CRADA that are reduced to practice under this CRADA, if prior to that reduction to practice, PHS has filed a patent application on the invention and has licensed it
or offered to license it to a third party. To the best of NCI’s knowledge after due inquiry on the date that NCI signed this CRADA no such Subject Invention exists. In the event that it is later determined that any such Subject Invention does
exist, Collaborator shall be granted an option to a nonexclusive license for any such Subject Invention licensed to a Third Party on a nonexclusive basis. The terms of the license will fairly reflect the nature of the invention, the relative
contributions of the Parties to the invention and the CRADA, the risks incurred by the Collaborator and the costs of subsequent research and development needed to bring the invention to the marketplace. The field of use of the license will be
commensurate with the scope of the RP. Collaborator has the right to transfer or sublicense any rights taken under this paragraph to additional partners. Any such sublicenses shall be subject to the terms of the applicable License agreement and upon
written approval by PHS, which approval will not be unreasonably withheld; and will reflect that any sub-licensee will not further sublicense. 

  

	7.2	Exercise of License Option. The option of Article 7.1 must be exercised by written notice mailed within three (3) months after either (i) Collaborator receives written
notice from PHS that the patent or other IP application has been filed; or (ii) the date Collaborator files such IP application. Exercise of this option by the Collaborator initiates a negotiation period that expires nine (9) months after the
exercise of the option. If the last proposal by the Collaborator has not been responded to in writing by PHS within this nine (9) month period, the negotiation period shall be extended to expire one (1) month after PHS so responds, during which
month the Collaborator may accept in writing the final license proposal of PHS. In the absence of such acceptance, or an extension of the time limits by PHS, PHS will be free to license such IP rights to others. In the event that the Collaborator
elects the option for an exclusive license, but no such license is executed during the negotiation period, PHS agrees not to make an offer for an exclusive license on more favorable terms to a third party for a period of six (6) months without first
offering Collaborator those more favorable terms. These times may be extended at the sole discretion of PHS upon good cause shown in writing by the Collaborator. 

  

	7.5	 Third Party License. Pursuant to 15 U.S.C. 3710a(b)(1)(B), if PHS grants an exclusive license to a Subject Invention made wholly by PHS employees or jointly
with Collaborator under this CRADA, the Government shall retain the right to require the Collaborator to grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense to use the 

  

	
	 CONFIDENTIAL

	7

	 	 
invention in Collaborator’s licensed field of use on terms that are reasonable under the circumstances; or if the Collaborator fails to grant such a
license, to grant the license itself. The exercise of such rights by the Government shall only be in exceptional circumstances and only if the Government determines (i) the action is necessary to meet health or safety needs that are not reasonably
satisfied by Collaborator, (ii) the action is necessary to meet requirements for public use specified by Federal regulations, and such requirements are not reasonably satisfied by the Collaborator; or (iii) the Collaborator has failed to comply with
an agreement containing provisions described in 15 U.S.C. 3710a(c)(4)(B). The determination made by the Government under this Article is subject to administrative appeal and judicial review under 35 U.S.C. 203(2). Subject to Article 7.4 herein, the
Collaborator shall retain ownership in any intellectual property to which the Collaborator has title prior to this CRADA, or which is outside the workscope of this CRADA . 

  
 Amend Article 8 “Proprietary
Rights and Publication” to read as follows: 
  

	8.1	Right of Access. PHS and the Collaborator agree to exchange all Subject Data and Research Materials produced in the course of research under this CRADA whether developed
solely by PHS, jointly with Collaborator or solely by the Collaborator. Research Materials will be shared equally by the Parties to the CRADA unless other disposition is agreed to by the Parties. All Parties to this CRADA will be free to utilize
Subject Data and Research Materials for their own purposes, consistent with their obligations under this CRADA. 

  

	8.3	Dissemination of Subject Data and Research Materials. To the extent permitted by law, the Collaborator and PHS agree to use reasonable efforts to keep Subject Data and
Research Materials confidential until published or until corresponding patent applications are filed. Any information that would identify human subjects of research or patients will always be maintained confidentially. To the extent permitted by law
and subject to the other provisions of Article 8, the Collaborator shall have the exclusive right to use any and all CRADA Subject Data in and for any regulatory filing by or on behalf of Collaborator, except that PHS shall have the exclusive right
to use Subject Data for that purpose, and authorize others to do so, if the CRADA is terminated or if Collaborator abandons its commercialization efforts. Collaborator acknowledges the basic research mission of the PHS, and agrees that after
publication, PHS may make unpatented research materials arising out of this CRADA available to third parties for further research. 

  
 Modify Article 8.4 as follows: 
  

	8.4.	 Proprietary/Confidential Information. Each Party agrees to limit its disclosure of Proprietary/Confidential Information to the amount necessary to carry out
the Research Plan of this CRADA, and shall place a confidentiality notice on all such information. Confidential oral communications shall be reduced to writing within 30 days by the disclosing Party. Each Party receiving Proprietary/Confidential
Information agrees that any information so designated shall be used by it only for the purposes described in the attached Research Plan. Any Party may object to the designation of information as Proprietary/Confidential Information by another Party.
Subject Data and Research Materials developed solely by the Collaborator may be designated as Proprietary/Confidential Information when they are wholly separable from the Subject Data and Research Materials developed jointly with PHS investigators,
and advance designation of such 

  

	
	 CONFIDENTIAL

	8

	 	 
data and material categories is set forth in the RP. The exchange of other confidential information, e.g. Identifiable Private Information, shall be subject
to the terms of Article 8.10. Jointly developed Subject Data and Research Material derived from the Research Plan may be disclosed by Collaborator to a third party under a confidentiality agreement for the purpose of possible sublicensing pursuant
to the Licensing Agreement and subject to Article 8.7. 

  

	8.6	Duration of Confidentiality Obligation. The obligation to maintain the confidentiality of Proprietary/Confidential Information shall expire at the earlier of the date
when the information is no longer Proprietary Information as defined in Article 2.7 or five (5) years after the expiration or termination date of this CRADA. The Collaborator may request an extension to this term when necessary to protect
Proprietary/Confidential Information relating to products not yet commercialized. 

  

	8.7	Publication. The Parties are encouraged to make publicly available the results of their research. Before either Party submits a paper or abstract for publication or
otherwise intends to publicly disclose information about a Subject Invention, Subject Data or Research Materials, the other Party shall be provided thirty (30) days to review the proposed publication or disclosure to assure that
Proprietary/Confidential Information is protected. The other party may request such publication to be revised if it discloses Proprietary/Confidential information. The publication or other disclosure shall be delayed for up to sixty (60) additional
days upon written request by any Party as necessary to preserve U.S. or foreign patent or other IP rights. If trade secret information or Collaborator Proprietary/Confidential is essential to publish or otherwise publicly disclose as outlined above,
Collaborator will cooperate to provide equivalent information to file such application. 

  
 Add a new Article 8.8 as follows: 
  

	8.8	Extramural Research and Data. In pursuing the development of Agent pursuant to this CRADA, NIH utilized extramural investigators for part or all of the completion of
this Research Plan. However, said extramural investigators are not Parties to this CRADA, and this CRADA does not address rights to intellectual property created by such investigators. Nonetheless, to the extent permitted by law and subject to the
other provisions of Article 8 of this CRADA, NIH shall maintain all IND, Clinical Data and Results, and Raw Data in NIH’s Possession and Control as Proprietary and CONFIDENTIAL, and make data related to NCI Protocol 00-C-0050 (P-92) including
the follicular lymphoma vaccine clinical data and results and raw data in NIH’s possession and control as defined in Article 2.16 and safety data generated from the use of the Agent that is in the possession and control of NIH as needed to
support the registration of the Agent by the FDA in this disease referenced in Article 3.7 of Appendix C and Item 6 under NCI Contributions of Appendix A available to the Collaborator, for its own use and for use in obtaining FDA approval for the
commercial marketing of Subject Inventions and Agent products. Accordingly, said data shall not be transferable to any third party by Collaborator without the written permission of the NCI, which will not be unreasonably withheld.

  
 Add a new Article 8.9
“Retention and Disposition of Patient Samples” as follows: 
  

	8.9	 Retention and Disposition of Patient Samples. The parties anticipate that certain patients 

  

	
	 CONFIDENTIAL

	9

	 	 
enrolled in the clinical trial performed under this CRADA will be removed from the study for any number of reasons including the following examples:

  

	 	1.	Patient unable to obtain a complete response with chemotherapy 

  

	 	2.	Tumor returns after chemotherapy while waiting to start vaccine 

  

	 	3.	Tumor returns after vaccinations are completed 

  

	 	4.	Patient is unable to tolerate the treatment 

  
 Collaborator agrees that in the event a patient is removed from the study performed under this CRADA for any reason, the patient shall be free to enter
any other trial and their biopsies, hybridomas and associated clinical or biopsy data needed for such a new trial will be transferred for use in that study. Collaborator will cooperate in transferring all required information upon receipt of written
patient authorization to such transfer to the specified recipient. Collaborator will not use patient samples or derivatives thereof for purposes not specified in this CRADA. 
  
 Collaborator assumes responsibility for storage, maintenance, and recordkeeping of any phase 3 biopsy samples, including any
phase 3 biopsy samples transferred from NCI to Collaborator, in accordance with FDA rules and regulations and subject to all of the terms of Article 8 as modifided in Appendix C herein. This responsibility will survive termination of the CRADA.

  
 Add a new Article 8.10 “Access Review and Receipt of Identifiable
Private Information” as follows: 
  

	8.10	Access, Review and Receipt of Identifiable Private Information. Collaborator access to and review of Identifiable Private Information shall be only for on-site quality
auditing. Collaborator will receive Identifiable Private Information only for purposes of satisfying FDA or other health authorities’ reporting requirements, and for internal research purposes directly related to obtaining regulatory approval
of Agent. Collaborator is prohibited from access, review, receipt, or use of such information for other purposes. All IRB approved protocol and informed consent documents related to this research project will clearly describe this practice. If the
Collaborator will have access to Identifiable Private Information, the protocol and the informed consent must clearly state (i) the existence of the Collaborator; (ii) the Collaborator’s access to Identifiable Private Information, if any; and
(iii) the extent to which confidentiality will be maintained . For clinical protocol involving a third party, the other party’s access, review, receipt, or use of Identifiable Private Information shall be subject to the same limitations as
described in this Article 8.10. 

  
 Add a new Article 8.11
“Multi-Party Data” as follows: 
  

	8.11	“Multi-Party Data” means clinical data which is collected from clinical studies sponsored by NCI for combinations of proprietary investigational agents supplied by
more than one Collaborator. 

  

	
	 CONFIDENTIAL

	10

 For clinical protocol(s) where Agent is used in combination with another proprietary investigational
agent which is the subject of another Clinical Trials Agreement or Cooperative Research and Development Agreement, the access to and use of data by Collaborator and party supplying other agent (hereinafter referred to as “Other Party”)
shall be as follows (data pertaining to such combination use shall hereinafter be referred to as “Multi-Party Data.”): 
  

	 	i.	NCI must provide all parties with written notice regarding the existence and nature of any agreements governing their collaboration with NIH, the design of proposed combination
protocol(s), and the existence of any obligations which would tend to restrict NCI’s participation in proposed combination protocols. 

  

	 	ii.	Collaborator shall agree to permit use of the Multi-Party Data from these clinical trials by Other Party to the extent necessary to allow Other Party to develop, obtain regulatory
approval of, or commercialize its own proprietary investigational agent, provided Other Party permits Collaborator similar, reciprocal rights to use Multi-Party Data. 

  

	 	iii.	Any Party having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely
for development, regulatory approval, and commercialization of its own proprietary investigational agent(s). 

  
 Amend Article 10 “Termination” as follows: 
  

	10.2	Unilateral Termination. Either PHS or the Collaborator may unilaterally terminate this entire CRADA at any time by giving written notice at least sixty (60) days prior
to the desired termination date, and any rights accrued in property, patents or other IP rights shall be disposed of as provided in paragraph 10.1, except that PHS may, at its option, retain funds transferred to PHS prior to unilateral termination
by Collaborator for use in completing the Research Plan solely or with another partner. However, in the event of unilateral termination by Collaborator, Collaborator’s obligation under Article 3.8 will survive termination to the extent
reasonably necessary to complete approved clinical studies under mutually agreed upon protocol. If Collaborator elects to terminate its development of Agent without the transfer of its development efforts to support a level of production equivalent
to that which was ongoing at the time of termination, and CCR, NCI elects to continue its development of Agent, then Collaborator agrees to maintain its IND, to provide a letter of cross-reference to Collaborator’s IND, and to provide financial
support for personnel, reagents, supplies, and equipment necessary to transfer back to CCR, NCI all vaccine production, including, but not limited to all relevant biological and immunological assays. Such obligation shall last until either a date on
which vaccine production and related assays are fully transferred back to NCI or one year after the notification from Collaborator to NCI that Collaborator elects to terminate its development of Agent, whichever comes first. Notwithstanding the
foregoing, if NCI has executed an agreement with a new collaborator or third party to be involved in development of Agent, Collaborator’s funding obligations shall be terminated immediately. CCR, NCI will be responsible for the IND to support
this study in the event of Collaborator termination. 

  

	10.3	 Staffing. If this CRADA is mutually or unilaterally terminated by the Collaborator prior to its expiration, funds will nevertheless remain available
to PHS for continuing any staffing 

  

	
	 CONFIDENTIAL

	11

	 	 
commitment made by the Collaborator pursuant to Article 5.1 above and Appendix B, if applicable, for a period of one year after such termination. If there
are insufficient funds to cover this expense, the Collaborator agrees to pay the difference. 

  
 Add a new Article 10.6 as follows: 
  

	10.6	Research License and Alternative Sources of Supply in the Event Collaborator Terminates Development of Agent  

  
 Collaborator hereby grants to NCI a nonexclusive, nontransferable,
irrevocable, paid-up license to practice or have practiced for or on behalf of the United States any Subject Invention which Collaborator may have or obtain on Agent, its manufacture, or on the process for use of Agent, throughout the world, for
medical research purposes, including those related to or connected with the therapy of cancer; but this license shall become effective only if and when Collaborator terminates its development of Agent without the transfer of its development efforts
to another party, and NCI elects to continue the development of Agent. 
  
 If Collaborator elects to terminate its development of Agent without the transfer of its development efforts to another party, and NCI elects to continue its development of Agent, then Collaborator will: 
  

	 	(i)	allow NCI to purchase at cost said Agent from Collaborator inventory; or 

  

	 	(ii)	arrange for an independent contractor to manufacture and provide for NCI purchase of said agent at cost; or 

  

	 	(iii)	provide to NCI all information necessary to allow NCI to contract and manufacture said Agent independent of Collaborator; or 

  

	 	(iv)	arrange for alternative and cost-effective method of Agent production 

  
 for use in preclinical studies and clinical trials. Such obligation shall last until either a date on which an alternate source of equivalent materials,
acceptable to NCI, can be obtained by NCI, or one year after the date of notification from Collaborator to NCI that Collaborator elects to terminate its development of Agent, whichever comes first. 
  
