kl01034_ex4-1.htm


    
      

    

    


    Exhibit
4.1


    


    


    


    


    


    L
DOS 47 cGMP PROCESS DEVELOPMENT, SCALE UP AND

    CLINICAL
SUPPLIES MANUFACTURING AGREEMENT

    


    


    


    


    BETWEEN

    


    HELIX
BIOPHARMA CORP.

    


    AND

    


    BIOVECTRA
INC.

    


    


    


    


    


    


    May
4, 2008

    


    


    


    


    


    


    


    


    


    


    CONFIDENTIAL TREATMENT
REQUESTED

     

    INFORMATION
FOR WHICH CONFIDENTIAL TREATMENT HAS BEEN REQUESTED IS OMITTED AND IS IDENTIFIED
BY THREE ASTERISKS, AS FOLLOWS “* * *”, AN UNREDACTED VERSION OF THIS DOCUMENT
HAS BEEN FILED SEPARATELY WITH THE SECURITIES AND EXCHANGE
COMMISSION.

     

    


     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    
    

     

    
      	ARTICLE 1 DEFINITIONS AND
      SCHEDULES.....................................................................................................................................................................................................................................................	5
	 	 
	1.1          Definitions...................................................................................................................................................................................................................................................................................................... 	5
	1.2          Schedules....................................................................................................................................................................................................................................................................................................... 	10
	 	 
	ARTICLE 2 THE
      SERVICES..................................................................................................................................................................................................................................................................................... 	10 
	 	 
	2.1          The
      Services.................................................................................................................................................................................................................................................................................................. 	10 
	2.2          Purchase
      Order.............................................................................................................................................................................................................................................................................................. 	10
	2.3          Service
      Standard........................................................................................................................................................................................................................................................................................... 	10 
	2.4          Quality
      Assurance
      Agreement................................................................................................................................................................................................................................................................... 	11 
	2.5          Additional
      Services......................................................................................................................................................................................................................................................................................	11 
	2.6          Change
      Orders.............................................................................................................................................................................................................................................................................................. 	11 
	2.7          Helix
      Personnel on
      Site................................................................................................................................................................................................................................................................................	11 
	2.8          Dispute
      Resolution......................................................................................................................................................................................................................................................................................	11 
	2.9          Approval
      of
      Subcontracting....................................................................................................................................................................................................................................................................... 	11 
	 	 
	ARTICLE 3 PRICING AND
      PAYMENT.................................................................................................................................................................................................................................................................. 	12
	 	 
	3.1          Price
      for
      Services...........................................................................................................................................................................................................................................................................................	12 
	3.2          Purchase
      Orders and
      Payment.....................................................................................................................................................................................................................................................................	12 
	3.3          Set
      up and Equipment
      Costs........................................................................................................................................................................................................................................................................	12 
	 	 
	ARTICLE 4
      DELIVERIES...........................................................................................................................................................................................................................................................................................	12 
	 	 
	4.1          Delivery
      Responsibilities..............................................................................................................................................................................................................................................................................	12 
	 	 
	ARTICLE 5 COMPLIANCE
      AUDITS......................................................................................................................................................................................................................................................................	12 
	 	 
	5.1          Manufacturing
      Audits..................................................................................................................................................................................................................................................................................	13 
	 	 
	ARTICLE 6 RECORDS AND
      REGULATORY
      ATTERS......................................................................................................................................................................................................................................	13 
	 	 
	6.1          Permits............................................................................................................................................................................................................................................................................................................. 	13 
	6.2          Compliance
      with
      cGMP.................................................................................................................................................................................................................................................................................	13 
	6.3          Access
      to
      Records........................................................................................................................................................................................................................................................................................	13 
	6.4          Record
      Maintenance.....................................................................................................................................................................................................................................................................................	13 
	6.5          Accurate
      Documentation..............................................................................................................................................................................................................................................................................	13 
	6.6          Claims
      and
      Complaints..................................................................................................................................................................................................................................................................................	14 
	6.7          Regulatory
      Communications and
      correspondence...................................................................................................................................................................................................................................	14 
	6.8          New
      Regulatory
      Requirements.....................................................................................................................................................................................................................................................................	14 
	6.9          Manufacturing
      Records and Maintenance	14 
	6.10        Cooperation
      in Obtaining Government
      Approvals...................................................................................................................................................................................................................................	14 
	6.11        Ownership
      of Regulatory
      Filings................................................................................................................................................................................................................................................................ 	14 
	6.12        Safety
      and Efficacy
      Claims...........................................................................................................................................................................................................................................................................	14 
	6.13        Accident
      Reports..........................................................................................................................................................................................................................................................................................	15 
	 	 
	ARTICLE 7 QUALITY ASSURANCE;
      QUALITY CONTROL;
      VALIDATION...............................................................................................................................................................................................	15 
	 	 
	7.1          Responsibility
      for Quality Assurance and Quality
      Control....................................................................................................................................................................................................................	15
	7.2          Qualification
      of BioVectra Facility; Utilities and
      Equipment...................................................................................................................................................................................................................	15 
	 	 
	ARTICLE 8
      NON-CONFORMANCE.......................................................................................................................................................................................................................................................................	15 
	 	 
	8.1          Non-Conformance..........................................................................................................................................................................................................................................................................................	15 
	8.2          No
      BioVectra Liability for Non-Conforming
      Product...............................................................................................................................................................................................................................	16 
	8.3          BioVectra
      Liability for Non-Conforming Product;
      Replacement............................................................................................................................................................................................................	16 
	8.4          Cooperation
      in Investigations; Disposition of Non-Conforming
      Product...........................................................................................................................................................................................	16 
	8.5          Third
      Party /
      Arbitration...............................................................................................................................................................................................................................................................................	16 


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    
      	 	 
	ARTICLE 9 LICENSE
      GRANTS..............................................................................................................................................................................................................................................................................	17 
	 	 
	9.1          Helix
      Licenses to BioVectra........................................................................................................................................................................................................................................................................ 	17 
	9.2          BioVectra
      Licenses to Helix........................................................................................................................................................................................................................................................................ 	17 
	 	 
	ARTICLE 10 OWNERSHIP OF
      INTELLECTUAL
      PROPERTY........................................................................................................................................................................................................................	17 
	 	 
	MATERIALS AND
      EQUIPMENT.............................................................................................................................................................................................................................................................................	17 
	 	 
	10.1          Intellectual
      Property................................................................................................................................................................................................................................................................................... 	17 
	10.2          Confidential
      Information........................................................................................................................................................................................................................................................................... 	17 
	10.3          Process
      Improvements.............................................................................................................................................................................................................................................................................. 	18 
	Product-Specific
      Process Improvements................................................................................................................................................................................................................................................................. 	18 
	10.4          General
      Process Improvements................................................................................................................................................................................................................................................................ 	18 
	10.5          Helix
      Materials...........................................................................................................................................................................................................................................................................................  	18 
	10.6          Helix
      Equipment.......................................................................................................................................................................................................................................................................................... 	18 
	10.7          BioVectra
      Assistance................................................................................................................................................................................................................................................................................ 	18 
	10.8          Limitation..................................................................................................................................................................................................................................................................................................... 	18 
	 	 
	ARTICLE 11 BIOVECTRA PRODUCT
      WARRANTIES.................................................................................................................................................................................................................................... 	18 
	 	 
	11.1          Product
      Warranties...................................................................................................................................................................................................................................................................................  	19 
	11.2          BioVectra
      Facility....................................................................................................................................................................................................................................................................................... 	19 
	 	 
	ARTICLE 12 REPRESENTATIONS AND
      WARRANTIES;
      COVENANTS....................................................................................................................................................................................................	19 
	 	 
	12.1          Mutual
      Representations and Warranties............................................................................................................................................................................................................................................... 	19 
	12.2          Representations
      and Warranties of Helix............................................................................................................................................................................................................................................... 	19 
	12.3          Representations
      and Warranties of BioVectra...................................................................................................................................................................................................................................... 	20 
	12.4          Additional
      Covenants..............................................................................................................................................................................................................................................................................  	22 
	 	 
	ARTICLE 13
      INDEMNIFICATION..........................................................................................................................................................................................................................................................................	22 
	 	 
	13.1          Indemnification
      By
      Helix............................................................................................................................................................................................................................................................................	22 
	13.2          Exception...................................................................................................................................................................................................................................................................................................... 	22 
	13.3          Indemnification
      By BioVectra................................................................................................................................................................................................................................................................... 	22 
	13.4          Indemnification
      Procedures...................................................................................................................................................................................................................................................................... 	23 
	 	 