 Modify the first sentence in Article 12.3 as follows: 
  
 The Collaborator agrees to hold the U.S. Government harmless and to
indemnify the Government for all liabilities, demands, damages, expenses and losses arising out of the use by the Collaborator for any purpose of the Subject Data, additional Clinical Data and Results and Raw Data in NIH’s Possession and
Control, Research Materials and/or Subject Inventions produced in whole or part by PHS employees under this CRADA, unless due to the negligence or willful misconduct of PHS, its employees, or agents. 
  

	
	 CONFIDENTIAL

	12

 Modify Article 13.1 as follows: 
  

	13.1	Governing Law. The construction, validity, performance and effect of this CRADA shall be governed by Federal law, as applied by the Federal Courts in the District of
Columbia. Federal law and regulations will preempt any conflicting or inconsistent provisions in this CRADA. NCI and Collaborator, if Collaborator is sponsoring trials at the NIH under this CRADA, shall comply with all Department of Health and Human
Services regulations relating to Human Subject use, and all Public Health Service policies relating to the use and care of laboratory animals. 

  
 Add the following to the beginning of Article 13.2 as follows: 
  

	13.2	The Parties hereby modify their rights under the following prior agreements: 

  

Confidential Disclosure Agreement: 
  
 # 2- 02244-01 
 Subject: “Discussions for
the entering into of a Cooperative Research & Development Agreement (“CRADA”) for the development and production of idiotype vaccines against B-cell lymphoma.” 
 Executed: September 20, 2000. 
  
 and the Parties agree that the information provided thereunder is now governed, retroactive to the date of the LOI (January, 09, 2001), by the
confidentiality and intellectual Property terms of this CRADA. 
  
 Add a new
Article 13.13 as follows: 
  

	13.13 	FDA Meetings. All meetings with FDA concerning clinical studies for the development of Agent within the scope of the CRADA Research Plan will be discussed by Collaborator and
NCI in advance and will be held on mutually agreed upon dates. Collaborator reserves the right to set jointly with NCI the agenda for any such meeting. 

  
 Modify Article 13.8 “Notices” as follows: 
  

	13.8	Notices. All notices pertaining to or required by this CRADA shall be in writing and shall be signed by an authorized representative and shall be delivered by hand or sent by
certified mail, return receipt requested, or by recognized national overnight carrier, with postage prepaid, to the addresses indicated on the signature page for each Party. Notices regarding the exercise of license options shall be made pursuant to
Article 7.2. Any Party may change such address by notice given to the other Party in the manner set forth above. 

  
 Modify Article 13.9 “Independent Contractors” as follows: 
  

	13.9	 Independent Contractors. The relationship of the Parties to this CRADA is that of independent contractors and not agents of each other or joint venturers or
partners. Each Party shall maintain 

  

	
	CONFIDENTIAL
	 

	 	 
sole and exclusive control over its personnel and operations. Collaborator employees who will be working at PHS facilities may be asked to sign a Guest
Researcher or Special Volunteer Agreement appropriately modified in view of the terms of this CRADA. If Collaborator elects to perform any portion of the Research Plan through a contractor or consultant, Collaborator agrees to incorporate into such
contracts all provisions necessary to ensure that the work of such contractors or consultants is governed by the terms of the CRADA. In addition, Collaborator will have incorporated in any agreement with any contractor or consultant contemplated
hereby a provision for the assignment of inventions of the contractor or consultant to the Collaborator; such inventions shall be deemed Subject Inventions of the Collaborator. Some of the studies of the Research Plan for this CRADA may be conducted
by a contractor working on behalf of the NIH. It is the intent of the NIH that the contractor not perform any duties likely to generate intellectual property. However, the Collaborator is aware that pursuant to the Bayh-Dole Act (codified art 35
USC, Chapter 18), the contractor may elect title to any inventions it makes in the performance of its contract duties. Such contractor inventions are not subject to the terms of this CRADA. 

  
 Amend Article 14.2 Survivability by including Articles 4.3
(Adverse Drug Experience Reporting) and 10.6 (Research License and Alternative Sources of Supply in the Event that Collaborator Terminates Development of Agent) and the last sentence of Article 10.2 (regarding drug supply in the event
of collaborator’s unilateral termination) as provisions that will survive termination of this CRADA. 
  

	14.2	Survivability. The provisions of Articles 4.2, 4.3, 5-8, Article 10.2, 10.3-10.5, 10.6, 11.1, 12.2-12.4, 13.1, 13.10 and 14.2 shall survive the termination of this CRADA.

  

	
	CONFIDENTIAL
	 

  
 APPENDIX D 
  
 LETTER OF INTENT 
  
 AND 
  
 EXTENSION TO LETTER OF INTENT 
  
 CRADA #01030 
  

							
	

	 	 DEPARTMENT OF HEALTH AND HUMAN SERVICES
	 	 Public Health Service

			
	 	 	December 14, 2000	 	 National Institutes of Health
 National Cancer
Institute
 Technology Development and
 Commercialization
Branch
 NCI-FCRDC
 P.O. Box B, FVC/502
 Frederick, MD 21702-1201

			
	 	 	 Dr. Christopher Kyriakides
 Chief Executive Officer
 Biovest International, Inc.
 8500 Evergreen Blvd.
 Coon Rapids, Minnesota 55433
	 	 Overnight Delivery Address
 1003 West Seventh
Street
 Fairview Center, Suite 502
 Frederick; MD
21702
  
 301-846-5465
 301-846-6820 FAX

	 	 	 REFERENCE:
	 	 
	 	 	 Proposed Cooperative Research and Development Agreement (CRADA)
	 	 
	 	 	 CRADA #: 01030
	 	 
	 	 	 NIH Principal Investigator:
	 	 Larry W. Kwak, M.D., Ph.D.
	 	 
	 	 	 Collaborator Investigator:
	 	 Dr. Christopher Kyriakides
	 	 
	 	 	 Development of Idiotype Tumor Vaccines for Treatment of B-cell Lymphomas
	 	 

  
 ***Letter of
Intent*** 
  
 Dear Dr. Kyriakides, 
  
 “ It is my understanding that a cooperative research and development project between the
parties referenced below is being considered. Accordingly, until a formal Collaborative Research and Development Agreement (CRADA) is reviewed by the CRADA Subcommittee and approved by the Director, National Cancer Institute (NCI), this letter is
offered to permitjoint research to commence. However, in the case of human clinical trials which are a part of the subject CRADA, the Parties agree that all such trials which may begin prior to the execution of the formal CRADA Agreement shall be
preceded by the appropriate US Food and Drug Administration IND approval (or international equivalents thereof). 
  
 It is acknowledged by the parties below that cooperative research pursuant to the Research Plan, attached as Appendix A, will be conducted informally by the NCI Principal
Investigator(s) and Collaborator pending formal approval of this CRADA. It is further acknowledged that patentable inventions may be made by NCI employees and employees of the Collaborator. Pursuant to its authority under the Federal Technology
Transfer Act of 1986, NCI agrees that should this CRADA be approved, it will have retroactive effect to the date that the last party has executed this Letter for any inventions that may be made under this Research Plan. NCI further agrees that
should this CRADA be approved it will have retroactive effect to the date that the last party has executed this Letter for confidentiality obligations specified in the NIH Model CRADA. The NIH Model CRADA provisions for the protection of proprietary
information are incorporated in this letter of intent by reference and are considered controlling during the period of informal joint research. These provisions include, but are not limited to, Articles 2.7 and 8.1-8.7. The NIH Model CRADA is
attached as Appendix B. 
  
 You understand, however, that this Letter is not a
commitment on the part of either party to enter into a CRADA. Further, this Letter is effective for a term of six months. The six month term may 

  

 
be extended, provided the CRADA is under active negotiation and the collaborative research is continuing. Assuming the necessary approvals are forthcoming,
we look forward to a successful collaboration. 
  

	
	Sincerely,
	
	 /s/ Kathleen Sybert

	 Kathleen Sybert, Ph.D.

	 Chief, TDCB, NCI

  
 ACCEPTED AND AGREED TO:  
  

					
	 National Cancer Institute
	 	 	 	 Biovest International, Inc.

			
	 /s/ Alan S. Rabson
	 	 	 	 /s/ Dr. Christopher Kyriakides

	Alan S. Rabson, M.D.	 	 	 	Dr. Christopher Kyriakides
	 Deputy Director, NCI
	 	 	 	 Chief Executive Officer

			
	 Date 12/22/00
	 	 	 	 Date 1/9/01

  

					
	

	 	DEPARTMENT OF HEALTH & HUMAN SERVICES                     .	  	Public Health Service
			
	 	 	 	  	 National Institutes of Health
 National Cancer Institute
 Technology Transfer Branch
 NCI-Frederick
 PO BOX B
 Fairview Center, Suite 502
 Frederick, MD 21702-1201
 (301) 846-5465
 (301) 846-6820 fax

  
 Dr. Christopher Kyriakides 

Chief Executive Officer 
 Biovest International, Inc. 
 8500 Evergreen Blvd. 
 Coon Rapids, Minnesota 55433 
  

	Re:	Proposed Cooperative Research and Development Agreement (CRADA) 

  
 Proposed CRADA #: 01030 
 NCI Principal Investigator: Larry W. Kwak, M.D.,
Ph.D. 
 Collaborator Investigator: Christopher Kyriakides, M.D. 
 Title: Development of Hybridoma-based Idiotypic Tumor Vaccines for the Treatment of Follicular B-cell Lymphoma. 
  
 Dear Dr. Kriakides, 
  
 It is my understanding that a cooperative research and development project between the parties referenced below is being considered. Accordingly, until a formal Collaborative Research and Development Agreement (CRADA)
is reviewed by the CRADA Subcommittee and approved by the Director, National Cancer Institute (NCI), the attached Letter of Intent and its associated appendices was executed to permit joint research to commence. At this time both parties agree to
extend the term of the Letter of Intent an additional 3 months. Upon signature of all parties to this extension of the Letter of Intent, the new expiration date of the Letter of Intent is October 09, 2001. All terms and conditions of the original
Letter of Intent shall be in force through the time period covered under this extension. 
  
 You understand, however, that the Letter of Intent is not a commitment on the part of either party to enter into a CRADA. Assuming the necessary approvals are forthcoming, we look forward to a successful
collaboration. 
  

	
	 Sincerely,

	
	 /s/ Kathleen K. Sybert

	 Kathleen K. Sybert, Ph.D., J.D.

	 Chief, TTB, NCI

  
 AUTHORIZED SIGNATURES
ON NEXT PAGE 
  

 Proposed CRADA #: 01030                 
Letter of Intent Extension 
 NCI Principal Investigator: Larry W. Kwak, M.D., Ph.D. 
 Collaborator Investigator: Christopher Kyriakides, M.D. 
 Title: Development of Hybridoma-based Idiotypic Tumor Vaccines
for the Treatment of Follicular B-cell Lymphoma. 
  
 ACCEPTED AND AGREED TO: 
  

					
	National Cancer Institute	 	 	 	Biovest International, Inc.
			
	 /s/ Alan Rabson
	 	 	 	 /s/ Christopher Kyriakides

	 Alan Rabson, M.D.
	 	 	 	 Christopher Kyriakides, M.D.

	 Deputy Director, NCI
	 	 	 	 Chief Executive Officer, Biovest

			
	 6/14/01
	 	 	 	 6/25/01

	 Date
	 	 	 	 Date

  
 Attachments: 
  
 Original Letter of Intent and Associated Appendices (A and B) 
  

 AMENDMENT #4 
  
 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT #01030 
  
 “Clinical Development of Hybridoma-based Idiotypic Vaccines for 
 Treatment of Follicular B-cell Lymphoma” 
  
 The purpose of this amendment is to change certain terms of the above-referenced Cooperative Research and Development Agreement (CRADA). These changes arc reflected
below, and except for these changes, all other provisions of the original CRADA remain in full force and effect. Two originals of this amendment are provided for execution; one is to remain with the National Cancer Institute and the other original
is to remain with the Collaborator. 
  
 The purpose of this amendment is to i)
replace the existing Research Plan, ii) modify the contributions of the parties, iii) make additional Appendix C modifications. CRADA #01030 is amended as follows: 
  

	 	1.	Replace the existing Appendix A: Research Plan, with the attached revised Research Plan. 

  

	 	2.	Replace the existing Appendix B: Financial and Staffing Contributions with the attached Appendix B. 

  

	 	3.	Replace the existing Appendix C: Exceptions or Modifications to this CRADA with the attached Appendix C. Changes to Appendix C, are as follows: 

  

	 	(a)	Change Section 3.4 to read: 

  

	 	3.4	Clinical Protocol Effective April 29, 2004, NCI protocol #00-C-0050 (P-92), entitled ‘Phase 3 Randomized Study of Autologous Lymphoma Derived Idiotype Specific
Vaccination Plus Sargramostim (GM-CSF) in Patients with lndolent Follicular Lymphoma in First Complete Remission’ will be conducted under Collaborator’s IND application # 5427. 

  

	 	(b)	Change Section 3.6 to read: 

  

	 	3.5	Investigational New Drug Application Collaborator’s IND #5427 cross-references NCI’s IND 85427. If Collaborator abandons its commercialization efforts, and NCI
decides to continue its development of the Agent that is the subject of this CRADA, Collaborator will supply information in support of NCI’s IND in the form of a Drug Master File directly to the FDA and Collaborator grants NIH a right to
cross-reference such information in its IND filing. In the event that Collaborator supplies CONFlDENTIAL information directly to NCI in support of an NCI IND, such information will be protected in accordance with the corresponding Confidentiality
provisions of Article 8 of this Agreement. 

  

	 	(c)	Change Section 3.7 to read: 

  

	 	3.7	Biologics License Application. Collaborator will submit a Biologics License Application to the FDA within six (6) months of the date the NIH Data Safety and Monitoring
Board’s final analysis of results of the clinical trial or be considered to have abandoned its commercialization efforts. Collaborator shall have the right to file an application for “fast-track” licensing of Agent at any time during
the term of this CRADA once Collaborator has an approved IND on file with the FDA. Biovest will have access to the follicular lymphoma vaccine clinical data and results and raw data in NIH’s possession and control as defined in Article 2.16 as
needed to support the registration of the Agent by the FDA in this disease. Furthermore, Biovest will be provided safety data 

  
 NCI CRADA 01030 
 Amendment #4 
 Page 1 of 6 

	 	 
generated from the use of the Agent that is in the possession and control of NIH as needed to support the FDA registration. Collaborator’s access to and
use of said data is subject to the terms of Article 8 hereunder and limited to use for regulatory filings only. 

  

	 	(d)	Change Section 3.8 to read: 

  

	 	3.8	Drug Information and Supply. Collaborator agrees to provide NCI without charge formulated and acceptably-labeled clinical-grade Agent in sufficient quantity to complete the
preclinical studies and clinical trial protocol sponsored by NCI within the scope of the CRADA Research Plan. It is understood that NCI shall take responsibility for and reasonable steps to maintain appropriate records and assure appropriate supply,
handling, storage, distribution and usage of these materials in accordance with the terms of this Agreement, the protocol and any applicable laws and regulations relating thereto. 

  
 Effective April 29, 2004, Collaborator agrees to take responsibility and
shall arrange directly with Immunex/Berlex for provision and distribution of adjuvant GM-CSF necessary to complete the clinical trial performed under this CRADA Changes in the composition or manufacture of the Agent for the studies performed under
this CRADA will be mutually agreed upon by both parties. 
  
 The
Collaborator contact will be Dr. Beverly Norris, Biovest (Telephone Number 508-793-0001). 
  

	 	(e)	Change Section 4.3 lo read: 

  

	 	4.3	Adverse Drug Experience Reporting Effective April 29, 2004, Collaborator shall report all serious or unexpected adverse events to FDA in accordance with the reporting
obligations of 21 CFR 312.32 and will, concurrently, forward all such reports to CCR, NCI. All other adverse event reports received by Collaborator shall be reported to the FDA consistent with 21 CFR 312.32 and 312.33. In addition, copies of the
Annual Reports and other pertinent IND data (including, but not limited to, Clinical Brochure data, formulation and preclinical data, including toxicology findings) will be provided to CCR, NCI as they become available. 

  
 The Collaborator will then notify the investigator(s)
conducting studies under the Collaborator-sponsored protocol. 
  

	 	(f)	Delete Section 4.4. 

  

	 	(g)	Change Section 6.2 to read: 

  

	 	6.2	Filing of Patent Applications. Each party shall be responsible for filing patent or other IP applications in a timely manner and at its own expense and after consultation
with the other Party. The Parties will consult and mutually determine a filing strategy for jointly-owned subject inventions. If either Party decides to abandon a patent or patent application covering a jointly owned subject invention it will
provide written notice to the other Party of this intention at least thirty (30) days prior to the date of any applicable deadline by which the patent or patent application would be deemed abandoned. If the non-abandoning Party elects to continue
the patent or patent application, the abandoning Party will cooperate in providing the other Party with needed information to continue the patent or patent application. The Party deciding to continue the patent or patent application will bear all
costs associated therewith. If trade secret information or Collaborator Confidential/Proprietary is essential to file a properly enabled patent application, Collaborator will cooperate to provide equivalent information to file such application.

  
  
  
  
 NCI CRADA 01030 
 Amendment #4 
 Page 2 of 6 

	 	(h)	Change Section 6.3 to read: 

  

	 	6.3	Patent Expenses. The expenses attendant to the filing or maintaining of jointly-owned patent or other IP applications generally shall be paid by the Party filing such
application. If Collaborator elects to take an exclusive license to any Subject Invention under paragraph 7.1, the Collaborator shall be responsible for all reasonable past and future out-of-pocket expenses in connection with the preparation,
filing, prosecution and maintenance of any applications claiming such exclusively-licensed inventions and any patents or other IP grants that may issue on such applications. The Collaborator may waive its exclusive license rights on any application,
patent or other IP grant at any time, and incur no subsequent compensation obligation for that application, patent or IP grant. 

  

	 	(i)	Change Section 6.4 to read: 

  

	 	6.4	Prosecution of Intellectual Property Applications. In connection with any patent or IP application relating to a subject invention filed pursuant to the CRADA, within one
month of receipt or filing, each Party shall provide the other Party with copies of the applications and all documents received from or filed with the relevant patent or other IP office in connection with the prosecution of such applications. Each
Party shall also provide the other Party with the power to inspect and make copies of all documents retained in the patent or other IP application files by the applicable patent or other IP office. Each Subject lnvention made solely by PHS employees
shall be solely owned by PHS. PHS agrees to exclude from any patent application Collaborator trade secret information or Collaborator Proprietary/Confidential Information. If such trade secret information or Collaborator Confidential/Proprietary is
essential to file a properly enabled patent application, Collaborator will cooperate to provide equivalent information to file such application. Each Subject Invention made solely by Collaborator employees shall be solely owned by Collaborator.
Collaborator agrees to exclude from any patent application PHS trade secret information or PHS Proprietary/Confidential Information. If such trade secret information or PHS Confidential/Proprietary is essential to file a properly enabled patent
application, PHS will cooperate to provide equivalent information to file such application. The Parties agree to consult with each other with respect to the prosecution of applications for PHS Subject Inventions and joint Subject Inventions. If the
Parties agree that Collaborator shall file and prosecute IP applications on joint Subject Inventions, then Collaborator agrees to all Customer Number Practice and/or granting of power(s) of attorney (or its equivalent) necessary to assure PHS access
to its United States, International, and Foreign intellectual property rights on said applications. 

  

	 	(j)	Change Section 7.1 to read: 

  

	 	7.1	Option for Commercialization License. With respect to Government IP rights to any Subject Invention not made solely by the Collaborator’s employees for which a patent or
other IP application is filed, PHS hereby grants to the Collaborator an exclusive option to elect an exclusive or nonexclusive commercialization license, which is substantially in the form of the appropriate model PHS license agreement. This option
does not apply to Subject Inventions conceived prior to the effective date of this CRADA that are reduced to practice under this CRADA, if prior to that reduction to practice, PHS has filed a patent application on the invention and has licensed it
or 

  
  
  
  
 NCI CRADA 01030 
 Amendment #4 
 Page 3 of 6 

	 	 
offered to license it to a third party. To the best of NCI’s knowledge after due inquiry on the date that NCI signed this CRADA no such Subject
Invention exists. In the event that it is later determined that any such Subject Invention does exist, Collaborator shall be granted an option to a nonexclusive license for any such Subject Invention licensed to a Third Party on a nonexclusive
basis. The terms of the license will fairly reflect the nature of the invention, the relative contributions of the Parties to the invention and the CRADA, the risks incurred by the Collaborator and the costs of subsequent research and development
needed to bring the invention to the marketplace. The field of use of the license will be commensurate with the scope of the RP. Collaborator has the right to transfer or sublicense any rights taken under this paragraph to additional partners. Any
such sublicenses shall be subject to the terms of the applicable License agreement and upon written approval by PHS, which approval will not be unreasonably withheld; and will reflect that any sub-licensee will not further sublicense.

  

	 	(k)	Change Section 8.8 to read: 

  

	 	8.8	Extramural Research and Data. In pursuing the development of Agent pursuant to this CRADA, NIH utilized extramural investigators for part or all of the completion of this
Research Plan. However, said extramural investigators were not Parties to this CRADA, and this CRADA does not address rights to intellectual property created by such investigators. Nonetheless, to the extent permitted by law and subject to the other
provisions of Article 8 of this CRADA, NIH shall maintain all IND, Clinical Data and Results, and Raw Data in NIH’s Possession and Control as Proprietary and CONFIDENTIAL, and make data related to NCI Protocol 00-C-0050 (P-92) including the
follicular lymphoma vaccine clinical data and results and raw data in NIH’s possession and control, as defined in Article 2.16, and safety data generated from the use of the Agent that is in the possession and control of NIH, as needed to
support the registration of the Agent by the FDA in this disease referenced in Article 3.7 of Appendix C and Item 6 under NCI Contributions of Appendix A, available to the Collaborator, for its own use and for use in obtaining FDA approval for the
commercial marketing of Subject Inventions and Agent products. Accordingly, said data shall not be transferable to any third party by Collaborator without the written permission of the NCI, which will not be unreasonably withheld.

  

	 	(1)	At the end of Section 8.9, add the following: 

  
 Collaborator assumes responsibility for storage, maintenance, and recordkeeping of any phase 3 biopsy samples, including any phase 3 biopsy samples
transferred from NCI to Collaborator, in accordance with FDA rules and regulations and subject to all of the terms of Article 8 as modified in Appendix C herein. This responsibility will survive termination of the CRADA. 
  

	 	(m)	Change Section 10.2 to read: 

  

	 	10.2	Unilateral Termination. Either PHS or the Collaborator may unilaterally terminate this entire CRADA at any time by giving written notice at least sixty (60) days prior to the
desired termination date, and any rights accrued in property, patents or other IP rights shall be disposed of as provided in paragraph 10.1, except that PHS may, at its option, retain funds transferred to PHS prior to unilateral termination by
Collaborator for use in completing the Research Plan solely or with another partner. However, in the event of unilateral termination by Collaborator, Collaborator’s obligation under Article 3.8 will survive termination to the extent reasonably
necessary to complete approved clinical studies under mutually agreed upon protocol. If 

  
  
  
  
 NCI CRADA 01030 
 Amendment #4 
 Page 4 of 6 

 Collaborator elects to terminate its development of Agent without the transfer of its development efforts to support a
level of production equivalent to that which was ongoing at the time of termination, and CCR, NCI elects to continue its development of Agent, then Collaborator agrees to maintain its IND, to provide a letter of cross-reference to
Collaborator’s IND, and to provide financial support for personnel, reagents, supplies, and equipment necessary to transfer back to CCR, NCI all vaccine production, including, but not limited to all relevant biological and immunological assays.
Such obligation shall last until either a date on which vaccine production and related assays are fully transferred back to NCI or one year after the notification from Collaborator to NCI that Collaborator elects to terminate its development of
Agent, whichever comes first. Notwithstanding the foregoing, if NCI has executed an agreement with a new collaborator or third party to be involved in development of Agent, Collaborator’s funding obligations shall be terminated immediately.
CCR, NCI will be responsible for the IND to support this study in the event of Collaborator termination. 
  
  
  
 SIGNATURES BEGIN ON THE NEXT PAGE

  
  
  
  
 NCI CRADA 01030 
 Amendment #4 
 Page 5 of 6 

 ACCEPTED AND AGREED TO: 
  
  
 For the
National Cancer Institute: 
  

					
			
	/s/ Anna D. Barker	 	 	 	04/06/05
	 Anna D. Barker, Ph.D.
 Deputy Director for Advanced
Technologies And Strategic Partnerships, NCI
	 	 	 	Date

  
 For the Collaborator:

  

					
			
	  	 	 	 	  
	 	 	 	 	Date

  
 NCI CRADA 01030 
 Amendment #4 
 Page 6 of 6 

 APPENDIX A 
  
 RESEARCH PLAN 
  
 Clinical Development of Hybridoma-Based Idiotypic Vaccines for 
 Treatment of Follicular B-Cell Lymphoma 
  
 NCI Principal Investigator(s) 
 Barry L. Gause, M.D. 
 Center for Cancer Research (CCR) 
 National Cancer Institute (NCI) 
  
 Collaborator Principal Investigator(s) 
 Stephane E. Allard, M.D. 
 Medical Director

 Biovest International, Inc. 
  
 Term of CRADA 
 Eight (8) years from the date of
the final CRADA signature. 
  
 A Letter of Intent (LOI) for this
CRADA was executed 
 by and between the Parties on January 9, 2001. 
 An Extension to the LOI was executed by and between 
 the Parties on June 25, 2001

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-1 

 GOALS OF THIS CRADA 
  
 The goal of this project is to develop an efficacious hybridoma-based idiotype vaccine to produce long-term disease-free survival in follicular B-cell lymphoma patients
who have attained a complete clinical response from chemotherapy and to compile data required to support a Biological License Application (BLA) to the U.S. Food and Drug Administration (FDA) for hybridoma-based idiotype follicular B-cell lymphoma
vaccine. 
  
 The Center for Cancer Research (CCR), National Cancer lnstitute (NCI)
and Collaborator shall work together toward the successful development of the hybridoma-based idiotype vaccine as a safe and effective novel anti-cancer treatment for follicular B-cell lymphoma. The CCR will work closely with Collaborator to obtain
and evaluate the clinical data that may be required to allow Collaborator to obtain regulatory approval by the FDA. Collaborator will provide expertise in the development, formulation and Good Manufacturing Practice (GMP) production of the vaccine.
Additionally, CCR will work with Collaborator in the ongoing clinical trial planned under this CRADA as well as all regulatory aspects and the BLA filings necessary for Collaborator to obtain marketing approval. 
  
 The scope of this CRADA includes the development of the processes required for large-scale
GMP production of adequate numbers of GMP-produced and formulated idiotype vaccines to complete the clinical development of this treatment for follicular B-Cell lymphoma. This vaccine strategy involves the use of an immunological adjuvant,
granulocyte-macrophage colony-stimulating factor (GM-CSF), which is being provided for this study under an agreement between Biovest and Immunex/Berlex. 
  
 BACKGROUND 
  
 INTRODUCTION 
  
 Current
Treatment of Indolent Follicular Lymphomas 
 The indolent follicular lymphomas (FL) are follicular small-cleaved cell (FSC) and follicular mixed lymphoma
(FM). Stage I and II patients comprise only 10% to 15% of all cases of follicular lymphomas and are best managed with radiation therapy. Eighty-five percent of patients with follicular lymphomas present with stage III or IV disease. The optimal
management of these patients remains controversial and has generally followed two divergent approaches (1, 2). An aggressive approach, which has included radiation therapy, combination chemotherapy, or combined modality therapy; and a conservative
approach that involves no initial treatment followed by a single-agent chemotherapy or involved-field radiotherapy when required (3, 4). Most forms of systemic therapy have the capacity to produce high complete response rates. However, they have
failed to produce long-term disease-free survival or to prolong overall survival; thus, it has become clear that the vast majority of patients with this disease will relapse and die of their lymphoma, despite its usually indolent course. 

 
 Technology Summary 
 The development of a vaccine against human malignancies has been a long-sought goal, which has yet to be achieved. Many of the efforts toward this end have been frustrated by the lack of identification of a
tumor-specific antigen which would allow tumor cells to be distinguished from normal cells. Conceptually, such an antigen could be used as a vaccine to induce the host’s immune system to reject cells bearing that antigen. 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-2 

 Immunoglobulin (Ig) molecules are composed of heavy and light chains, which possess highly specific variable regions at
their amino termini. The variable regions of heavy and light chains combine to form the unique antigen-recognition site of the Ig protein. These variable regions contain determinants that can themselves be recognized as antigens, or
idiotypes. B-cell malignancies are composed of clonal proliferations of cells synthesizing a single antibody molecule with unique variable regions in the heavy and light chains. B-cell lymphomas are neoplasms of mature resting and reactive
lymphocytes, which generally express synthesized Ig on the cell surface. The idiotypic determinants of the surface Ig of a B-cell lymphoma can thus serve as a tumor-specific marker for the malignant clone. 
  