	ARTICLE 14
      INSURANCE....................................................................................................................................................................................................................................................................................... 	23 
	 	 
	14.1          BioVectra  Insurance.................................................................................................................................................................................................................................................................................. 	23 
	14.2          Helix
      Insurance............................................................................................................................................................................................................................................................................................ 	23 
	14.3          Evidence
      of Insurance............................................................................................................................................................................................................................................................................... 	24 
	 	 
	ARTICLE 15
      CONFIDENTIALITY.......................................................................................................................................................................................................................................................................... 	24 
	 	 
	15.1          BioVectra
      Confidentiality
      Obligations..................................................................................................................................................................................................................................................... 	24 
	15.2          Helix
      Confidentiality Obligations 	24 
	15.3          Responsibility
      for Compliance with Confidentiality and Non-Use
      Obligations............................................................................................................................................................................... 	24 
	15.4          Terms
      of Agreement................................................................................................................................................................................................................................................................................... 	24 
	15.5          Notification
      of Mandatory Disclosure.................................................................................................................................................................................................................................................... 	25
	15.6          No
      Licenses................................................................................................................................................................................................................................................................................................. 	25 
	15.7          Equitable
      Relief........................................................................................................................................................................................................................................................................................... 	25 
	15.8          Prior
      Confidentiality Agreement............................................................................................................................................................................................................................................................... 	26 
	 	 
	ARTICLE 16 PRESS RELEASES; USE
      OF
      NAMES............................................................................................................................................................................................................................................ 	26 
	 	 
	16.1          Press
      Releases............................................................................................................................................................................................................................................................................................. 	26 
	16.2          Use
      of Names.............................................................................................................................................................................................................................................................................................. 	26 
	 	 
	ARTICLE 17 TERMINATION &
      CANCELLATION........................................................................................................................................................................................................................................... 	26 
	 	 
	17.1          Termination.................................................................................................................................................................................................................................................................................................. 	26 
	17.2          Consequences
      of Termination 	28 
	17.3          Surviving
      Rights......................................................................................................................................................................................................................................................................................... 	29 
	17.4          Cancellation
      of Services............................................................................................................................................................................................................................................................................ 	29 


    

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    
      	 	 
	ARTICLE 18 FORCE
      MAJEURE............................................................................................................................................................................................................................................................................. 	30
	 	 
	18.1          Effects
      of Force Majeure........................................................................................................................................................................................................................................................................... 	30 
	18.2          Notice
      of Force Majeure; Obligations of Parties During Force  Majeure
      Event............................................................................................................................................................................... 	30 
	18.3          Termination.................................................................................................................................................................................................................................................................................................. 	30 
	 	 
	ARTICLE 19 ASSIGNMENT;
      TRANSFER.............................................................................................................................................................................................................................................................	31 
	 	 
	19.1          Assignment.................................................................................................................................................................................................................................................................................................. 	31 
	 	 
	ARTICLE 20
      MISCELLANEOUS............................................................................................................................................................................................................................................................................ 	31 
	 	 
	20.1          Notices.......................................................................................................................................................................................................................................................................................................... 	31 
	20.2          Applicable
      Law............................................................................................................................................................................................................................................................................................ 	31 
	20.3          Headings....................................................................................................................................................................................................................................................................................................... 	31 
	20.4          Exhibits.........................................................................................................................................................................................................................................................................................................  	32 
	20.5          Severability..................................................................................................................................................................................................................................................................................................  	32 
	20.6          Independent
      Contractors........................................................................................................................................................................................................................................................................... 	32 
	20.7          Waiver........................................................................................................................................................................................................................................................................................................... 	32 
	20.8          Counterparts................................................................................................................................................................................................................................................................................................  	32 
	20.9          Entirety;
      Amendments................................................................................................................................................................................................................................................................................ 	32 
	20.10        Preference...................................................................................................................................................................................................................................................................................................... 	33 
	20.11        Limitation
      on
      Damages................................................................................................................................................................................................................................................................................ 	33 
	20.12        Time...............................................................................................................................................................................................................................................................................................................  	33 
	 	 
	 	 


    

     

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    L
DOS 47 GMP PROCESS DEVELOPMENT, SCALE UP AND

    CLINICAL
SUPPLIES MANUFACTURING AGREEMENT

     

    THIS AGREEMENT
is made as of May 4, 2008 (the “Effective
Date”)

     

    BY
AND BETWEEN:

     

    HELIX
BIOPHARMA CORP., having its principal offices located
at

    305
Industrial Parkway South, Unit 3, Aurora, Ontario, L4G 6X7,

    (hereinafter
referred to as “Helix”)

     

    and

     

    BIOVECTRA
INC.,

    having
offices at 16 McCarville Street, Charlottetown, Prince Edward
Island,

    C1E
2A6, Canada

    (hereinafter
referred to as (“BioVectra”)

     

    (each
a Party and together the Parties).

     

    WHEREAS
BioVectra and Helix intend that the terms and conditions of this Agreement shall
govern the general manufacturing process development, scale-up and the cGMP
manufacturing of clinical supplies of Helix’s L DOS 47.

     

    NOW,
THEREFORE, in consideration of the mutual promises and covenants herein
contained and other good and valuable consideration, the receipt and sufficiency
of which is hereby acknowledged, BioVectra and Helix agree as
follows:

     

    
      
        ARTICLE
1 DEFINITIONS AND SCHEDULES

      

    

     

    1.1    Definitions

    The
following capitalized terms, whether used in the singular or plural, shall have
the meanings assigned to them below for purposes of this Agreement, including
the Schedules hereto:

     

    Actual & Reasonable Costs and
Expenses, means, in the case of property acquired by BioVectra from, or
costs and expenses incurred to, an arm’s length Third Party, BioVectra’s actual
acquisition cost of such property or actual costs paid to the arm’s length Third
Party, and in the case of costs and expenses incurred internally or to a
non-arm’s length Third Party, the lesser of BioVectra’s actual costs and
expenses and the fair market value of the property or other consideration
acquired or rendered in consideration of such costs.

     

    Affiliate means, with
respect to either Party, any other corporation or business entity that directly,
or indirectly through one or more intermediaries, controls, is controlled by or
is under common control with such Party. For purposes of this definition, the
term control means direct or indirect ownership of more than fifty percent (50%)
of the securities or other ownership interests representing the equity voting
stock or general partnership or membership interest of such entity or the power
to direct or cause the direction of the management or policies of such entity,
whether through the ownership of voting securities, by contract, resolution or
otherwise.

     

    Batch means a specific
quantity of Product produced by BioVectra.

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    Production Record means
all of the documentation associated with the production of a given Batch,
including the manufacture, testing, bulk packaging, storage, and labeling of
such Batch.  This documentation shall include: (a) all manufacturing
batch documents and packaging batch documents referred to in the Quality
Assurance Agreement or otherwise pertaining to the Batch; (b) any change control
documents, deviation reports and other quality investigation reports; and (c)
BioVectra's Certificate of cGMP Compliance.

     

    Certificate of cGMP
Compliance means, for each clinical Batch and each Batch produced for
stability testing, a document prepared by BioVectra in form and substance
reasonably satisfactory to Helix:

     

    
      	
              (a)  

            	
              listing
      the manufacturing date, unique Batch number, and quantity of Product in
      such Batch,

            


    

    
      	
              (b)  

            	
              certifying
      that such Batch was manufactured in accordance with the Master
      Formula,  and cGMP;

            


    

    
      	
              (c)  

            	
              certifying
      that all required quality assurance investigations are completed and
      listing the same; and

            


    

    
      	
              (d)  

            	
              certifying
      that the Batch meets the Master Formula and cGMP quality control
      requirements.

            


    

     

    


    Confidential
Information means Helix Confidential Information or BioVectra
Confidential Information, as the context requires.

    


    cGMP or GMP shall mean the
good manufacturing practices as set out in the ICH Q7 International Guidelines
in effect at a particular time, for the manufacture and testing of active
pharmaceutical ingredients, and the corresponding requirements of each
Regulatory Authority.