 Studies in experimental animals, as well as in man, have demonstrated the utility of the Ig
idiotype as a tumor-specific antigen (5, 6). Lynch and Eisen were the first to demonstrate that active immunization against idiotypic determinants on malignant B cells could produce resistance to tumor growth, and this phenomenon of idiotype tumor
resistance has been reproduced subsequently in a number of syngeneic experimental tumor models, as well as specific anti-tumor therapy against established tumors (7-16). These results, taken together, provided the rationale for testing autologous
tumor-derived idiotypic surface Ig (Id) as a therapeutic “vaccine” against human B-cell lymphoma. 
  
 Summary of Previous Clinical Studies Sponsored by NCI 
  
 Phase 1 Clinical Trial. 
  
 Kwak et al. first immunized human patients with B-cell lymphoma with autologous Id protein (17). The Id-keyhole limpet hemocyanin (ld-KLH) was emulsified
in a Pluronic polymer-based adjuvant vehicle formulation. Ultimately, approximately 40 patients were treated on this protocol. Because the study population was heterogeneous, it was not designed to answer the question of anti-tumor efficacy. Rather,
this first study assessed the question of immunogenicity; i.e., is it even possible to immunize a patient against a self-tumor antigen? In this context, this study was important, because it demonstrated that patients with B-cell lymphoma could be
induced to make primarily idiotype-specific antibody responses, but with little evidence for T-cell immunity. 
  
 Improving the potency of the Id-KLH Vaccine. 
  
 At the NCI, the objective of Id vaccine development has been to further optimize the immunogenicity of this vaccine. To this end, NCI focused on the use
of novel immunological adjuvants, which were 1), more potent and 2) more effective in the induction of cell-mediated immune responses, particularly CD8+ T-cells, compared with the pluronic polymer-based adjuvant used in the pilot study. 

 
 As a preclinical aim, Kwak et al. utilized a murine B cell tumor as a
model system in which to screen promising immunological adjuvants. A number of these included cytokines, and among these, GM-CSF emerged as a promising adjuvant for idiotypic Ig antigen (18). 
  
 The results demonstrated that the augmented survival benefit afforded by
immunization with relevant Id-KLH alone could be significantly enhanced by the addition of GM-CSF at either the 100 or 10,000 unit dose. A curious but reproducible observation was the loss of this protective effect at 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-3 

 a higher dose of GM-CSF of 50,000 units. These data suggest that GM-CSF may have a potent adjuvant effect
in vivo for Id-KLH antigen, especially at relatively low doses. Furthermore, T-cell subset depletion experiments demonstrated that effector CD8+ T-cells were required for anti-tumor immunity. 
  
 Phase 2 Clinical Trial. 
  
 Based on the findings of this preclinical study, the NCI sponsored a Phase 2
clinical study to evaluate the ability of this new idiotype vaccine to elicit tumor-specific T-cell immunity, as measured by the ability of patient T cells to specifically lyse their own tumor cells in vitro, and to exert antitumor effects as
measured by the elimination of t(l4;18)-bearing cells from the peripheral blood of uniformly treated FL patients in first CR (complete remission). Patients in this study were previously untreated and received a uniform chemotherapy regimen, PACE;
Prednisone, Adriamycin, Cytoxan, and Etoposide. (modified ProMACE without methotrexate). By design, therefore. they comprised a very homogeneous patient population in a minimal residual disease state. Of 35 patients, 23 (66%) achieved CR by standard
clinical criteria. One of the patients was lost to analysis because of early relapse within six months, and two were excluded because a vaccine could not be made. This left a total study group of 20 patients in CR. Six to 15 months after completion
of chemotherapy, these 20 patients were treated with a series of five monthly vaccinations with autologous FL Ig protein (0.5 mg) conjugated to KLH, together with local granulocyte-macrophage colony-stimulating factor (GM-CSF, 100 or 500 mcg/m2)
subcutaneously (19). 
  
 Eighteen of 20 patients remain in
continuous, first complete remission (median: 42+ months from completion of chemotherapy, range: 284+ to 53+). UPN 9 and 14 relapsed at 15 and 7 months after completion of vaccine therapy, respectively. UPN 9 had never cleared the t(14;18)-bearing
cells from the peripheral blood; UPN 14 did not have the MBR rearrangement and thus, molecular CR status could not be established. 
  
 The rationale for a pivotal, randomized trial, which is the subject of this CRADA is thus based on three independent results from this completed Phase 2
study: (I) tumor-specific CD8+ T-cell responses (cytotoxicity against autologous FL targets and cytokine production) were seen in 17 of 20 (85%) vaccinated patients, (2) 8 of 1 1 (73%) patients sampled after completion of vaccination converted to
PCR negative and have maintained both PCR negativity and clinical CR, and (3) with a median follow-up of 36+ months after completion of chemotherapy (range 22+ to 47+ months), 18 of 20 (90%) patients remain in continuous clinical CR. 
  
 Taken together, these data suggest that idiotype vaccination can elicit a
tumor-specific response that is associated with clearance of residual tumor cells from the blood in the majority of patients with FL. It remains to be determined whether molecular CR is associated with prolonged disease-free survival. However, this
systematic analysis of molecular response rate provides the first evidence for an anti-tumor effect of vaccination. Finally, this study established GM-CSF as an essential component of the vaccine strategy, particularly for induction of CD8+ T-cell
responses. 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-4 

 CCR, NCI 
  
 Dr. Kwak and his group pioneered the first human studies of vaccines for B-cell malignancies. Dr. Kwak’s group had a broad range of scientific and clinical interests
spanning tumor immunology, adoptive T cell therapy, and management of lymphomas and myelomas. Specific work in his NCI laboratory was focused on studies of immunobiology and immunotherapy of hematological malignancies. The NCI laboratory’s
principal objective was to obtain conclusive proof for the cancer vaccine concept; i.e., simply that it is possible to induce an immune response against a self protein, which is inherently poorly immunogenic, in human cancer patients. The goals for
vaccine development are: (1) to increase the potency of vaccine formulations, and (2) to develop formulations which are more effective in activating the ceIlular arm of the immune response. The working hypothesis is that achieving the eventual goal
of demonstrating clinical efficacy will depend on the ability of vaccines to elicit sustained, potent cell-mediated responses. 
  
 The current clinical trial of Id vaccination in previously untreated patients with follicular lymphomas initiated by Dr. Kwak’s laboratory, which is the subject of
this CRADA, features a new formulation of the prototype Id-KLH conjugate vaccine using GM-CSF as a potent immunological adjuvant. CD8+ T cell responses, capable of lysing autologous tumor targets, and molecular remissions have been observed in the
vast majority of vaccinated patients. 
  
 BIOVEST INTERNATIONAL INC.

  
 INTRODUCTION 
  
 The proprietary technology of Biovest (hollow fiber bioreactor instrumentation) that will be
applied under this CRADA utilizes a patented process that optimizes fluid flow dynamics within perfused bioreactors to maintain high cell densities and continuously harvest secreted protein for extended periods of time. An experienced team of
mechanical, electrical, software and biochemical engineers was established at Biovest to develop this technology. As a result of these efforts, the company gained significant expertise in the large-scale application of cGMP mammalian cell culture,
which has subsequently been applied to a wide variety of cell lines for hollow fiber bioreactor production of recombinant or fusion based proteins. Combined with this existing expertise, a cGMP process will be developed that will be designed to
facilitate commercial application of patient-specific vaccines. 
  
 Biovest’s
cell culture expertise was recognized when the National Center for Research Resources, NIH, awarded the National Cell Culture Center to Biovest. This research resource facility was awarded to Biovest in 1990 through a competitive five-year
Cooperative Agreement Award, which has been renewed twice, currently funded through September 2005. This resource was created to provide the biomedical research community with subsidized access to professional large-scale cell culture services.
During that time, Biovest has received hundreds of cell lines from academic investigators within many major research institutions in the United States, for the purpose of large-scale production. The majority of these lines are hybridoma, transfected
or chimeric lines, created for the production of immunoglobulin. 
  
 NCI CRADA
01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-5 

 In addition, for the past ten years, Biovest has provided contract services to biotechnology and pharmaceutical companies
for use in clinical (cGMP) applications, produced in isolation suites within Biovest’s manufacturing facility. For the vast majority of these cell lines, automated hollow fiber bioreactor instrumentation is utilized for protein production.
Biovest instrumentation, combined with years of process development experience for high-cell density perfusion culture, is one principal advantage of Biovest’s contract laboratory. This ability to modify hardware and understand the biochemical
aspects of high-density culture has allowed us to develop successfully many processes unique to large-scale culture, which are typically incorporated into cGMP manufacture of the final product. Currently, a documentation system exists that addresses
cGMP production requirements for numerous specialized cell lines and processes with hollow fiber bioreactor technology in a multi-use facility. 
  
 Similar to cGMP cell culture procedures, the existing instrumentation was developed as a Class I medical device, suitable for clinical application. This experience will
be an important asset to the development and large-scale manufacture of instrumentation that can be applied to vaccine production. 
  
 Biovest International, Inc. (formerly Cellex Biosciences) is a leading manufacturer of hollow fiber bioreactor instrumentation and contract production services worldwide.
In 1984, the corporation began development of instrumentation that automated the culture of mammalian cells on a large scale. Subsequently, the company utilized this hollow fiber bioreactor technology to create a cGMP production process that
accommodates economic production of large amounts or specific cell-secreted protein (e.g. monoclonal antibodies) from numerous cell lines within one facility. During the past two decades, Biovest has developed a range of hollow fiber bioreactor
instruments to address production at the research level through large-scale pharmaceutical needs. This patented technology is now widely accepted by numerous biotechnology and pharmaceutical companies throughout the world. As a result, Biovest, with
perfusion cell culture methodology (hollow fiber bioreactor), offers a well-defined cGMP approach to large-scale commercial production of clinical and pharmaceutical grade proteins. 
  
 In December 1999, Biovest was awarded a contract with NCI to produce idiotype (antibody) as crude supernatant from heteromyeloma patient
cell lines, created in Dr. Kwak’s laboratory. This idiotype was subsequently used to create the Id-keyhole limpet hemocyanin (Id-KLH) lymphoma vaccine for study in an ongoing Phase 3 clinical trial, which is the subject of this CRADA. Creation
of this vaccine is extremely labor intensive and Biovest, along with Dr. Kwak, recognized that commercial application would ultimately be dependent on research and development of a simplified or automated process. As such, Biovest responded to an
NCI CRADA announcement and proposed a collaboration toward this end. Biovest will leverage its cell culture, purification, and clinical instrument expertise to facilitate production and commercialization of the idiotype tumor vaccine for B-cell
lymphoma. Under the CRADA, a process and accompanying automated technology will be designed to produce and purify idiotype from each patient-specific cell line, both rapidly and cost effectively in a cGMP environment. Biovest recognizes that this
patient-specific approach is dependent on technology designed to address these needs. Unlike conventional biologicals or drugs, which benefit from mass production or economy of scale, this new technology will be designed with the aim of allowing
thousands of patient-specific vaccines to be manufactured efficiently each year. 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL

  

 A-6 

 Work Under this CRADA: The Phase 3 Clinical Trial. 
  
 To definitively answer the question of clinical efficacy, the NCI opened a multi-institutional, controlled, randomized Phase 3 clinical
trial in January 2000 under the auspices of the NCI Vaccine Working Group and with support from the Office of the Director. Given the fact that no cancer vaccine has been licensed for use in the United States, designing this trial as a
scientifically rigorous test of the cancer vaccine hypothesis, with scientific proof of principle as the primary objective, was felt to be paramount. Therefore, no changes in the key variables were (or will be) considered. Specifically, the design
of the study remains identical to that of the Phase 2 study. Specifically, only patients with previously untreated lymphoma of follicular types are eligible, all patients receive uniform PACE chemotherapy, and vaccination is therefore administered
to a homogeneous group of patients in first complete remission. Importantly, the vaccine formulation is also identical to that used in the Phase 2 trial, using the same hybridoma fusion technology to generate the vaccine, and using the same dose,
schedule, and route of vaccine administration. A multi-center consortium of clinical sites has been assembled, including Northwestern University, University of Pennsylvania, Duke University, Moffitt Cancer Center, and the NIH Clinical Center with
additional sites under consideration. 
  
 The trial is anticipated to enroll a
total of 563 patients, approximately 2/3 of whom are expected to achieve a clinical complete remission from PACE chemotherapy. Patients achieving a complete remission are randomized to begin treatment with either a specific vaccine consisting of
Id-KLH + GM-CSF, or non-specific vaccine consisting of KLH + GM-CSF, in a 2:1 ratio (in favor of specific vaccine) starting six months after completion of chemotherapy. 
  
 This trial anticipates accrual over five years, and because of the long natural history of Follicular lymphoma, an additional three years of
follow-up time is projected to observe at least a 20% improvement in disease-free survival (study endpoint) for the experimental group. 
  
 The achievement of scientific proof of concept remains the primary objective of this Phase 3 trial. The addition of a CRADA partner will allow the data from this trial to
be put together in support of a BLA with the FDA, which is necessary to help bring this vaccine to market. Furthermore, the CRADA partner’s contribution of intellectual property will allow for development of an automated system for the
practical production of a vaccine to be brought to market and fulfill a currently unmet public health need. Finally, the addition of a corporate partner may make it possible to accelerate patient accrual in order to complete the trial and provide
data necessary to support a BLA with the FDA in a shorter period of time. 
  
 Production of Id Vaccines. 
  
 Since Id is a clonal marker
unique to each lymphoma, vaccines must be produced on an individualized basis for each patient. The strategy used to isolate immunogloblin from the surfaces of human B-cell lymphomas consists of performing a hybridization between the lymphoma cell
and a modified mouse/human heteromyeloma cell that grows in vitro and that has the cellular machinery to synthesize and secrete large quantities of immunoglobulin. Such myeloma fusion partners have been engineered not to secrete any
immunoglobulin of their own; therefore, the immunoglobulin that is secreted following fusion is derived purely from the human tumor. 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-7 

 The production of Id protein begins with the isolation of malignant cells from tumor biopsy specimens, most commonly
involved lymph nodes, although tumor cells isolated from peripheral blood, bone marrow or spleen can be used. The minimal starting material consists of about 75 million tumor cells. These cells are then fused with a
hypoxanthine-aminopterin-thymidine (HAT) – sensitive fusion partner, and hybridomas selected in HAT medium that secrete immuoglobulin with the type of heavy and light chains corresponding to the known immunophenotype of the tumor specimen are
identified. This is vaccine production process step 1. 
  
 Polymerase chain
reaction (PCR) amplification of the immunoglobulin variable region genes from both the hybridoma and the primary tumor specimen are performed, and the sequences are compared to establish the identify of the secreted immunoglobulin. This is vaccine
production step 2. 
  
 Heterohybridomas identified in this way are
expanded. This is vaccine production process step 3. 
  
 Id protein is the
purified from collected culture supernatants by affinity chromatography depending on the isotype of the lymphoma immunoglobulin. Each idiotype protein is then conjugated to KLH. These two processes are collectively referred to as vaccine production
process step 4. 
  