    


    BioVectra Confidential
Information means all technical and other information, whether patented
or unpatented, relating to the BioVectra Facility or BioVectra processes
(including General Process Improvements), methods, operations, technologies,
forecasts and business information, that is disclosed or supplied to, or used on
behalf of, Helix by BioVectra pursuant to this Agreement, or of which Helix may
become aware through the presence of their employees or agents at BioVectra
offices or at the BioVectra Facility, including, without limitation, trade
secrets, know-how, processes, concepts, experimental methods and results and
business and scientific plans and information and facility layout and
schematics, but does not include the Helix Confidential
Information.  Notwithstanding the foregoing, BioVectra Confidential
Information shall not include any information that:

    


    
      	
              (i)  

            	
              is
      known publicly or hereafter becomes known publicly through no fault of
      Helix, its Affiliates or agents;

            


    

    


    
      	
              (ii)  

            	
              becomes
      available to Helix from a Third Party which is not legally prohibited from
      disclosing such information, provided such information was not acquired
      directly or indirectly from Helix;

            


    

    


    
      	
              (iii)  

            	
              was
      developed by Helix independently of information obtained from BioVectra as
      evidenced by written records;

            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    
 

    
      	
              (iv)  

            	
              was
      already known to Helix before receipt from BioVectra, as shown by its
      prior written records, provided that such information was not acquired
      directly or indirectly from BioVectra;
or

            


    

    


    
      	
              (v)  

            	
              is
      released with the prior written consent of BioVectra
      hereunder.

            


    

    


    In the
event any BioVectra Confidential Information has entered the public domain, only
that portion of said Confidential Information that has become public shall be
excluded under this definition and portions remaining confidential shall retain
their status as BioVectra Confidential Information.

    


    BioVectra Facility
means the manufacturing facilities owned and operated by BioVectra.

    


    BioVectra Intellectual
Property means all Intellectual Property owned or controlled by BioVectra
and shall include, but not be limited to, BioVectra Confidential
Information.

    


    EMEA means the
European Agency for the Evaluation of Medicinal Products, or any successor
agency.

    


    FDA means the United
States Food and Drug Administration, or any successor agency
thereto.

    


    FD&C Act shall
mean the United States Federal Food, Drug and Cosmetic Act and regulations
thereunder, as amended from time to time.

    


    Force Majeure Event
has the meaning set forth in Section 18.1.

    


    Governmental
Authority means any:

    


    
      	
              (a)  

            	
              nation,
      province, county, city, town, village, district or other jurisdiction of
      any nature,

            


    

    
      	
              (b)  

            	
              federal,
      provincial, local, municipal, foreign or other
  government,

            


    

    
      	
              (c)  

            	
              governmental
      or quasi-governmental authority of any nature (including any governmental
      agency, branch, department, official or entity and any court or other
      tribunal, including an arbitral tribunal, such as the FDA, EMEA and Health
      Canada as are described in this Agreement),
or

            


    

    
      	
              (d)  

            	
              body
      exercising, or entitled to exercise, any administrative, executive,
      judicial, legislative, police, regulatory or taxing power of any
      nature.

            


    

    


    Health Canada shall
mean the Canadian Federal government department known as Health Canada or its
successor agency.

    


    Helix Confidential
Information means, but is not limited to, the Product, all Helix Records,
and all clinical data and information, business plans, regulatory and product
strategies and all technical and other information, whether patented or
unpatented, relating to the products, processes, test methods, operations,
technologies, forecasts and business information of Helix or any of its
Affiliates that is disclosed or supplied to BioVectra by or on behalf of Helix
or any of its Affiliates pursuant to this Agreement or that is Intellectual
Property owned by Helix as referred to in Section 10.1,
or information of which BioVectra may become aware of through the presence of
its employees or agents at the offices or facilities of Helix or any of its
Affiliates or at facilities that manufacture the Product, including, without
limitation, trade secrets, know-how, processes, concepts, experimental,
analytical and test methods and results, and business and

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    scientific
plans and information and facility layout and
schematics.  Notwithstanding the foregoing, Helix Confidential
Information shall not include any information that:

    


    
      	
              (i)  

            	
              is
      known publicly or hereafter becomes known publicly through no fault of
      BioVectra, its Affiliates or
agents;

            


    

    


    
      	
              (ii)  

            	
              becomes
      available to BioVectra from a Third Party which is not legally prohibited
      from disclosing such information, provided such information was not
      acquired directly or indirectly from
BioVectra;

            


    

    


    
      	
              (iii)  

            	
              was
      developed by BioVectra independently of information obtained from Helix as
      evidenced by written records;

            


    

    


    
      	
              (iv)  

            	
              was
      already known to BioVectra before receipt from Helix, as shown by its
      prior written records, provided that such information was not acquired
      directly or indirectly from BioVectra;
or

            


    

    


    
      	
              (v)  

            	
              is
      released with the prior written consent of Helix
  hereunder.

            


    

    


    In the
event any Helix Confidential Information has entered the public domain, only
that portion of said Confidential Information that has become public shall be
excluded under this definition and portions remaining confidential shall retain
their status as Helix Confidential Information.

    


    Helix Intellectual Property
means any Intellectual Property owned or controlled by Helix, and shall
include, but not be limited to, the Helix Confidential Information.

    


    Helix Records means
all Records as defined in section 6.3, other than those that relate specifically
to the BioVectra Confidential Information.

    


    INDA shall mean an
Investigational New Drug Application, as defined in the FD&C
Act.

    


    Intellectual
Property means all
Patents and other Patent rights, copyrights, trade secrets, know-how, processes
and all other intellectual property rights, including all applications and
registrations with respect thereto, and  all information, data,
concepts, designs, processes, software, algorithms, inventions, and all relevant
documents, instruments and other records, whether or not the subject, or capable
of being the subject, of patent, copyright, industrial, trade secret, trademark
or other forms of protection, and includes all trademarks, trade names, service
marks, logos and other corporate identifiers.

    


    Master Formula means
the document changed from time to time in accordance with this Agreement and
approved by Helix in writing, that defines the manufacturing methods,
manufacturing processes, test methods, materials, and other procedures,
directions and controls associated with the manufacture and testing of Product.
The Master Formula shall also include or be deemed to incorporate by reference,
without limitation, such information as raw materials specifications, in process
and final Product sampling standards and Product specifications contained in
Schedule A and B, equipment and instrumentation specifications and BioVectra’s
standard operating procedures, including, without limitation, standard operating
procedures for in-process quality control testing.

    


     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    Non-Conforming
Product or non-conforming means
Product or similar material that fails to conform to all of the warranties set
forth in Section 11.1 or Product or similar material that
was manufactured at a time when the BioVectra Facility failed to conform to the
warranties set forth in Section 11.2.

    


    Patents shall mean,
with respect to an invention, any patent or patent application, and any patent
issuing therefrom, together with any extensions, reissues, reexaminations,
substitutions, renewals, divisions, continuations and continuations-in-part
thereof, and any patent or patent application claiming priority to any
application in common with any such patent containing a disclosure substantially
similar to any such patent, all to the extent the foregoing contain claims
covering such invention.

    


    Process Improvements
has the meaning set forth in Section10.3.

    


    Product means Helix’s
L-DOS 47 produced pursuant to the Master Formula.

    


    Purchase Order means
the purchase order related to the services as set out in Schedule C and when
issued by Helix shall be the authorization for BioVectra to perform the Services
associated with each purchase order as set out and described in detail in
Schedule ‘A’ for the price setout in Schedule C.

    


    Quality Assurance
Agreement means the Quality Assurance Agreement, which is attached as
Schedule B hereto and hereby incorporated into this Agreement by
reference.

    


    Raw Materials means
all materials, including without limitation, raw materials  acquired
by BioVectra for use in manufacturing the Product or performing the Services
under this Agreement.

    


    Records  has
the meaning set forth in Section 6.3.

    


    Regulatory
Authority or
Regulatory Authorities means the FDA, EMEA or Health Canada, or all of
the foregoing, as the case requires.

    


    Regulatory Filing
means any or all applications, correspondence or petitions, to Regulatory
Authorities in connection with the development, testing, manufacture or sale of
Product, or modifying or supplementing existing filings and subsequent
amendments and supplements thereto, including any foreign counterparts thereof
and any other filings required by Regulatory Authorities relating to the
manufacture, testing, sale or distribution of the Product under this
Agreement.

    


    Regulatory
Requirements means:

    


    
      	
              (a)  

            	
              obtaining
      and maintaining any and all permits, licenses, filings and certifications
      required by the Regulatory
Authorities,

            


    

    
      	
              (b)  

            	
              compliance
      with the cGMP applicable to any manufacturing or processing activities
      hereunder or the BioVectra Facility or other facilities at which any of
      the Master Formula work is performed,
and

            


    

    
      	
              (c)  

            	
              any
      laws, rules, guidelines, regulations, guidance, points to consider
      documents and standards of any Governmental Authority, that apply to the
      activities to be carried
      out  by  BioVectra  or to the BioVectra
      Facility .