 This Id-conjugate is then used to immunize the patient
from whose tumor it was originally isolated. 
  
 Phase 3 clinical trial vaccine
production steps 1-2 and 4 were performed by NCI, and step 3 was performed by Biovest under NCI’s IND application from the inception of this CRADA until April 29, 2004, when Biovest International received FDA approval of its IND application for
the Phase 3 clinical trial. Beginning April 29, 2004, performance of all steps of the vaccine production process for the Phase 3 clinical trial was assumed by Biovest and is now conducted under Biovest’s IND application. The technology for
heterohybridoma fusion and selection and PCR sequencing will continue to be optimized for GMP production at Biovest International. As noted above, the ultimate goal of this CRADA is to fully develop the technology allowing optimized Id vaccine
production under GMP conditions that would be necessary for FDA approval for human clinical use. As part of that goal, NCI and Biovest will investigate the automation of this stepwise production of Id vaccines using Biovest’s proprietary
instrument. 
  
 Under optimal conditions, approximately three months are required
for production of the final product. This time period does not constitute a limitation, as the vaccine administration occurs following six to eight months of cytoreduction with conventional chemotherapy and an additional six month rest period.

  
 Overall, the CRADA is an extension and combination of existing NCI and Biovest
systems and procedures for cell culture, purification and clinical instrument development. NCI and Biovest staff will undertake the cell fusion, gene sequencing, and purification/conjugation procedures. Combined with Biovest’s existing
intellectual property and instrument manufacturing experience, these procedures will be incorporated into a single instrument that can be applied to production and purification of personalized cancer vaccines in a clinical setting. It is envisioned
that several principle steps required to create this vaccine can be incorporated into an affordable, user-friendly technology, designed specifically for commercial production of this vaccine. 
  
 Ultimately, successful commercialization will depend on the capability to service large
numbers of patients economically. The autologous nature of this therapy places significant emphasis on creating an automated, yet individualized, manufacturing process for each patient. This “personalized” approach precludes the

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-8 

 efficiencies or economies of scale typically observed in commercial antibody production. It is estimated that a minimum
of 15,000 patients (US only) per annum will seek vaccination. To realize that number (200 to 300 per week), an efficient and affordable patient-specific Current Good Manufacturing Process (cGMP) is required. As such, an automated process for
antibody production and purification becomes a key to the success of this approach. 
  
 Biovest is committed to expanding its technological capabilities in parallel with the first two years of the Phase 3 clinical trial. Based on past experience, this is a reasonable timeline and will allow for equivalency studies, initial
validation testing, and instrument manufacture suitable for FDA approval. Biovest laboratories also contain cGMP space, as well as build-out capacity, if required, that can be dedicated to commercialization efforts. Beyond that space, an additional
12,000 square feet of FDA validated cGMP space is available for production and purification as the Phase 3 clinical trial expands. Biovest has utilized hollow fiber technology for over 3 years and successfully operated isolation suites that parallel
the needs for personal vaccine production. 
  
 The goal is to transfer to Biovest
the B-cell isolation techniques and the unique cell fusion, molecular sequencing and conjugation expertise developed at NCI, and the transfer took place in June 2004. Biovest and NCI will work together to train skilled cellular immunologists and
protein biochemists at Biovest. The ultimate objective is to establish material duplication of these procedures in other laboratories. Based on 15,000 vaccinations per year (U.S.), the ability to set up at least one cGMP production facility for cell
fusion, screening and molecular sequencing is essential. This will be done in parallel with the ongoing Phase 3 clinical trial to expedite the commercialization process. 
  
 Enhancing Patient Accrual. 
  
 Additionally, Biovest intends to enhance patient accrual for the Phase 3 clinical trial by providing access to patients through the New York University (NYU) hospitals.
NCI and Biovest intend to further participate in patient accrual and shorten the time required to complete this study. 
  
 Further, Biovest will enhance national physician and patient awareness of this clinical trial by assuming responsibility for the marketing strategy. To do this, Biovest
is prepared to take several actions designed to increase patient accrual for the Phase 3 clinical trial. Biovest’s marketing firm has represented that these actions will include both direct and indirect promotional and marketing efforts.
Biovest’s promotional and marketing efforts related to and during the term of this CRADA will be reviewed and approved by NCI. It is anticipated that this promotional campaign will greatly accelerate patient accrual for this clinical trial.

  
 As set forth in the preceding sections, Biovest is equipped scientifically and
financially to collaborate with NCI to successfully perform all aspects of bringing this idiotype tumor vaccine through the final clinical trial and into commercial production. Because of their expertise in the field of hollow fiber perfusion
technology, they possess the necessary team of experienced engineers and scientific personnel to develop the cGMP process crucial to therapeutic application of this vaccine. It is anticipated that this vaccine production process will be complete and
a broadly accessible therapy prior to conclusion of this Phase 3 study. Associated with instrumentation, and following FDA approval, the hollow fiber bioreactor manufacturing will be implemented to fulfill the large number of anticipated vaccines.
The objective is to incorporate automated technology with cGMP production processes, such that this personalized approach to the treatment of lymphoma can be brought to market to answer an unmet public health need. 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-9 

 WORK SCOPE OF PROPOSED CRADA 
  
 The scope of this CRADA includes the development of the processes required for large-scale
GMP production of adequate numbers of GMP-produced and formulated idiotype vaccines to complete the clinical development of this treatment for follicular B-Cell lymphoma. This vaccine strategy involves the use of an immunological adjuvant, CM-CSF,
which is being provided for this study under an agreement between Biovest and Immunex/Berlex. Such processes may include, but are not limited to refinement of GMP process and automation of the vaccine production. 
  
 RESPECTIVE CONTRIBUTIONS OF
THE PARTIES 
  

	A.	Joint Responsibilities 

  

	1.	Steering Committee- Effective April 29, 2004, the Parties agree to establish a joint clinical development team whose responsibility will be the oversight of the ongoing Phase 3
Clinical Trials performed under the Collaborators IND related to this CRADA. The Steering Committee will comprise the following NCI staff: the Principal Investigator, the Project Officer for Vaccine Production, the Protocol Coordinator, the Protocol
Chairman, and the following Collaborator staff: Principal Investigator, and appropriate Collaborator staff in the areas of clinical monitoring, pharmacy, statistics, manufacturing and publicity. Although the members of the Steering Committee shall
be considered as having been delegated to the Steering Committee, they shall continue to remain employed by their respective employers under their respective terms of employment. 

  

	2.	Both parties to the CRADA will provide independent statistical expertise and work closely together to ensure that the CRADA clinical trial moves forward expeditiously. Activities
conducted in support of this obligation include providing public notice and promotion of the clinical trial to foster patient accrual. 

  

	3.	Both parties to the CRADA shall collaborate in the collection and analysis of data from the clinical trial. 

  

	4.	Both parties to the CRADA will evaluate the study as it progresses to ensure that the appropriate questions are being addressed and to ensure that the study is modified as required
based on the developing data. The DCTD will utilize its existing procedures and mechanisms to follow the clinical study to ensure that the study meets the pertinent FDA regulations until Biovest receives an approved IND for this technology.

  

	5	Both parties to the CRADA will meet with the FDA jointly to discuss protocol and requirements necessary for the study to support a Biologic License Application with the FDA

  

	6.	Both parties to the CRADA will work closely together to develop processes for commercial cGMP production of Id-KLH follicular B-cell lymphoma vaccine with GM-CSF as adjuvant.

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-10 

	B.	NCI Responsibilities 

  
 The National Cancer Institute contribution to the collaborative research and clinical development of Id-KLH indolent follicular lymphoma vaccine includes the following: 
  

	1.	Effective March 1, 2004, Dr. Barry Gause will serve as the NCI Principal Investigator for this CRADA. Authorship of publications concerning research performed under this CRADA shall
be in accordance with scientific customs and subject to the terms of Article 8. Proprietary Rights and Publication hereunder. 

  

	2.	Subject to the provisions of Articles 8.3 and 10.6 hereunder, the CCR will collaborate solely with Collaborator for development of Agent under Biovest’s Protocol #BV 301 and
NCI’s protocol #00-C-0050 (P-92). 

  

	3.	The CCR Data Safety and Monitoring Board will be responsible for reviewing, at least annually, the accumulated toxicity and efficacy data of Biovest Protocol #BV 301/NCI protocol
#00-C-0050 (P-92) and providing a report summarizing its recommendations to Collaborator. 

  

	4.	The CCR will work with Biovest in development of processes necessary for Collaborator to perform vaccine production steps 1 - 4 in the production of Id-KLH indolent
follicular lymphoma vaccine in support of Biovest Protocol #BV 301/NCI Protocol #00-C-0050 (P-92). 

  

	5.	Using NCI immunologic assays, the CCR will examine these surrogate endpoints in support of Biovest Protocol #BV 301/NCI protocol #00-C-0050 (P-92). 

  

	6.	Biovest will have access to the follicular lymphoma vaccine clinical data and results and raw data in NIH’s possession and control as defined in Article 2.16 as needed to
support the registration of the Agent by the FDA in this disease. Furthermore, Biovest will be provided safety data generated from the use of the Agent that is in the possession and control of NlH as needed to support the FDA registration.
Collaborator’s access to and use of said data is subject to the terms of Article 8 hereunder and limited to use for regulatory filings only. 

  

	C.	Biovest Responsibilities 

  

	1.	Subject to the provisions of Articles 8.4, 8.10 and 13.1 hereunder, effective April 29, 2004, the Collaborator will be responsible for: adverse event monitoring and reporting, drug
distribution, clinical data collection, and protocol amendments for NCI Protocol #00-C-0050 (P-92). 

  

	2.	Effective April 29, 2004, Collaborator will be responsible for supply of Immunex/Berlex GM-CSF for NCI Protocol 

	 	#00-C-0050 (P-92). 

  

	3.	Effective April 29, 2004, Collaborator will perform vaccine production steps 1, 2, 3, and 4 in the production of Id-KLH indolent follicular lymphoma vaccine in support of NCI
Protocol #00-C-0050 (P-92). 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-11 

	4.	Collaborator will conduct studies as necessary with the goal of optimizing and automating vaccine production and refining and validating production procedures as required by the
FDA. 

  

	5.	Subject to the provisions of Articles 8.4, 8.10 and 13.1 hereunder, Collaborator will develop an electronic archive for storage and retrieval of study-related data as required by
the FDA for submission of data in support of a BLA. 

  

	6.	Effective April 29, 2004, Collaborator will be responsible for conduct of data monitoring activities related to NCI Protocol #00-C-0050 (P-92). 

  

	7.	Collaborator will provide long-term patient monitoring to determine overall survival outcomes and will furnish such data to NCI. This responsibility will survive termination of the
CRADA. 

  

	8.	Collaborator will arrange, host and provide support for: meetings associated with the Protocol Steering Committee and the Oversight Committee and; quarterly site visits by
appropriate NCI and Biovest staff to each clinical consortium site and; clinical investigators meetings as needed (anticipated every 6-12 months). 

  

	9.	For activities conducted pursuant to this CRADA in the United States of America, Collaborator, to the extent it engages in applicable conduct, agrees to comply with all appropriate
DHHS regulations relating to Human Subjects Use, all U.S. Department of Agriculture regulations, the decisions of the NCI Data Safety and Monitoring Board, and all Public Health Service policies relating to the use and care of laboratory animals.
For activities conducted pursuant to this CRADA outside of the United States of America, Collaborator shall conduct such in accordance with Good Laboratory Practices (GLPs) and all applicable rules, regulations and statutes, both local and national,
governing such activity in that country. 

  

	10.	Biovest will seek, with NCI approval, to accelerate patient accrual to NCI Protocol #00-C-0050 (P-92) by: 

  

	 	(1)	supporting protocol-related patient care and personnel costs at extramural consortium sites and; (2) by providing aggressive promotional and marketing efforts subject to NCI
approval. These efforts will be comprehensive, including, at a minimum, engaging a professional marketing firm, nationwide direct marketing to referring doctors, organizing and sponsoring seminars in each of the geographic areas represented by
current and future clinical consortium centers nationwide, and developing an interactive website. 

  

	11.	Biovest will assume responsibility for storage, maintenance, and recordkeeping of any phase 3 biopsy samples, including any phase 3 biopsy samples transferred from NCI to Biovest,
in accordance with FDA rules and regulations and subject to the terms of Article 8 as modified in Appendix C of this Agreement. This responsibility will survive termination of the CRADA. 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-12 

 References: 
  
 1. Longo DL, Young RC, DeVita VT. What is so good about the “good prognosis” lymphoma? in Williams CG, Whithouse JMA (eds.): Recent Advances in Clinical
Oncol Edinburgh, Churchill-Livingstone, pp. 223-231, 1982. 
  
 2. Portlock CS.
“Good risk” non-Hodgkin’s lymphomas: Approaches to management. Sem Hematol, 1980, 20:25-34. 
  
 3. Portlock CS, Rosenberg SA. No initial therapy for stage 3 and IV non-Hodgkin’s lymphomas of favorable histologic types. Ann Intern Med, 1979, 90:l0-13.

  
 4. Homing SJ, Rosenberg SA. The natural history of initially untreated
low-grade non-Hodgkin’s lymphomas. N Engl J Med, 1984, 311:147-5. 
  
 5. Stevenson GT, Stevenson FK. Antibody to molecularly defined antigen confined to a tumor cell surface. Nature, 1975, 254:714-6. 
  
 6. Stevenson GT, Elliott EV, Stevenson FK. ldiotypic determinants on the surface immunoglobulin of neoplastic lymphocytes: a therapeutic target. Fed Proc, 1977,
36:2268-71. 
  
 7. Sirisinha S, Eisen HN. Autoimmune-like antibodies to the
ligand-binding sites of myeloma proteins. Proc Natl Acad Sci USA, 1971, 68:3130-5. 
  
 8. Lynch, R. G., R. J. Graff, S. Sirisinha, E. S. Simms, and H. N. Eisen. Myeloma proteins as tumor-specific transplantation antigens. Proc. Natl. Acad. Sci. USA, 1972, 69:1540. 
  
 9. Jorgensen T, Gaudernack G, Hannestad K. Immunization with the light Chain and the VL
domain of the isologous myeloma protein 315 inhibits growth of mouse plasmacytoma MOPC-315. Scand J Immunol, 1980, 11:29-35. 
  
 10. Daley MJ, Gebel HM, Lynch RG. Idiotype-specific transplantation resistance to MOPC-315: Abrogation by post-immunization thymectomy. J Immunol, 1978,
120:1620-4. 
  
 11. Bridges SH. Participation of the humoral immune system in the
myeloma-specific transplantation resistance. J lmmunol, 1978, 121:479-83. 
  
 12. Freedman PM, Autry JR, Tokuda S, Williams RC, Jr. Tumor immunity Induced by preimmunization with BALB/c mouse myeloma protein. J Natl Cancer Inst 1976, 56:735-740. 
  
 13. Sugai S, Palmer DW, Talal N, Witz IP. Protective and cellular immune responses to idiotypic determinants on cells from a spontaneous
lymphoma of NZB/NZWFl mice. J Exp Med, 1974, 140:1547-58. 
  
 NCI CRADA
01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-13 

 14. Stevenson FK, Gordon J. Immunization with idiotypic immunoglobulin Protects against development of B lymphocytic
leukemia, but emerging tumor cells can evade antibody attack by modulation. J Immunol, 1983, 130:970-973. 
  
 15. George AJT, Tutt AL, Stevenson FK. Anti-idiotypic mechanisms involved in the suppression of a mouse B cell lymphoma, BCL. J Immunol, 1987, 138:628-634.

  
 16. Kaminski MS, Kitamura K, Maloney DG, Levy R. Idiotype vaccination Against
murine B cell lymphoma. Inhibition of tumor immunity by free idiotype protein. J Immunol, 1987, 138:1289-1296. 
  
 17. Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R. Induction of immune responses in patients with B cell lymphoma against the surface immunoglobulin
idiotype expressed by their tumors. N Engl J Med, 1992, 327:1209-1215. 
  
 18. Kwak LW, Young HA, Pennington RW, Weeks SD, Vaccination with syngeneic, lymphoma-derived immunoglobulin idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T-cell
response. Proc Natl Acad Sci USA 1996 Oct 1;93(20): 10972-7. 
  
 19. Bendandi ME, Gocke C, Kobrin C, Benko F, Sternas L, Pennington R, Watson T, Reynolds C, Cause B, Duffey P, Jaffe E, Creekmore S, Longo D, and Kwak LW. Complete molecular remissions induced by patient-specific
vaccination plus GM-CSF against lymphoma. Nat Med, 5:1171-1177, 1999. 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL

  

 A-14 

 DESCRIPTION OF OTHER NCI-BIOVEST
INTERNATIONAL, INC. AGREEMENTS AND INTELLECTUAL 
 PROPERTY OF THE PARTIES 
  

			
	 CRADAs:
	    	None
		
	 MTAs:
	    	None
		
	 CTAs:
	    	None
		
	 CDAs:
	    	2-02244-01; “Discussions for the entering into of a Cooperative Research &
	 	    	Development Agreement (‘CRADA’) for the development and production of
	 	    	idiotype vaccines against B-cell lymphoma”; Executed November 20, 2000.

  
 PATENTS/PATENT APPLICATIONS:

  
 Biovest International 
  
 Patents 
  

	 	US  Patent  	4,804,628, Hollow Fiber Cell Culture Device and Method of Operation. 

	 	US  Patent  	5,079,168. Cell Culture Apparatus. 

	 	US  Patent  	5,416,022. Cell Culture Apparatus. 

	 	US  Patent  	5,330,915. Pressure Control System for a Bioreactor 

	 	US  Patent  	4,629,686. Apparatus for Delivering a Controlled Dosage of a Chemical Substance. 

	 	US  Patent  	4,618,586. Apparatus for Delivering a Controlled Dosage of a Chemical Substance Having an Improved Culture Chamber. 

	 	US  Patent  	4,650,766. Culturing Apparatus. 

	 	US  Patent  	297,620. Multi-Port Fitting for a Flask. 

	 	US  Patent  	5,202,254. Process for Improving Mass Transfer in a Membrane Bioreactor Providing a More Homogeneous Culture Environment. 

	 	US  Patent  	4,722,902. Apparatus and Method for Culturing Cells, Removing Waste, and Concentrating Product. 

	 	US  Patent  	4,973,558. Method of Culturing Cells Using Highly Gas Saturated Media. 

	 	US  Patent  	6,001,585. Micro Hollow Fiber Bioreactor. 

	 	US  Patent  	4,889,812. Bioreactor Apparatus. 

	 	US  Patent  	4,894,342. Bioreactor System. 

	 	US  Patent  	5,656,421. Multi-Bioreactor HolIow Fiber Cell Propagation System and Method. 

	 	US  Patent  	5,998,184. Basket-Type Bioreactor. 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-15 

 Non-Patented Intellectual Property 
  
 Biovest has been a leader in developing the hollow fiber bioreactor market. In the process, Biovest has developed a number of preferred and
alternate methods, vendors, and customers. This knowledge base is proprietary and is not the subject of this CRADA. 
  
 Abstract of the Research Plan of the CRADA 
  
 The National Cancer Institute (NCI) has initiated an FDA-approved, multi-institutional Phase 3 clinical trial of protein-based immunoglobulin idiotype vaccines for the
treatment of low-grade follicular B-cell lymphoma. B-cell tumors are composed of clonally-expanded cells synthesizing a single antibody molecule containing unique variable regions known as idiotypic determinants. The idiotypic determinants of B-cell
derived tumors comprise tumor-specific antigens that can serve as a target for immunotherapy. Based on success of earlier clinical trials (Nature Medicine 5: 1171-1177, Oct. 1999), NCI has decided to partner with Biovest International, Inc.
(Biovest) in furtherance of the clinical study and scale-up work necessary for further vaccine production and eventual FDA product commercialization. A specific goal of this CRADA will be development of the processes required for automated
large-scale GMP production of adequate numbers of GMP produced and formulated idiotype vaccines as needed to complete the clinical development of this agent for the treatment of follicular B-cell lymphoma. 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 A-16 

 APPENDIX B 
  
 FINANCIAL AND STAFFING CONTRIBUTIONS OF THE PARTIES 
  
 National Cancer Institute 
  
 Personnel 
  
 The NCI estimates that 0.85 professional person years/year of effort will be dedicated to its participation in the clinical study, Steering
Committee Meetings, compiling data, data management and monitoring in support of the clinical trial, and pathology. Such estimate of PHS staff includes its Principal Investigator (0.25 person years/year) and sufficient staffing to execute and
fulfill the obligations of the CRADA, including a Protocol Chairman (0.5 person years/year), and a Central Pathologist (0.1 person years/year). 
  
 NCI will provide no funding to the Collaborator for collaborative research and development pursuant to this CRADA inasmuch as financial contributions by the U.S.
government to non-federal parties under a CRADA are not authorized under the Federal Technology Transfer Act (15 U.S.C. §3710(d)(l)). 
  
 Biovest International 
  
 Personnel: 
  
 Biovest intends to commit 50 to 60 person years per year of effort to permit the timely execution of the study implemented under this CRADA. More specifically, this staffing shall include Biovest full-time employees,
consultants to the company, external contract agencies and contract research organizations and personnel. 
  
 FUNDING: 
  
 NCI-CCR
Costs 
  
 Collaborator shall provide a total of $825,170.00 dollars for
calendar year 2004 for reasonable and necessary expenses incurred by NCI in carrying out its responsibilities associated with conduct of the clinical trial under this CRADA. On February 13, 2004, NCI received a check in the amount of $530,000.00
from Collaborator. Therefore, the outstanding amount of CRADA funds due to NCI from Collaborator for calendar year 2004 is $295,170.00, which Collaborator shall remit to NCI within 30 days of execution of CRADA Amendment #4. 
  
 Beginning January 1, 2005, Collaborator shall provide $45,170.00 dollars quarterly for
reasonable and necessary expenses incurred by NCl in carrying out its responsibilities associated with conduct of the clinical trial under this CRADA and are to be deposited to an NCI CAN account established for the administration of this CRADA. No
full-time tenured employees will be supported under this CRADA by Biovest International, Inc. These expenses include, but are not limited to, costs associated with cGMP lymph node 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 B-1 

 biopsy processing, molecular and immunologic monitoring, publication of clinical trial, supplementation of support
services contracts and shipment of samples, associated administration support and professional meetings support related to the CRADA, transportation and lodging costs to support the participation of NCI staff at semi-annual Principal Investigator
meetings and for quarterly site visits to consortium centers. Travel costs are limited by the Federal Travel Rules and Regulations for all government staff whether paid for by government funds or private Collaborators. Collaborator may provide
direct support, under the 348 travel mechanism, for the travel and associated costs for attendance of NCI staff at selected scientific or development meetings. 
  

A check in the amount of $385,510.00, which includes the outstanding $295,170.00 2004 CRADA funding, will be provided
to the NCI by Biovest within thirty (30) days of the execution of CRADA Amendment #4. Checks should be made payable to the “National Cancer Institute”, should reference the CRADA #01030 and be sent lo: CRADA Funds Coordinator, Technology
Transfer Branch, EPS-450, 6120 Executive Blvd., Rockville, MD 20852. 
  
 Any
adjustments will be made by amendment pursuant to Article 13.6 hereunder. Adjustments to the above-noted costs will be made on a yearly basis as mutually agreed upon by both parties, taking into account the level of control Biovest assumes for these
responsibilities, the rate of patient accrual, and the overhead costs associated with, but not limited to, increase in cost of living. 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 B-2 

 APPENDIX C 
  
 EXCEPTIONS OR MODlFlCATIONS TO THIS CRADA 
  
 Modify Article 1 to read as follows: 
  
 Article 1.    Introduction 
  
 This Cooperative Research and Development Agreement (CRADA) between PHS and the Collaborator will be effective when signed by all Parties. The research and development
activities which will be undertaken by each of the Parties in the course of this CRADA are detailed in the Research Plan (RP) which is attached as Appendix A. The funding and staffing commitments of the Parties are set forth in Appendix B. Any
exceptions or changes to the CRADA are set forth in Appendix C. A copy of the Letter of Intent and Extension to the Letter of Intent are included as Appendix D for informational purposes. This Cooperative Research and Development Agreement (CRADA)
between PHS and the Collaborator will be fully executed when signed by all Parties and effective retroactively with regard to intellectual property and confidentiality to January 09, 2001, which is the date of the execution of the Letter of Intent
(LOI). This CRADA is made under the authority of the Federal Technology Transfer Act, 15 U.S.C. 3710a and is governed by its terms. 
  
 Modify Article 2.11 as follows: 
  

	2.11	“Subject Data” means all recorded information first produced in the performance of this CRADA by the parties. “Subject Data” shall specifically exclude
“Identifiable Private Information.” 

  
 Add the following
new sections to the Article 2. Definitions: 
  

	2.12	“Adverse Drug Experience” means an adverse clinical experience as defined under 21 C.F.R. 312.32. 

  

	2.13	“Agent” means Id-KLH follicular B-cell lymphoma vaccine administered in combination with GM-CSF adjuvant. 

  

	2.14	“Annual Report” means the brief report of the progress of an IND associated investigation which the IND sponsor is required to submit to the FDA within 60 days of
the anniversary date that the IND went into effect (pursuant to 21 C.F.R. 312.33). 

  

	2.15	“Clinical Data and Results” means all information, data and results developed or obtained in connection with clinical trials conducted within the scope of the CRADA
Research Plan whether by intramural research scientists or extramural grantee or contract investigators. 

  

	2.16	“Clinical Data and Results and Raw Data in NIH’s Possession and Control” means all information collected from NIH intramural preclinical or clinical studies
performed pursuant to the 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-1 

	  	Research Plan, all data obtained by NIH under contracts with extramural contract investigators for completion of studies within the scope of the CRADA Research Plan, and all
information and data in the NCI-sponsored IND for Agent. 

  

	2.17	“Contract” means a funding agreement that is a research and development contract that provides that the contractor perform for the benefit of the Government, with
an expectation of completion of the stated research goals and the delivery of a report, data, materials or other product. Generally, Contracts are administered under the Federal Acquisition Regulations (FAR) codified at Title 48 C.F.R., Chapter 1 or
the Health Services Acquisition Regulations (HSAR) codified at Title 48 C.F.R., Chapter 3. 

  

	2.18	“Cooperative Agreement” means a Funding Agreement that is a species of a grant, whereby the funding Federal agency intends to be substantially involved in carrying
out the research program. Cooperative Agreements may be used where the Federal agency intends for its scientists to directly collaborate with the researchers of the funded institution on a joint research project. The Federal agency may then pay for
the research of both its employees and those of the funded institution (see 45 C.F.R. Part 74). 

  

	2.19	“CTA” means Clinical Trial Agreement. 

  

	2.20	“CTEP” means the Cancer Therapy Evaluation Program, DCTD, NCI, the program within NCI which plans, assesses and coordinates all aspects of clinical trials including
extramural clinical research programs, internal resources, treatment methods and effectiveness, and compilation and exchange of data. 

  

	2.21	“DCTD” means Division of Cancer Treatment and Diagnosis, NCI. 

  

	2.22	“FDA” means US Food and Drug Administration. 

  

	2.23	“Funding Agreement” means a Contract, Grant or Cooperative Agreement entered into between a Federal agency and another party for the performance of experimental,
developmental, or research work funded in whole or in part by the Federal Government. 

  

	2.24	“Grant” means a funding agreement that is an award of financial assistance which may be provided for support of basic research in a specific field of interest to
the funding Federal agency. 

  

	2.25	“IND” means an Investigational New Drug Application submitted to the FDA to receive approval to conduct experimental clinical trials. 

  

	2.26	“Multi-Party Data” means clinical data from clinical studies sponsored by NCI pursuant to CTAs or CRADAs, where such data are collected under protocol involving
combinations of investigational agents from more than one CTA or CRADA collaborator. 

  

	2.27	“NCI” means the National Cancer Institute, NIH, PHs, DHHS. 

  

	2.28	“Protocol Review Committee” (or “PRC”) means the CTEP/DCTD committee that reviews and approves studies involving NCI investigational agents and/or
activities supported by NCI. 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-2 

	2.29	“Raw Data” means the primary quantitative and empirical data first collected by the intramural and extramural investigators from experiments and clinical trials
conducted within the scope of the Research Plan of this CRADA. 

  

	2.30	“Steering Committee” means a joint clinical development team (hereinafter referred to as the “Steering Committee”) the Parties agree to establish once
Biovest establishes its own IND whose responsibility will be the oversight of the ongoing Phase 3 Clinical Trials performed under the Collaborators IND related to this CRADA. The Steering Committee will comprise the following NCI staff: the
Principal Investigator, the Project Officer for Vaccine Production, the Protocol Coordinator, the Protocol Chairman, and the following Collaborator staff: Principal Investigator, and appropriate Collaborator staff in the areas of clinical
monitoring, pharmacy, statistics, manufacturing and publicity. Although the members of the Steering Committee shall be considered as having been delegated to the Steering Committee, they shall continue to remain employed by their respective
employers under their respective terms of employment. 

  

	2.31	“Oversight Committee” means the joint NCI Collaborator research and development team to be established upon execution of this CRADA and whose composition shall
include, but not be limited to: The NCI PI, the Collaborator P.I., the Project Officer for Vaccine Production, and the Vice-President of the Collaborator. The responsibilities of the Oversight Committee will include oversight of the fiscal
expenditures under the CRADA and review and approval of any possible third party involvement in any aspect of the CRADA Research Plan. Others may be added to this committee as mutually agreed upon by both parties. Although the members of the
Oversight Committee shall be considered as having been delegated to the Oversight Committee, they shall continue to remain employed by their respective employers under their respective terms of employment. 