            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    Services means the
services to be performed by BioVectra as set out in the attached Schedules ‘A’
and ‘B’  and such other services as the parties agree may agree to in
writing.

    


    Subcontractor means
any independent entity that BioVectra contracts with to perform any services or
meet any obligations that are required under the terms and conditions of this
Agreement.

    


    Term means the term
of five (5) years commencing on the Effective Date, unless terminated sooner
pursuant to the terms of this Agreement.

    


    Third Party means any
party other than Helix, BioVectra, their respective Affiliates and their
respective directors, officers, employees and agents.

     

    
      1.2    Schedules

    

     

    The
following Schedules are attached hereto and incorporated into this Agreement by
reference:

    


    Schedule
‘A’        –           Stage
2 Production Proposal

    Schedule
‘B’         –           Quality
Assurance Agreement

    Schedule
‘C’         –           Purchase
Orders / Services / Price / Delivery Date

    Schedule
‘D’      
  –           Equipment
List and Prices

    


    In the
event of a conflict between the provisions of the body of this Agreement and the
provisions of a Schedule, the provisions of the body of this Agreement shall
prevail.

     

    ARTICLE
2 THE SERVICES


    
      2.1    The
Services

    

    BioVectra
agrees to provide to Helix the Services described in the attached Schedule
‘A’  “Stage 2 Production Proposal,” and the services described in the
attached Schedule ‘B’ “the Quality Assurance Agreement” (collectively the
“Services” ) and such other services as the parties may agree upon in writing
from time to time.

    


    
      2.2    Purchase
Order

    

    BioVectra
shall not render any Services described in or related to  Schedule ‘A’
unless and until Helix notifies BioVectra to do so in writing by submitting a
written Purchase Order for such Services to BioVectra. Helix has no obligation
to issue a Purchase Order to BioVectra. Schedule ‘C’ to this Agreement is a
summary of the Services to be provided with respect to each Purchase Order and
the agreed price to be paid for the Services. Helix shall number the Purchase
Orders in the manner set out in Schedule C and deliver same to BioVectra. Upon
receipt of a Purchase Order BioVectra shall use commercially reasonable efforts
to commence and complete the applicable Services within the time frame set out
in Schedule ‘A’, or within such other time frame as the parties may otherwise
agree upon.  The Parties acknowledge that the timing and results of
the Services can not be guaranteed and hereby agree that reasonable deviations
shall not be deemed a failure to adequately perform the Services.

    


    
      2.3    Service
Standard

    

    BioVectra
will provide the Services with due care and diligence, and, without limiting the
generality of the foregoing, in accordance with (i) this Agreement; (ii) all
applicable Regulatory Requirements; (iii) the  Quality Assurance
Agreement; and (iv) cGMP.

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      2.4    Quality Assurance
Agreement

    

    The
Quality Assurance Agreement specifies certain services, including certain
testing, storage, release, cGMP, regulatory and other quality assurance
requirements to be performed by BioVectra as part of the Services, all of which
shall be deemed a material part of this Agreement.

    


    
      2.5    Additional
Services

    

    BioVectra
will use reasonable commercial efforts to accommodate any request which Helix
may make for services not contemplated in the attached Schedule A and should
BioVectra and Helix agree upon the provision and pricing of such services, such
additional services shall be deemed to form part of the Services hereunder and
shall be governed by the provisions of this Agreement.

    


    
      2.6    Change
Orders

    

    Helix
shall have the right to request reasonable changes in or modifications to the
Services, to be provided in accordance with this Agreement, provided that such
change or modification shall not in the opinion of BioVectra, acting reasonably,
increase the price of the Services in total.

    


    
      2.7    Helix Personnel on
Site

    

    From
time-to-time and upon reasonable advance notice, Helix may designate selected
Helix personnel to be present at the BioVectra Facility during the execution of
the Services.  BioVectra shall allow such designated personnel access
to those portions of the BioVectra Facility where Services are conducted for the
purposes contemplated in this Agreement, provided that the Helix personnel are
accompanied by BioVectra staff and comply with all applicable rules, protocols
and safety measures at all times while they are present at the BioVectra
Facility.

    


    
      2.8    Dispute
Resolution.

    

    In the
event of a disagreement or decision-deadlock between the Parties as to any
material matter within the scope of this Agreement, or matters that a Party
considers to be, or potentially cause, a breach of a material term hereunder, or
matters requiring the consent or agreement of both Parties, the Parties will
diligently and in good faith seek to resolve the matter in dispute, and each
Party shall act diligently and in good faith in seeking to resolve the matter.
In the event that no mutual agreement is reached by the Parties, neither Party
shall incur any liability to the other Party solely as a result of failing to
resolve a disagreement or decision-deadlock under this 2.8.

    


    
      2.9    Approval of
Subcontracting 

    

    BioVectra
shall not have the right to subcontract, sublicense or otherwise delegate all or
any portion of its obligations under this Agreement without Helix's prior
written approval. Notwithstanding the foregoing, BioVectra may propose certain
pre-defined, non-essential or routine tasks that BioVectra desires to
subcontract out, and Helix will review and reasonably approve BioVectra to
subcontract any or all of such tasks to the Subcontractors of BioVectra's
choosing. To the extent such approvals are granted,
BioVectra  shall

    


    
      	
              (a)  

            	
              fully
      qualify each such Subcontractor, and Helix shall have the right to
      participate in such qualification
process;

            


    

    


    
      	
              (b)  

            	
              ensure
      that all such qualified Subcontractors comply with the provisions of this
      Agreement, including, but not limited to, the confidentiality provisions;
      and

            


    

    


    
      	
              (c)  

            	
              be
      responsible for each such Subcontractors performance hereunder (including,
      without limitation, any breach of this Agreement by such Subcontractor),
      as if BioVectra  were itself performing such
      activities.

            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    ARTICLE
3 PRICING AND PAYMENT

    


    
      3.1    Price for
Services 

    

    Subject
to section 3.3,
the parties agree that the price set out in Schedule ‘C’ for each Purchase Order
includes compensation for all Services to be rendered by BioVectra in connection
with such Purchase Order, including any services to be provided pursuant to the
Quality Assurance Agreement.

    


    
      3.2    Purchase Orders and
Payment

    

    Upon the
issuance of a Purchase Order Helix shall pay a sum equal to 30% of the total
price of each Purchase Order as set out in Schedule ‘C’. BioVectra may invoice
Helix for the price set out in an Purchase Order at anytime on or after
BioVectra’s completion and delivery of all Services to be rendered in connection
with the said Purchase Order excepting only Services to be performed or which
may be required following release of Product, for which
BioVectra  shall continue to remain responsible (such as, without
limitation, Services related to product recall, sample retention, document
retention).  Invoices so rendered by BioVectra will be paid by Helix
within thirty (30) days of receipt.

    


    
      3.3    Set up and Equipment
Costs

    

    BioVectra
will need to acquire certain pieces of equipment listed on Schedule ‘D’ in order
to provide the Services. The sum of *** being the estimated cost of the
equipment has been advanced by Helix to BioVectra pursuant to the Equipment
Funding Agreement which shall be terminated on execution of this agreement. The
pricing estimates set out in Schedule ‘D’ are estimates of equipment cost only,
provided that the actual cost shall not exceed 10% of the amounts listed on
Schedule D unless the prior approval of Helix is obtained. ON execution of this
Agreement the said sum of *** shall be treated as payment in full of Purchase
Order 1.2  set out in Schedule C. On termination of this agreement
Helix shall have the right to purchase the equipment pursuant to the provisions
of section 10.6.

     

    ARTICLE
4  DELIVERIES

    


    
      4.1    Delivery
Responsibilities

    

    Delivery
responsibilities are as set out in the Quality Assurance
Agreement.  The delivery date for each batch of Product shall be
commercially reasonably determined by Helix.

    


    Delivery
of any Product shipped from BioVectra shall be FCA BioVectra to Helix or Helix’s
designee in accordance with applicable law.  Freight, duty, taxes, and
insurance shall be for the account of Helix, and title and the risk of loss,
delay, damage in transit shall be passed to Helix upon delivery to Helix’s or
Helix’s designee’s designated carrier.  BioVectra shall package the
Product for shipment in accordance with its customary practices therefore,
unless otherwise specified in writing by Helix, in which event any extra
reasonable cost incurred by BioVectra on account of changes requested by Helix
will be incorporated into the price of Product charged to
Helix.  BioVectra shall include the following for each shipment of
Product: (a) the Purchase Order number; (b) the lot and batch numbers; (c) the
quantity of Product; and (d) the Certificate of cGMP Compliance.

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    ARTICLE
5 COMPLIANCE AUDITS


    
      5.1    Manufacturing
Audits

    

    Helix
shall have the right to perform, directly or through its representatives,
certain manufacturing compliance audits as set forth in the Quality Assurance
Agreement, or as otherwise agreed in writing by BioVectra and Helix from time to
time.  Helix shall be responsible for all Third Party costs of all
compliance audits.

    


    ARTICLE
6 RECORDS AND REGULATORY MATTERS


    
      6.1    Permits

    

    BioVectra
shall secure and maintain in good order, at its sole cost and expense, such
current governmental registrations, permits and licenses and other Regulatory
Requirements as are required by Governmental Authorities, having jurisdiction
over BioVectra activities, in order for BioVectra to perform all of its
obligations under this Agreement.

    


    
      6.2    Compliance with
cGMP

    

    BioVectra
shall use its best efforts to produce the Product under cGMP
conditions.  Provided however that BioVectra shall be obligated to
ensure that the third Batch of Product is produced under cGMP
conditions.  BioVectra shall monitor and maintain reasonable records
respecting its compliance with cGMP, including those referenced in the Quality
Assurance Agreement, or as Helix may otherwise reasonably request from time to
time.   BioVectra further agrees to comply with any and all
corrective actions mutually agreed to by the Parties pursuant to any audit
performed pursuant to section 5.1.  Actual
and Reasonable Costs and Expenses incurred by BioVectra with regards to any
mutually agreeable implemented corrective actions, except in the event and to
the extent that such costs are directly attributable to BioVectra’s breach of
the warranties set forth in Sections 11.1 and 11.2 shall be borne by
Helix.

    


    
      6.3    Access to
Records

    

    BioVectra
shall maintain all records required by the terms and conditions of the Quality
Assurance Agreement, or as Helix may otherwise reasonably request from time to
time. Helix shall have access, on reasonable prior written notice, and the right
to duplicate and use all documents, information, batch records, or other records
otherwise prepared or compiled and associated with the Services or undertaken
pursuant to, or required by, this Agreement (collectively referred to as the
“Records”), and BioVectra shall provide Helix with copies of the foregoing upon
request. BioVectra shall make such Records available to Helix and, subject to
section 15.2,
Helix may use the information contained in the Records as it sees fit, including
the disclosure of such information to third parties. BioVectra will notify Helix
before destroying any Records developed under this Agreement and Helix retains
the option of having the Records delivered to Helix.   All Helix
Records shall be maintained by BioVectra in confidence and shall only be
disclosed in accordance with this Agreement.

    


    
      6.4    Record
Maintenance

    

    BioVectra
will maintain adequate and accurate Records in order to ensure the Products’
development and manufacturing activities are documented in compliance with
applicable Regulatory Requirements.

    


    
      6.5    Accurate
Documentation

    

    Each
Party shall use diligent efforts to ensure all Records and documentation
provided to the other Party in connection with the Services shall be accurate in
all material respects, as more precisely described in the Quality Assurance
Agreement, or as otherwise agreed in writing by BioVectra and
Helix.

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      6.6    Claims and
Complaints

    

    Helix
shall have responsibility for reporting any complaints relating to the Product
to Regulatory Authorities, including, but not limited to, complaints relating to
the manufacture of the Product and adverse drug experience or event reports in
accordance with the terms and conditions of the Quality Assurance Agreement, or
as otherwise agreed in writing by BioVectra and Helix. Helix shall pay BioVectra
for all Actual & Reasonable Costs and Expenses incurred by
BioVectra  in connection with any assistance that BioVectra provides
with respect to such reporting, except in the event and to the extent that such
complaints are directly attributable to BioVectra's breach of the warranties set
forth in Sections 11.1
and 11.2.

    


    
      6.7    Regulatory Communications
and Correspondence

    

    Any and
all communications from and to Regulatory Authorities related to this Agreement
or the Services hereunder shall be handled as agreed in writing by BioVectra and
Helix.

    


    
      6.8    New Regulatory
Requirements

    

    Either
party shall promptly notify the other party new Regulatory Requirements of which
it obtains actual knowledge and which are relevant to the Services under this
Agreement and which are required by the FDA, other applicable Regulatory
Authority, or other applicable laws or governmental regulations and the parties
shall confer with each other with respect to the best means to comply with such
requirements.

    


    
      6.9    Manufacturing Records and
Maintenance

    

    BioVectra
shall prepare and maintain all manufacturing records, certificates,
authorizations, data and other records that directly or indirectly pertain to
the manufacture of the Product, as further set forth in the Quality Assurance
Agreement or as otherwise agreed in writing by BioVectra and Helix.

    


    
      6.10    Cooperation in Obtaining
Government Approvals

    

    As set
forth in the Quality Assurance Agreement, or as otherwise agreed to in writing
by BioVectra and Helix, at Helix's request, BioVectra shall provide Helix with
such existing documents and information (or copies thereof) held by BioVectra to
assist Helix in securing and maintaining Regulatory Authority approvals for the
Product. In addition, BioVectra shall provide Helix with such information as is
reasonably requested in writing by Helix relating to the the Master Formula, the
Services performed under this Agreement or other Product-related documentation.
Any Helix requests for documents or other work product that do not exist as of
the date of such request and are not otherwise required by this Agreement,
including the schedules hereto, or any other substantive requests for assistance
in compiling any Regulatory Filing shall be conducted at Helix’s
expense.

    


    
      6.11    Ownership of Regulatory
Filings

    

    Helix
shall prepare, maintain, share with BioVectra as appropriate, and be the sole
owner, to the extent possible, of all applicable or relevant Regulatory Filings
and all governmental approvals granted by any Regulatory Authority with respect
to the Product, including all copyright and BioVectra waives all its moral
rights therein.  Notwithstanding the above, BioVectra shall file for
the drug master file, and shall maintain the drug master file in accordance with
cGMP.

    


    
      6.12    Safety and Efficacy
Claims

    

    BioVectra
shall promptly notify Helix of any information or notice of which it becomes
aware concerning the safety or efficacy claims of the Product, including,
without limitation, any threatened or pending action by any Regulatory Authority
regarding the Product. Helix shall be responsible for handling all complaints
and communications from Regulatory Authorities with

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    respect
to the Product. BioVectra shall cooperate in resolving such complaints and
responding to such communications to the extent they pertain to Product and are
reasonably requested by Helix in connection therewith. Helix shall pay BioVectra
for all Actual & Reasonable Costs and Expenses incurred by BioVectra in
connection with the performance of BioVectra's obligations under this Section 6.12 except in the event and to the extent
that such complaints or communications are directly attributable to BioVectra's
breach of the warranties set forth in Sections 11.1
and 11.2.

    


    
      6.13    Accident
Reports

    

    Each
Party shall report to the other as soon as possible all material accidents
related to the manufacture, handling, use or storage of any Raw Materials or
Product, including, without limitation:

    


    
      	
              (a)  

            	
              accidents
      resulting in significant personal injury requiring more than first aid
      treatment,

            


    

    


    
      	
              (b)  

            	
              accidents
      resulting in chronic illness or loss of
  consciousness,

            


    

    


    
      	
              (c)  

            	
              accidents
      resulting in material property
damage,

            


    

    


    
      	
              (d)  

            	
              accidents
      resulting in material environmental release,
and

            


    

    


    
      	
              (e)  

            	
              accidents
      that result in external regulatory, safety, health or environmental
      audits.

            


    

     

    ARTICLE
7 QUALITY ASSURANCE; QUALITY CONTROL; VALIDATION

    


    
      7.1    Responsibility for Quality
Assurance and Quality Control

    

    Responsibility
for quality assurance and quality control of Product shall be allocated between
Helix and BioVectra as set forth in the Quality Assurance Agreement and in those
BioVectra standard operating procedures which have been agreed upon in writing
by Helix and BioVectra from time to time.

    


    
      7.2    Qualification of BioVectra
Facility; Utilities and Equipment

    

    BioVectra
shall maintain cGMP compliant quality system and shall maintain an FDA audited
facility and shall qualify all utilities and equipment used in the manufacture
of Product at the BioVectra Facility for compliance with cGMP, and shall make
relevant qualification reports applicable thereto (edited, if deemed necessary
by BioVectra, to remove information not related to the manufacture of Product)
available to Helix for review at BioVectra's Facility, at Helix's reasonable
request.