  

	2.32	“Identifiable Private Information” means patient-identifying data from medical records or attached to patient specimens, to be obtained prospectively or from stored
medical records or specimens, that can be linked to individual human subjects, either directly or indirectly through codes. 

  
 Add the following new sections to the Article 3. Cooperative Research: 
  

	3.3	Review of Work. Periodic conferences shall be held by the Steering Committee to review work progress. It is understood that the nature or this cooperative research precludes
a guarantee of its completion within the specified period of performance or limits of allocated financial or staffing support. Accordingly, research under this CRADA is to be performed on a best efforts basis. 

  

	3.4	Clinical Protocol Effective April 29, 2004, NCI protocol #00-C-0050 (P-92), entitled ‘Phase 3 Randomized Study of Autologous Lymphoma Derived ldiotype Specific
Vaccination Plus Sargramostim (GM-CSF) in Patients with Indolent Follicular Lymphoma in First Complete Remission’ will be conducted under Collaborator’s IND application #5427. 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-3 

	3.6	Investigational New Drug Application Collaborator’s IND #5427 cross-references NCI’s IND #5427. If Collaborator abandons its commercialization efforts, and NCI
decides to continue its development of the Agent that is the subject of this CRADA, Collaborator will supply information in support of NCI’s IND in the form of a Drug Master File directly to the FDA and Collaborator grants NIH a right to
cross-reference such information in its IND filing. In the event that Collaborator supplies CONFIDENTIAL information directly to NCI in support of an NCI IND, such information will be protected in accordance with the corresponding Confidentiality
provisions of Article 8 of this Agreement. 

  

	3.7	Biologics License Application. Collaborator will submit a Biologics License Application to the FDA within six (6) months of the date the NTH Data Safety and Monitoring
Board’s final analysis of results of the clinical trial or be considered to have abandoned its commercialization efforts. Collaborator shall have the right to file an application for “fast-track” licensing of Agent at any time during
the term of this CRADA once Collaborator has an approved IND on file with the FDA. Biovest will have access to the follicular lymphoma vaccine clinical data and results and raw data in NIH’s possession and control as defined in Article 2.16 as
needed to support the registration of the Agent by the FDA in this disease. Furthermore, Biovest will be provided safety data generated from the use of the Agent that is in the possession and control of NIH as needed to support the FDA registration.
Collaborator’s access to and use of said data is subject to the terms of Article 8 hereunder and limited to use for regulatory filings only. 

  

	3.8	Drug Information and Supply. Collaborator agrees to provide NCI without charge formulated and acceptably-labeled clinical-grade Agent in sufficient quantity to complete the
preclinical studies and clinical trial protocol sponsored by NCI within the scope or the CRADA Research Plan. It is understood that NCI shall take responsibility for and reasonable steps to maintain appropriate records and assure appropriate supply,
handling, storage, distribution and usage of these materials in accordance with the terms of this Agreement, the protocol and any applicable laws and regulations relating thereto. 

  

	  	Effective April 29, 2004, Collaborator agrees to take responsibility and shall arrange directly with Immunex/Berlex for provision and distribution of adjuvant GM-CSF necessary to
complete the clinical trial performed under this CRADA. Changes in the composition or manufacture of the Agent for the studies performed under this CRADA will be mutually agreed upon by both parties. 

  
 The Collaborator contact will be Dr. Beverly Norris, Biovest (Telephone
Number 508-793-0001). 
  

	3.9	Protection of Human Subjects and Appropriate Care of Laboratory Animals. All human clinical trials performed under this CRADA shall conform to the appropriate Federal law,
including, but not limited to all applicable FDA regulations and DHHS regulations relating to the protection of human subjects (see 45 C.F.R. Part 46, 21 C.F.R. Parts 50 and 56). NCI and Collaborator also agree to comply with all applicable Federal
statutes and Public Health Service policies relating to the use and care of laboratory animals (see 7 U.S.C. 2131 et seq.) Additional information is available from the Office for Human Research Protections, Telephone: 301-496-7163. In accordance
with the HHS Office for Human Research Protections guidelines, private patient identifiable information shall only be used by Collaborator for licensing applications to the FDA, if required. All other uses of information under this Agreement shall
assure that no private patient identifiable information is disclosed. 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL

  

 C-4 

 Amend Article 4.1 “Interim Reports” to read as follows: 
  

	4.1	Interim Reports. The Parties shall exchange formal written interim progress reports on a schedule agreed to by the PIs, but at least within six (6) months after this CRADA
becomes effective and at least within every six (6) months thereafter. Such reports shall set forth the technical progress made, identifying such problems as may have been encountered and establishing goals and objectives requiring further effort,
any modifications to the Research Plan pursuant lo Article 3.2, and identify Subject Inventions pursuant to Article 6.1. Oversight Committee reports or copies of CRADA Annual Reports updating the progress of the CRADA research shall satisfy the
reporting requirements under this Article 4.1. In addition, copies of the Annual Reports and other pertinent IND data related to NCI protocol # 00-C-0050 (P-92) (including, but not limited to, clinical brochure data, and formulation and preclinical
data, including toxicology findings) shall be exchanged by the Parties as they become available. 

  
 Add a new Article 4.3 as follows: 
  

	4.3	Adverse Drug Experience Reporting Effective April 29, 2004, Collaborator shall report all serious or unexpected adverse events to FDA in accordance with the reporting
obligations of 21 CFR 312.32 and will, concurrently, forward all such reports to CCR, NCI . All other adverse event reports received by Collaborator shall be reported to the FDA consistent with 21 CFR 312.32 and 312.33. In addition, copies of the
Annual Reports and other pertinent IND data (including, but not limited to, Clinical Brochure data, formulation and preclinical data, including toxicology findings) will be provided to CCR, NCI as they become available. 

  
 The Collaborator will then notify the investigator(s) conducting studies
under the Collaborator-sponsored protocol. 
  
 Amend Article 5
“Financial and Staffing Obligations” as follows: 
  

	5.1	PHS and Collaborator Contributions. The contributions of the Parties, including personnel, services, property and payment schedules, if applicable, are set forth in Appendix
B. PHS shall not be obligated to perform any or the research specified herein or to take any other action required by this CRADA if the funding is not provided as set forth in Appendix B. PHS shall return excess funds to the Collaborator when it
sends its final fiscal report pursuant to Article 5.2, except for staffing support pursuant to Article 10.3. Collaborator acknowledges that the U.S. Government will have the authority to retain and expend any excess funds for up to one (1) year
subsequent to the expiration or unilateral termination of the CRADA to cover any costs incurred during the term of the CRADA in undertaking the work set forth in the RP. 

  

	5.2	Accounting Records. PHS shall maintain separate and distinct current accounts, records, and other evidence supporting all its obligations under this CRADA, and shall provide
the Collaborator a final fiscal report reflecting the use of Collaborator funds, technical progress, established goals and objectives pursuant to Article 4.2. 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-5 

 Amend Article 6 “Patent Applications” as follows: 
  

	6.2	Filing of Patent Applications. Each party shall be responsible for filing patent or other IP applications in a timely manner and at its own expense and after consultation
with the other Party. The Parties will consult and mutually determine a filing strategy for jointly-owned subject inventions. If either Party decides to abandon a patent or patent application covering a jointly owned subject invention it will
provide written notice to the other Party of this intention at least thirty (30) days prior to the date of any applicable deadline by which the patent or patent application would be deemed abandoned. If the non-abandoning Party elects to continue
the patent or patent application, the abandoning Party will cooperate in providing the other Party with needed information to continue the patent or patent application. The Party deciding to continue the patent or patent application will bear all
costs associated therewith. If trade secret information or Collaborator Confidential/Proprietary is essential to file a properly enabled patent application, Collaborator will cooperate to provide equivalent information to file such application.

  

	6.3	Patent Expenses. The expenses attendant to the filing or maintaining of jointly-owned patent or other IP applications generally shall be paid by the Party filing such
application. If Collaborator elects to take an exclusive license to any Subject Invention under paragraph 7.1, the Collaborator shall be responsible for all reasonable past and future out-of-pocket expenses in connection with the preparation,
filing, prosecution and maintenance of any applications claiming such exclusively-licensed inventions and any patents or other IP grants that may issue on such applications. The Collaborator may waive its exclusive license rights on any application,
patent or other IP grant at any time, and incur no subsequent compensation obligation for that application, patent or IP grant. 

  

	6.4	Prosecution of Intellectual Property Applications. In connection with any patent or IP application relating to a subject invention filed pursuant to the CRADA, within one
month of receipt or filing, each Party shall provide the other Party with copies of the applications and all documents received from or filed with the relevant patent or other IP office in connection with the prosecution of such applications. Each
Party shall also provide the other Party with the power to inspect and make copies of all documents retained in the patent or other IP application files by the applicable patent or other IP office. Each Subject Invention made solely by PHS employees
shall be solely owned by PHS. PHS agrees to exclude from any patent application Collaborator trade secret information or Collaborator Proprietary/Confidential Information. If such trade secret information or Collaborator Confidential/Proprietary
Information is essential to file a properly enabled patent application, Collaborator will cooperate to provide equivalent information to file such application. Each Subject Invention made solely by Collaborator employees shall be solely owned by
Collaborator. Collaborator agrees to exclude from any patent application PHS trade secret information or PHS Proprietary/Confidential Information. If such trade secret information or PHS Confidential/Proprietary Information is essential to file a
properly enabled patent application, PHS will cooperate to provide equivalent information to file such application. The Parties agree to consult with each other with respect to the prosecution of applications for PHS Subject Inventions and joint
Subject Inventions. If the Parties agree that Collaborator shall file and prosecute IP applications on joint Subject Inventions, then Collaborator agrees to all Customer Number Practice and/or granting of power(s) of attorney (or its equivalent)
necessary to assure PHS access to its United States, International, and Foreign intellectual property rights on said applications. 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-6 

 Amend Article 7 “Licensing” to read as follows: 
  

	7.1	Option for Commercialization License. With respect to Government IP rights to any Subject Invention not made solely by the Collaborator’s employees for which a patent or
other IP application is filed, PHS hereby grants to the Collaborator an exclusive option to elect an exclusive or nonexclusive commercialization license, which is substantially in the form of the appropriate model PHS license agreement. This option
does not apply to Subject Inventions conceived prior to the effective date of this CRADA that are reduced to practice under this CRADA, if prior to that reduction to practice, PHS has filed a patent application on the invention and has licensed it
or offered to license it to a third party. To the best of NCI’s knowledge after due inquiry on the date that NCI signed this CRADA no such Subject Invention exists. In the event that it is later determined that any such Subject Invention does
exist, Collaborator shall be granted an option to a nonexclusive license for any such Subject Invention licensed to a Third Party on a nonexclusive basis. The terms of the license will fairly reflect the nature of the invention, the relative
contributions of the Parties to the invention and the CRADA, the risks incurred by the Collaborator and the costs of subsequent research and development needed to bring the invention to the marketplace. The field of use of the license will be
commensurate with the scope of the RP. Collaborator has the right to transfer or sublicense any rights taken under this paragraph to additional partners. Any such sublicenses shall be subject to the terms of the applicable License agreement and upon
written approval by PHS, which approval will not be unreasonably withheld; and will reflect that any sub-licensee will not further sublicense. 

  

	7.2	Exercise of License Option. The option of Article 7.1 must be exercised by written notice mailed within three (3) months after either (i) Collaborator receives written notice
from PHS that the patent or other IP application has been filed; or (ii) the date Collaborator files such IP application. Exercise of this option by the Collaborator initiates a negotiation period that expires nine (9) months after the exercise of
the option. If the last proposal by the Collaborator has not been responded to in writing by PHS within this nine (9) month period, the negotiation period shall be extended to expire one (1) month after PHS so responds, during which month the
Collaborator may accept in writing the final license proposal of PHS. In the absence of such acceptance, or an extension of the time limits by PHS, PHS will be free to license such IP rights to others. In the event that the Collaborator elects the
option for an exclusive license, but no such license is executed during the negotiation period, PHS agrees not to make an offer for an exclusive license on more favorable terms to a third party for a period of six (6) months without first offering
Collaborator those more favorable terms. These times may be extended at the sole discretion of PHS upon good cause shown in writing by the Collaborator. 

  

	7.5	Third Party License. Pursuant to 15 U.S.C. 3710a(b)(l)(B), if PHS grants an exclusive license to a Subject Invention made wholly by PHS employees or jointly with Collaborator
under this CRADA, the Government shall retain the right to require the Collaborator to grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense to use the invention in Collaborator’s licensed field of use on
terms that are reasonable under the circumstances; or if the Collaborator fails to grant such a license, to grant the license itself. The exercise of such rights by the Government shall only be in exceptional circumstances and only if the Government
determines (i) the action is necessary to meet health or safety needs that are not reasonably satisfied by Collaborator, (ii) the 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-7 

	  	action is necessary to meet requirements for public use specified by Federal regulations, and such requirements are not reasonably satisfied by the Collaborator; or (iii) the
Collaborator has failed to comply with an agreement containing provisions described in 15 U.S.C. 3710a(c)(4)(B). The determination made by the Government under this Article is subject to administrative appeal and judicial review under 35 U.S.C.
203(2). Subject to Article 7.4 herein, the Collaborator shall retain ownership in any intellectual property to which the Collaborator has title prior to this CRADA, or which is outside the workscope of this CRADA. 

  
 Amend Article 8 “Proprietary Rights and Publication” to read
as follows: 
  

	8.1	Right of Access. PHS and the Collaborator agree to exchange all Subject Data and Research Materials produced in the course of research under this CRADA whether developed
solely by PHS, jointly with Collaborator or solely by the Collaborator. Research Materials will be shared equally by the Parties to the CRADA unless other disposition is agreed to by the Parties. All Parties to this CRADA will be free to utilize
Subject Data and Research Materials for their own purposes, consistent with their obligations under this CRADA. 

  

	8.3	Dissemination of Subject Data and Research Materials. To the extent permitted by law, the Collaborator and PHS agree to use reasonable efforts to keep Subject Data and
Research Materials confidential until published or until corresponding patent applications are filed. Any information that would identify human subjects of research or patients will always be maintained confidentially. To the extent permitted by law
and subject to the other provisions of Article 8, the Collaborator shall have the exclusive right to use any and all CRADA Subject Data in and for any regulatory filing by or on behalf of Collaborator, except that PHS shall have the exclusive right
to use Subject Data for that purpose, and authorize others to do so, if the CRADA is terminated or if Collaborator abandons its commercialization efforts. Collaborator acknowledges the basic research mission of the PHS, and agrees that after
publication, PHS may make unpatented research materials arising out of this CRADA available to third parties for further research. 