    


    ARTICLE
8  NON-CONFORMANCE

    


    
      8.1    Non-Conformance

    

    Helix may
reject any Product on the ground that it is non-conforming by giving written
notice thereof to BioVectra (an “NC Notice”) within sixty (60) days after the
delivery date for such Product. Such written notice shall specify the manner in
which such Product fails to conform to the warranties set forth in Sections 11.1
and 11.2
and shall be accompanied by any test results or reports evidencing such
non-conformity.  For a period of twenty-one (21) days following
BioVectra’s receipt of an NC Notice, the Parties shall diligently and in good
faith seek to reach

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    agreement
on whether a nonconformity exists and, if so, whether such nonconformity was
caused by BioVectra’s breach of the warranties set forth in Sections 11.1 and
11.2.

    


    
      8.2     No BioVectra Liability for
Non-Conforming Product

    

    If it is
determined by agreement of the Parties  that either: (i) there is no
nonconformity, or (ii) there is nonconformity but the nonconformity was not
caused by BioVectra's breach of the warranties set forth in Sections 11.1
and 11.2
and ; BioVectra
shall have no liability to Helix with respect thereto.

    


    
      8.3    BioVectra Liability for
Non-Conforming Product; Replacement

    

    If it is
determined by agreement of the Parties that any nonconformity claimed by Helix
pursuant to Section 8.1 was caused by BioVectra's breach of any warranty set
forth in Section 11.1 or 11.2,
BioVectra shall replace such Non-Conforming Product with conforming Product at
BioVectra’s sole expense within such timeframe as Helix may reasonably
require.

    


    
      8.4    Cooperation in
Investigations; Disposition of Non-Conforming Product

    

    If
Helix desires to make a claim against BioVectra with respect to and causing the
rejection of a Batch of Non-Conforming Product pursuant to Section 8.1, Helix
agrees that it shall not dispose of or allow such Product to be disposed of
without written authorization and instructions from BioVectra either to dispose
of or return to BioVectra such Non-Conforming Product. Upon written request by
Helix, BioVectra agrees promptly to give Helix such authorization and
instructions within a reasonable period of time. Each Party shall act in good
faith and shall cooperate with the other Party and with any Third Party or
arbitrator appointed pursuant to Section 8.5 in connection with an investigation as to
the existence of or source of any Non-Conforming Product supplied under this
Agreement. At the request of Helix, BioVectra will provide all Non-Conforming
Product to Helix at a price (including shipping and delivery expenses) to be
agreed upon between the Parties and in accordance with the delivery terms set
forth in Section 4 hereof.  Helix may make whatever further use of
such Non-Conforming Product as it shall determine; provided, however, that Helix
agrees that:

    


    
      	
              (a)  

            	
              such
      Non-Conforming Product shall not be used in humans,
  and

            


    

    


    
      	
              (b)  

            	
              the
      warranties provided in Sections 11.1 and
      11.2
      of this Agreement shall not apply to such Non-Conforming
      Product.

            


    

    


    BioVectra
shall dispose of any Non-Conforming Product returned by Helix in accordance with
all relevant Regulatory Requirements for such disposal, at BioVectra's expense,
if BioVectra was liable for such Non-Conforming Product in accordance with
Section 8.3
and at Helix's expense if BioVectra was not liable for such Non-Conforming
Product in accordance with Section 8.2.

    


    
      8.5    Third Party /
Arbitration

    

    In the
event the parties are unable to come to an agreement within 21 days of the date
Helix first gave notice to BioVectra under Section 8.1,
the matter may be referred by either Party to a mutually acceptable, qualified
and independent Third Party laboratory for final determination of conformance of
Product to the Master Formula, whose fees shall be paid by the non-prevailing
Party.   If the parties are unable to agree upon a qualified and
independent Third Party within twenty-one (21) calendar days of the date a Party
first notifies the other that it wishes to so refer the matter, then the matter
shall be resolved by arbitration conducted in English in Toronto, Ontario in
accordance with the Commercial
Arbitration Act (Ontario) as the same may be amended from time to
time.  The arbitration shall be conducted as follows: (a)  either
Party may require arbitration by giving written notice to arbitrate to the other
Party; (b)  if the Parties are

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    able to
agree upon a single arbitrator, the arbitration shall be conducted before the
single arbitrator; (c)  if the Parties have been unable to agree upon the
selection of a single arbitrator within fourteen (14) calendar days after
receipt of the notice requiring arbitration, each Party shall within seven
(7) further calendar days by notice in writing given to the other
Party nominate one (1) neutral arbitrator.  If either Party fails to
nominate an arbitrator, the single arbitrator nominated by the other Party shall
proceed to conduct the arbitration alone.  If both Parties nominate neutral
arbitrators, the two arbitrators so nominated shall nominate a third arbitrator
within seven (7) calendar days of their nomination.  The Parties agree that
it is important that the matter be resolved promptly and the Parties agree that
the arbitration will be required to be conducted expeditiously and that the
final disposition shall be accomplished within fourteen (14) calendar days of
the appointment of the single arbitrator or the third arbitrator.  The
Parties shall ensure that the arbitrator or arbitrators upon accepting
nomination agree that they have the time available for the timely handling of
the arbitration in order to achieve the final disposition within fourteen (14)
calendar days.  The decision of the arbitrator or arbitrators shall be
rendered in writing, without reasons and shall be binding upon the
Parties.

    


    ARTICLE
9 LICENSE GRANTS

    


    
      9.1    Helix Licenses to
BioVectra

    

    During
the Term (subject to early termination in accordance with ARTICLE
17 hereof), Helix
hereby grants to BioVectra a royalty-free, non-exclusive, non transferable
license under any and all Helix Intellectual Property that is necessary for
BioVectra to perform its obligations under this Agreement, including, without
limitation, all rights necessary for the development and use of the Helix
Confidential Information for the sole and limited purpose of BioVectra's
performance of its obligations under this Agreement, including, without
limitation, to manufacture Product for Helix.

    


    
      9.2    BioVectra Licenses to
Helix 

    

    BioVectra
hereby grants to Helix a perpetual, fully paid, royalty-free, non-exclusive,
license, with the right to grant and authorize sub-licenses, under any and all
BioVectra Intellectual Property that BioVectra uses for the performance of the
Services or that is necessary to the practice of the Services solely for the
limited purposes of manufacturing, using and selling the Product. Helix shall
include a provision in all agreements with Third Party contractors for the
manufacture, use or sale of the Product that clearly states that such Third
Party contractor’s right to use such BioVectra Intellectual Property is
exclusively limited to the Product.

     

    ARTICLE
10 OWNERSHIP OF INTELLECTUAL PROPERTY,

    MATERIALS
AND EQUIPMENT

    


    
      10.1    Intellectual
Property

    

    BioVectra
acknowledges and agrees that Helix shall own exclusively all Intellectual
Property relating specifically to the Product that is made, created, conceived
or reduced to practice in the course of or resulting from performance of the
Services by either Party or its employees or agents and BioVectra waives any
moral rights therein.

    


    
      10.2    Confidential
Information

    

    Helix
shall own all Helix Confidential Information, and BioVectra shall own all
BioVectra Confidential Information.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      10.3    Process
Improvements

    

    The
parties acknowledge that BioVectra may develop improvements to the Master
Formula or procedure  in the course of performing the Services under
this Agreement (“Process Improvements”). BioVectra agrees to promptly disclose
all Process Improvements to Helix as they occur.

    


    Product-Specific Process
Improvements

    BioVectra
agrees that all Process Improvements specific to the manufacture of the Product
(“Product-Specific Process Improvements”) shall be owned solely by Helix and
Helix may obtain patent, copyright and other proprietary protection
therewith.

    


    
      10.4    General Process
Improvements

    

    All
P    rocess
Improvements that are not specific to the manufacture of the Product that have
general application to the contract manufacturing of chemical or pharmaceutical
compounds (“General Process Improvements”) shall be owned by
BioVectra.

    


    
      10.5    Helix
Materials

    

    Helix
shall own all rights in and title to the Helix Intellectual Property, and any
and all improved or enhanced versions of the foregoing that are created by
either Party in the course of or resulting from this Agreement, including,
without limitation, any derivatives or variants of the foregoing. BioVectra
hereby assigns to Helix any improvements that directly relate to the Helix
Intellectual Property or the Product and shall not provide them to any third
party without Helix’s prior written consent and BioVectra waives all moral
rights therein.

    


    10.6    Helix
Equipment

    Helix
shall have the right but not the obligation on termination of the agreement to
give written notice requiring BioVectra to sell and transfer to Helix all of the
equipment listed on Schedule D for the total purchase price of $10.00, provided
that Helix shall be responsible for and pay to BioVectra on delivery of the
equipment all Actual & Reasonable Costs and Expenses incurred by BioVectra
with respect to the de-installation and preparing the equipment for
shipping.  Helix shall notify BioVectra in writing within sixty (60)
days of termination whether Helix will be exercising its option to purchase the
equipment listed on Schedule D.

    


    
      10.7    BioVectra
Assistance

    

    BioVectra
agrees to provide all reasonable assistance, including without limitation,
executing documents, to secure, perfect or prosecute Helix’s legal rights and
worldwide ownership of any inventions, materials or equipment owned by Helix,
including but not limited to documents relating to patent, trademark and
copyright assignments and applications and BioVectra waives all moral rights
therein.  Helix shall pay BioVectra for all Actual & Reasonable
Costs and Expenses incurred by BioVectra in connection with any assistance that
BioVectra provides pursuant to this provision.

    


    
      10.8    Limitation

    

    Notwithstanding
any provision of this Article 10 or this Agreement to the contrary, BioVectra’s
proprietary manufacturing or other processes and related know-how shall not
become or be deemed to be Helix Intellectual Property or Helix Confidential
Information and shall not be subject to any ownership or other rights of Helix
or a Third Party.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    ARTICLE
11 BIOVECTRA PRODUCT WARRANTIES

    


    
      11.1    Product
Warranties

    

    


    BioVectra
warrants to Helix that all Product manufactured hereunder will:

    


    
      	
              (a)  

            	
              have
      been manufactured, tested, stored, labeled and controlled  in
      conformance with the Master
Formula;

            


    

    


    
      	
              (b)  

            	
              have
      been transferred to Helix with a Certificate of cGMP Compliance, which is
      accurate and complete with respect to each
  Batch;

            


    

    


    
      	
              (c)  

            	
              have
      been manufactured, packaged, handled, stored and labeled in accordance
      with cGMP and all applicable Regulatory
  Requirements;

            


    

    


    
      	
              (d)  

            	
              not
      be adulterated or misbranded by BioVectra within the meaning of the
      FD&C Act; and

            


    

    


    
      	
              (e)  

            	
              have
      been transferred free and clear of any liens or encumbrances of any
      kind.

            


    

    


    Notwithstanding
the foregoing, the parties may agree in writing to except out any of the above
warranties in respect of one or more trial developmental batches.

    


    
      11.2    BioVectra
Facility

    

    BioVectra
hereby warrants that it owns or lawfully controls the BioVectra Facility, and
that, provided the Master Formula is successfully implemented including the
procurement and installation of all required product-specific equipment, and
provided no Force Majeure Event shall occur, BioVectra has sufficient
manufacturing capacity to enable BioVectra to conduct the Services required by
this Agreement.   BioVectra hereby warrants that the BioVectra
Facility shall be maintained in accordance with cGMP and in such condition as
will allow BioVectra to conduct the Services in compliance with cGMP, all
applicable laws, and in conformance with the Master Formula.


    


    ARTICLE
12 REPRESENTATIONS AND WARRANTIES; COVENANTS

    


    
      12.1    Mutual Representations and
Warranties

    

    Each
Party hereby represents and warrants to the other Party that:

    


    
      	
              (a)  

            	
              this
      Agreement, as executed and delivered, constitutes the valid and binding
      agreement of such Party, its successors and assigns, and is enforceable in
      accordance with its terms;

            


    

    


    
      	
              (b)  

            	
              the
      execution, delivery and performance of this Agreement does not conflict
      with any agreement, instrument or understanding, oral or written, to which
      such Party may be bound, nor violate any law or regulation of any court,
      governmental body or administrative or other agency having jurisdiction
      over it; and

            


    

    


    
      	
              (c)  

            	
              it
      has obtained all necessary authorizations and consents required to enter
      into this Agreement and to perform its obligations
    hereunder.

            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      12.2    Representations and
Warranties of Helix

    

    Helix
hereby represents and warrants to BioVectra, as of the date hereof and
throughout the term of this Agreement, that:

    


    
      	
              (a)  

            	
              To
      the best of Helix's knowledge as of the Effective Date, after reasonable
      inquiry, Helix is free to supply to BioVectra the Helix Confidential
      Information and any other information supplied by Helix to
      BioVectra;

            


    

    


    
      	
              (b)  

            	
              To
      the best of Helix's knowledge as of the Effective Date, after reasonable
      inquiry, there is no lawsuit pending against Helix that alleges patent
      infringement based on the manufacture, use or sale of the Product, and as
      of the Effective Date, Helix has not received any written notice alleging
      infringement of a Third Party Patent based on the manufacture, use or sale
      of the Product;

            


    

    


    
      	
              (c)  

            	
              To
      the best of Helix's knowledge as of the Effective Date, after reasonably
      inquiry, Helix's supply to BioVectra of the Helix Confidential Information
      and Helix Intellectual Property and any other information Helix intends to
      supply to BioVectra hereunder, and BioVectra's use thereof in accordance
      with the terms of and in performance of its obligations under this
      Agreement, does not infringe any intellectual property rights of any Third
      Party for which Helix lacks the right to grant BioVectra a valid
      sublicense to manufacture the
Product;

            


    

    


    
      	
              (d)  

            	
              To
      the best of Helix’s knowledge as of the Effective Date, after reasonably
      inquiry, the Master Formula for the Product in effect as of the Effective
      Date does not infringe any intellectual property rights of any Third Party
      for which Helix lacks the right to grant BioVectra a valid sublicense to
      manufacture the Product;

            


    

    


    
      	
              (e)  

            	
              there
      is no fact known to Helix which it has not disclosed to BioVectra or
      included in its public documents filed on SEDAR at www.sedar.com
      which  adversely affects, or which may adversely affect, the
      assets, liabilities (contingent or otherwise), capital, affairs, business,
      prospects, operations or condition (financial or otherwise) of Helix or
      the ability of Helix to perform its obligations under this
      Agreement;

            


    

    


    
      	
              (f)  

            	
              To
      the best of Helix’s knowledge as of the Effective Date, after reasonable
      inquiry, Helix has made BioVectra aware of any known hazards involved in
      handling the Helix Intellectual Property, Master Formula and Product;
      and

            


    

    


    
      	
              (g)  

            	
              Helix
      has the financial capacity to enter into and carry out this entire
      Agreement.

            


    

    


    
      12.3    Representations and
Warranties of BioVectra

    

    BioVectra
hereby represents and warrants to Helix, as at the date hereof and throughout
the term of this Agreement, that:

    


    
      	
              (a)  

            	
              To
      the best of BioVectra's knowledge, BioVectra is free to supply BioVectra
      Confidential Information to Helix (excluding any information related to
      other BioVectra clients that Helix inadvertently becomes aware of through
      the presence of their employees or agents at BioVectra offices or at the
      BioVectra Facility);

            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      	
              (b)  

            	
              BioVectra
      has the financial capacity to enter into and carry out this entire
      Agreement;

            


    

    


    
      	
              (c)  

            	
              To
      the best of BioVectra's knowledge after reasonable
  inquiry,

            


    

    


    
      	
              (i)  

            	
              BioVectra
      has the legal right to grant Helix the licenses set forth in Section 9.2
      above;

            


    

    


    
      	
              (ii)  

            	
              as
      of the Effective Date, BioVectra has not entered into any obligation that
      would prohibit BioVectra from granting the licenses set forth in Section
      9.2 above, and BioVectra shall
      not enter into any obligation in the future that would prohibit BioVectra
      from granting the licenses set forth in Section 9.2
      above;

            


    

    


    
      	
              (iii)  

            	
              BioVectra
      has not and will not use in any capacity the services of any persons
      prohibited in any way in connection with its development or manufacture of
      the Product;

            


    

    


    
      	
              (iv)  

            	
              neither
      BioVectra nor any BioVectra official or employee has been convicted of a
      felony under U.S. federal law for conduct relating to the development or
      approval, including the process for development or approval, of any drug,
      product, INDA, or any other drug product
  application;

            


    

    


    
      	
              (v)  

            	
              that
      neither it, nor any of its employees or agents performing hereunder, have
      ever been, are currently, or are the subject of a proceeding that could
      lead to it or such employees or agents becoming, as applicable, a Debarred
      Entity or Individual, an Excluded Entity or Individual or a Convicted
      Entity or Individual as defined by the FDA pursuant to 21 U.S.C. §335a (a)
      or (b);

            


    

    


    
      	
              (vi)  

            	
              there
      is no fact known to BioVectra which it has not disclosed to Helix
      which  adversely affects, or which may adversely affect, the
      assets, liabilities (contingent or otherwise), capital, affairs, business,
      prospects, operations or condition (financial or otherwise) of BioVectra
      or the ability of BioVectra to perform its obligations under this
      Agreement;

            


    

    


    
      	
              (vii)  

            	
              there
      are no legal or governmental actions, suits, proceedings or investigations
      pending or, to the knowledge of BioVectra, threatened, to which BioVectra
      is or may be a party or of which property owned or leased by BioVectra is
      or may be the subject, or related to environmental or discrimination
      matters.  BioVectra or its operations, BioVectra is not a party
      to or subject to the provisions of any injunction, judgment, decree or
      order of any court, regulatory body, administrative agency or other
      governmental body; and

            


    

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      	
              (viii)  

            	
              BioVectra
      is not in violation of or in default under, any lien, mortgage, lease,
      agreement or instrument, including without limitation, its financial
      arrangements with any Third Party.