  
 Modify Article 8.4 as follows: 
  

	8.4	Proprietary/Confidential Information. Each Party agrees to limit its disclosure of Proprietary/Confidential Information to the amount necessary to carry out the Research Plan
of this CRADA, and shall place a confidentiality notice on all such information. Confidential oral communications shall be reduced to writing within 30 days by the disclosing Party. Each Party receiving Proprietary/Confidential Information agrees
that any information so designated shall be used by it only for the purposes described in the attached Research Plan. Any Party may object to the designation of information as Proprietary/Confidential Information by another Party. Subject Data and
Research Materials developed solely by the Collaborator may be designated as Proprietary/Confidential Information when they are wholly separable from the Subject Data and Research Materials developed jointly with PHS investigators, and advance
designation of such data and material categories is set forth in the RP. The exchange of other confidential information, e.g. Identifiable Private Information, shall be subject to the terms of Article 8.10. Jointly developed Subject Data and
Research Material derived from the Research Plan may be disclosed by Collaborator to a third party under a confidentiality agreement for the purpose of possible sublicensing pursuant to the Licensing Agreement and subject to Article 8.7.

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-8 

	8.6	Duration of Confidentiality Obligation. The obligation to maintain the confidentiality of Proprietary/Confidential Information shall expire at the earlier of the date when
the information is no longer Proprietary Information as defined in Article 2.7 or five (5) years after the expiration or termination date of this CRADA. The Collaborator may request an extension to this term when necessary to protect
Proprietary/Confidential Information relating to products not yet commercialized. 

  

	8.7	Publication. The Parties are encouraged to make publicly available the results of their research. Before either Party submits a paper or abstract for publication or otherwise
intends to publicly disclose information about a Subject Invention, Subject Data or Research Materials, the other Party shall be provided thirty (30) days to review the proposed publication or disclosure to assure that Proprietary/Confidential
Information is protected. The other party may request such publication to be revised if it discloses Proprietary/Confidential information. The publication or other disclosure shall be delayed for up to sixty (60) additional days upon written request
by any Party as necessary to preserve U.S. or foreign patent or other IP rights. If trade secret information or Collaborator Proprietary/Confidential is essential to publish or otherwise publicly disclose as outlined above, Collaborator will
cooperate to provide equivalent information to file such application. 

  
 Add a new Article 8.8 as follows: 
  

	8.8	Extramural Research and Data. In pursuing the development of Agent pursuant to this CRADA, NIH utilized extramural investigators for part or all of the completion of this
Research Plan. However, said extramural investigators were not Parties to this CRADA, and this CRADA does not address rights to intellectual property created by such investigators. Nonetheless, to the extent permitted by law and subject to the other
provisions of Article 8 of this CRADA, NIH shall maintain all IND, Clinical Data and Results, and Raw Data in NIH’s Possession and Control as Proprietary and CONFIDENTIAL, and make data related to NCI Protocol 00-C-0050, (P-92) including the
follicular lymphoma vaccine clinical data and results and raw data in NIH’s possession and control as defined in Article 2.16, and safety data generated from the use of the Agent that is in the possession and control of NIH, as needed to
support the registration of the Agent by the FDA in this disease referenced in Article 3.7 of Appendix C and Item 6 under NCI Contributions of Appendix A available to the Collaborator, for its own use and for use in obtaining FDA approval for the
commercial marketing of Subject Inventions and Agent products. Accordingly, said data shall not be transferable to any third party by Collaborator without the written permission of the NCI, which will not be unreasonably withheld.

  
 Add a new Article 8.9 “Retention and Disposition of
Patient Samples” as follows: 
  

	8.9	Retention and Disposition of Patient Samples. The parties anticipate that certain patients enrolled in the clinical trial performed under this CRADA will be removed from the
study for any number of reasons including the following examples: 

  

	 	1.	Patient unable to obtain a complete response with chemotherapy 

	 	2.	Tumor returns after chemotherapy while waiting to start vaccine 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-9 

	 	3.	Tumor returns after vaccinations are completed 

	 	4.	Patient is unable to tolerate the treatment 

  

	 	  	Collaborator agrees that in the event a patient is removed from the study performed under this CRADA for any reason, the patient shall be free to enter any other trial and their
biopsies, hybridomas and associated clinical or biopsy data needed for such a new trial will be transferred for use in that study. Collaborator will cooperate in transferring all required information upon receipt of written patient authorization to
such transfer to the specified recipient. Collaborator will not use patient samples or derivatives thereof for purposes not specified in this CRADA. 

  

	 	  	Collaborator assumes responsibility for storage, maintenance, and recordkeeping of any phase 3 biopsy samples, including any phase 3 biopsy samples transferred from NCI to
Collaborator, in accordance with FDA rules and regulations and subject to all of the terms of Article 8 as modified in Appendix C herein. This responsibility will survive termination of the CRADA. 

  
 Add a new Article 8.10 “Access Review and Receipt of Identifiable Private
Information” as follows: 
  

	 	8.10	Access, Review and Receipt of Identifiable Private Information. Collaborator access to and review of Identifiable Private Information shall be only for on-site quality
auditing. Collaborator will receive Identifiable Private Information only for purposes of satisfying FDA or other health authorities’ reporting requirements, and for internal research purposes directly related to obtaining regulatory approval
of Agent. Collaborator is prohibited from access, review, receipt, or use of such information for other purposes. All IRB approved protocol and informed consent documents related to this research project will clearly describe this practice. If the
Collaborator will have access to Identifiable Private Information, the protocol and the informed consent must clearly state (i) the existence of the Collaborator; (ii) the Collaborator’s access to Identifiable Private Information, if any; and
(iii) the extent to which confidentiality will be maintained. For clinical protocol involving a third party, the other party’s access, review, receipt, or use of Identifiable Private Information shall be subject to the same limitations as
described in this Article 8.10. 

  
 Add a new Article 8.11
“Multi-Party Data” as follows: 
  

	 	8.11	“Multi-Party Data” means clinical data which is collected from clinical studies sponsored by NCI for combinations of proprietary investigational agents supplied by
more than one Collaborator. 

  
 For clinical
protocol(s) where Agent is used in combination with another proprietary investigational agent which is the subject of another Clinical Trials Agreement or Cooperative Research and Development Agreement, the access to and use of data by Collaborator
and party supplying other agent (hereinafter referred to as “Other Party”) shall be as follows (data pertaining to such combination use shall hereinafter be referred to as “Multi-Party Data.”): 
  

	 	i.	NCI must provide all parties with written notice regarding the existence and nature of any agreements governing their collaboration with NIH, the design of proposed combination
protocol(s), and the existence or any obligations which would tend to restrict NCI’s participation in proposed combination protocols. 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-10 

	 	ii.	Collaborator shall agree to permit use of the Multi-Party Data from these clinical trials by Other Party to the extent necessary to allow Other Party to develop, obtain regulatory
approval of, or commercialize its own proprietary investigational agent, provided Other Party permits Collaborator similar, reciprocal rights to use Multi-Party Data. 

  

	 	iii.	Any Party having the right to use the Multi-Party Data from these trials must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely
for development, regulatory approval, and commercialization of its own proprietary investigational agent(s). 

  
 Amend Article 10 “Termination” as follows: 
  

	 	10.2	Unilateral Termination. Either PHS or the Collaborator may unilaterally terminate this entire CRADA at any time by giving written notice at least sixty (60) days prior to the
desired termination date, and any rights accrued in property, patents or other IP rights shall be disposed of as provided in paragraph 10.1, except that PHS may, at its option, retain funds transferred to PHS prior to unilateral termination by
Collaborator for use in completing the Research Plan solely or with another partner. However, in the event of unilateral termination by Collaborator, Collaborator’s obligation under Article 3.8 will survive termination to the extent reasonably
necessary to complete approved clinical studies under mutually agreed upon protocol. If Collaborator elects to terminate its development of Agent without the transfer of its development efforts to support a level of production equivalent to that
which was ongoing at the time of termination, and CCR, NCI elects to continue its development of Agent, then Collaborator agrees to maintain its IND, to provide a letter of cross-reference to Collaborator’s IND, and to provide financial support
for personnel, reagents, supplies, and equipment necessary to transfer back to CCR, NCI all vaccine production, including, but not limited to all relevant biological and immunological assays. Such obligation shall last until either a date on which
vaccine production and related assays are fully transferred back to NCI or one year after the notification from Collaborator to NCI that Collaborator elects to terminate its development of Agent, whichever comes first. Notwithstanding the foregoing,
if NCI has executed an agreement with a new collaborator or third party to be involved in development of Agent, Collaborator’s funding obligations shall be terminated immediately. CCR, NCI will be responsible for the IND to support this study
in the event of Collaborator termination. 

  

	 	10.3	Staffing. If this CRADA is mutually or unilaterally terminated by the Collaborator prior to its expiration, funds will nevertheless remain available to PHS for continuing any
staffing commitment made by the Collaborator pursuant to Article 5.1 above and Appendix B, if applicable, for a period of one year after such termination. If there are insufficient funds to cover this expense, the Collaborator agrees to pay the
difference. 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-11 

 Add a new Article 10.6 as follows: 
  

	10.6	Research License and Alternative Sources of Supply in the Event Collaborator Terminates Development of Agent 

  

	  	Collaborator hereby grants to NCI a nonexclusive, nontransferable, irrevocable, paid-up license to practice or have practiced for or on behalf of the United States any Subject
Invention which Collaborator may have or obtain on Agent, its manufacture, or on the process for use of Agent, throughout the world, for medical research purposes, including those related to or connected with the therapy or cancer; but this license
shall become effective only if and when Collaborator terminates its development of Agent without the transfer of its development efforts to another party, and NCI elects to continue the development of Agent. 

  

	  	If Collaborator elects to terminate its development of Agent without the transfer of its development efforts to another party, and NCI elects to continue its development of Agent,
then Collaborator will: 

  

	 	(i)	allow NCI to purchase at cost said Agent from Collaborator inventory; or 

  

	 	(ii)	arrange for an independent contractor to manufacture and provide for NCI purchase of said agent at cost; or 

  

	 	(iii)	provide to NCI all information necessary to allow NCI to contract and manufacture said Agent independent of Collaborator; or 

  

	 	(iv)	arrange for alternative and cost-effective method of Agent production 

  
 (i) 
  

	  	for use in preclinical studies and clinical trials. Such obligation shall last until either a date on which an alternate source of equivalent materials, acceptable to NCI, can be
obtained by NCI, or one year after the date of notification from Collaborator to NCI that Collaborator elects to terminate its development of Agent, whichever comes first. 

  
 Modify the first sentence in Article 12.3 as follows: 
  

	  	The Collaborator agrees to hold the U.S. Government harmless and to indemnify the Government for all liabilities, demands, damages, expenses and losses arising out of the use by the
Collaborator for any purpose of the Subject Data, additional Clinical Data and Results and Raw Data in NIH’s Possession and Control, Research Materials and/or Subject inventions produced in whole or part by PHS employees under this CRADA,
unless due to the negligence or willful misconduct of PHS, its employees, or agents. 

  
 Modify Article 13.1 as follows: 
  

	13.1	Governing Law. The construction, validity, performance and effect of this CRADA shall be governed by Federal law, as applied by the Federal Courts in the District of
Columbia. Federal law 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-12 

	  	and regulations will preempt any conflicting or inconsistent provisions in this CRADA. NCI and Collaborator, if Collaborator is sponsoring trials at the NIH under this CRADA, shall
comply with all Department of Health and Human Services regulations relating to Human Subject use, and all Public Health Service policies relating to the use and care of laboratory animals. 

  
 Add the following to the beginning of Article 13.2 as follows: 
  

	13.2	The Parties hereby modify their rights under the following prior agreements: 

  
 Confidential Disclosure Agreement: 
  

# 2- 02244-01 
 Subject: “Discussions
for the entering into of a Cooperative Research & Development Agreement (“CRADA”) for the development and production of idiotype vaccines against B-cell lymphoma.” 
 Executed: September 20, 2000. 
  
 and the Parties agree that the information provided thereunder is now governed, retroactive to the date of the LOI (January, 09, 2001), by the
confidentiality and intellectual Property terms of this CRADA. 
  
 Add a new
Article 13.13 as follows: 
  

	13.13	FDA Meetings. All meetings with FDA concerning clinical studies for the development of Agent within the scope of the CRADA Research Plan will be discussed by Collaborator and
NCI in advance and will be held on mutually agreed upon dates. Collaborator reserves the right to set jointly with NCI the agenda for any such meeting. 

  
 Modify Article 13.8 “Notices” as follows: 
  

	13.8	Notices. All notices pertaining to or required by this CRADA shall be in writing and shall be signed by an authorized representative and shall be delivered by hand or sent by
certified mail, return receipt requested, or by recognized national overnight carrier, with postage prepaid, to the addresses indicated on the signature page for each Party. Notices regarding the exercise of license options shall be made pursuant to
Article 7.2. Any Party may change such address by notice given to the other Party in the manner set forth above. 

  
 Modify Article 13.9 Independent Contractors” as follows: 
  

	13.9	Independent Contractors. The relationship of the Parties to this CRADA is that of independent contractors and not agents of each other or joint venturers or partners. Each
Party shall maintain sole and exclusive control over its personnel and operations. Collaborator employees who will be working at PHS facilities may be asked to sign a Guest Researcher or Special Volunteer Agreement appropriately modified in view of
the terms of this CRADA. If Collaborator elects to perform any portion of the Research Plan through a contractor or consultant, Collaborator agrees to incorporate 

  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-13 

	  	into such contracts all provisions necessary to ensure that the work of such contractors or consultants is governed by the terms of the CRADA. In addition, Collaborator will have
incorporated in any agreement with any contractor or consultant contemplated hereby a provision for the assignment of inventions of the contractor or consultant to the Collaborator; such inventions shall be deemed Subject Inventions of the
Collaborator. Some of the studies of the Research Plan for this CRADA may be conducted by a contractor working on behalf of the NIH. It is the intent of the NIH that the contractor not perform any duties likely to generate intellectual property.
However, the Collaborator is aware that pursuant to the Bayh-Dole Act (codified art 35 USC, Chapter 18), the contractor may elect title to any inventions it makes in the performance of its contract duties. Such contractor inventions are not subject
to the terms of this CRADA. 

  
 Amend Article 14.2
Survivability by including Articles 4.3 (Adverse Drug Experience Reporting) and 10.6 (Research License and Alternative Sources of Supply in the Event that Collaborator Terminates Development of Agent) and the last
sentence of Article 10.2 (regarding drug supply in the event of collaborator’s unilateral termination) as provisions that will survive termination of this CRADA. 
  
 14.2 Survivability. The provisions of Articles 4.2, 4.3, 5-8, Article 10.2, 10.3-10.5, 10.6, 11.1, 12.2-12.4, 13.1, 13.10 and 14.2
shall survive the termination of this CRADA. 
  
 NCI CRADA 01030 
 Amendment #4 
 CONFIDENTIAL 
  

 C-14

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00085-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00085-of-00352.parquet"}]]