            


    

     

    
      	
              (e)  

            	
              BioVectra
      has and will maintain in place all equipment, personnel, facilities, and
      supply agreements necessary to perform its obligations
      hereunder.

            


    

    


    
      12.4    Additional
Covenants

    

    


    
      	
              (a)  

            	
              Helix
      shall comply with all applicable laws and regulations in the performance
      of Helix's obligations under this
Agreement.

            


    

    


    
      	
              (b)  

            	
              BioVectra
      shall comply with all applicable laws and regulations in the performance
      of BioVectra's obligations under this
Agreement.

            


    

    


    
      	
              (c)  

            	
              Each
      Party shall notify the other in writing immediately in the event that any
      representation and warranty contained in this Agreement becomes
      untrue.

            


    

     

    ARTICLE
13 INDEMNIFICATION 


    
      13.1    Indemnification By
Helix

    

    


    Subject
to Section 13.2,
Helix agrees to indemnify, defend and hold BioVectra and its directors,
officers, employees and agents harmless from and against any damages, claims,
liabilities and expenses (including, but not limited to, reasonable legal fees)
(collectively, “Liabilities”) resulting from any Third Party claims, suits,
actions or proceedings (collectively, “Claims”) against BioVectra arising out
of

    


    
      	
              (a)  

            	
              Helix's
      breach of any of its representations, warranties or covenants contained in
      this Agreement; or

            


    

    


    
      	
              (b)  

            	
              Helix's
      negligent acts or omissions or willful
  misconduct.

            


    

    


    
      13.2    Exception

    

    Notwithstanding
Section 13.1, Helix will not be
required to indemnify, defend and hold BioVectra or its directors, officers,
employees and agents harmless from or against any Liabilities in connection with
any Claims to the extent arising out of:

    


    
      	
              (a)  

            	
              BioVectra's
      breach of any of its representations, warranties, or covenants contained
      in  this Agreement; or

            


    

    


    
      	
              (b)  

            	
              BioVectra’s
      negligent acts or omissions or willful
  misconduct.

            


    

    


    
      13.3    Indemnification By
BioVectra

    

    BioVectra
agrees to indemnify, defend and hold Helix and its directors, officers,
employees and agents harmless from and against any Liabilities resulting from
any Claims against Helix arising out of

    


    
      	
              (a)  

            	
              BioVectra's
      breach of any of its representations, warranties or covenants contained in
      this Agreement; or

            


    

    


    
      	
              (b)  

            	
              BioVectra's
      negligent acts or omissions or willful
  misconduct.

            


    

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    Notwithstanding
the foregoing, BioVectra will not be required to indemnify, defend and hold
Helix or its directors, officers, employees and agents harmless from or against
any Liabilities in connection with any Claims to the extent arising out
of

    


    
      	
              (a)  

            	
              Helix's
      breach of any of its representations, warranties or covenants contained in
      this Agreement; or

            


    

    


    
      	
              (b)  

            	
              Helix's
      negligent acts or omissions or willful
  misconduct.

            


    

    


    13.4    Indemnification
Procedures

    Where
either party to this Agreement (the “Indemnitee”) seeks indemnification from the
other (the “Indemnitor”) in respect of any Claim, the Indemnitee shall provide
written notice of the Claim to the Indemnitor as soon as reasonably practicable
upon becoming aware of the Claim, provided, however, the failure to provide such
notice within a reasonable period of time shall not relieve the Indemnitor of
any of its obligations hereunder except to the extent the Indemnitor is
prejudiced by such failure.  The Indemnitor shall be entitled, but
shall not be obligated, to participate in or assume the defence of the Claim,
provided that if the defence is assumed, it shall be through legal counsel
acceptable to the Indemnitee, acting reasonably, and the Indemnitee shall also
have the right, but not the obligation, to employ separate counsel, in which
event the fees and expenses of such counsel shall be borne by the
Indemnitee.  Each Indemnitee shall reasonably cooperate with the
Indemnitor and its legal representatives in the investigation or defence of any
Claims covered under this Agreement.  No Claim may be settled by an
Indemnitee or an Indemnitor without the prior written consent of the other,
which consent shall not be unreasonably withheld, unless in the case of a
settlement by an Indemnitor, the settlement acknowledges in writing that no
liability, negligence, guilt or other wrongful act or omission of the Indemnitee
is admitted or assumed, and such settlement acts as a complete bar to future or
other claims of, by or under the parties with whom such settlement is reached,
arising or which may arise out of any act, matter or thing prior to the date of
settlement.


    


    ARTICLE
14 INSURANCE

    


    
      14.1    BioVectra  Insurance

    

    


    BioVectra
shall maintain in full force and effect, at its expense:

    


    
      	
              (a)  

            	
              At
      all times during the period in which BioVectra is making any of the
      Products,  general liability insurance coverage in an amount not
      less than $10,000,000 (CAD) per occurrence (annual general aggregate of
      not less than $10,000,000 (CAD)) covering bodily injury, broad-form
      property insurance and including blanket contractual
    coverage;

            


    

    
      	
              (b)  

            	
              At
      all times during the period in which BioVectra is making any of the
      Products and, if the insurance is on a “claims made” basis, for a period
      of three (3) years thereafter, products liability / completed operations
      hazard insurance coverage in an amount not less than $10,000,000 (CAD) per
      claim (annual general aggregate of not less than $10,000,000 (CAD))
      covering bodily injury, broad-form property insurance and including
      blanket contractual coverage.

            


    

    


    
      14.2    Helix
Insurance

    

    


    Helix
shall maintain insurance in an amount considered accepted practice in the
industry.

    .

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    
      14.3    Evidence of
Insurance

    

    Upon
request, each Party shall provide to the other Party evidence of the insurance
required under this Article.

    


    


    ARTICLE
15 CONFIDENTIALITY

    


    
      15.1    BioVectra Confidentiality
Obligations

    

    BioVectra
shall not use Helix Confidential Information except as authorized under this
Agreement and shall not disclose Helix Confidential Information to anyone else
other than:

    


    
      	
              (i)  

            	
              its
      employees or employees of its Affiliates who are bound by similar
      obligations of confidentiality and non-use and who have a need to know
      such information in order to perform their duties in carrying out
      BioVectra's obligations under this
Agreement;

            


    

    


    
      	
              (ii)  

            	
              contractors
      who are bound by similar obligations of confidentiality and non-use and
      who have a need to know such information in order to provide direction to
      BioVectra or Helix regarding their respective obligations under this
      Agreement; or

            


    

    


    
      	
              (iii)  

            	
              Regulatory
      Authorities, to the extent required by law or as necessary to perform the
      Services.

            


    

    


    
      15.2    Helix Confidentiality
Obligations

    

    Helix
shall not use BioVectra Confidential Information except as authorized under this
Agreement and shall not disclose any BioVectra Confidential Information to
anyone else other than:

    


    
      	
              (i)  

            	
              employees,
      consultants, agents or contractors of Helix or Helix's Affiliates who are
      bound by similar obligations of confidentiality and nonuse and who have a
      need to know such information in order to perform their duties in carrying
      out Helix's obligations under this Agreement, or in order to provide
      direction to Helix regarding production, testing, storage or quality of
      the Product or regulatory or compliance issues related to the Product;
      or

            


    

    


    
      	
              (ii)  

            	
              Regulatory
      Authorities, to the extent required by law or as Helix considers necessary
      in connection with the development, manufacturing, distribution or sale of
      the Product.; or

            


    

    


    
      	
              (iii)  

            	
              to
      Third Parties in accordance with the exercise of the licenses granted to
      Helix under ARTICLE
      9.

            


    

    


    
      15.3    Responsibility for
Compliance with Confidentiality and Non-Use
Obligations

    

    Each
Party shall be responsible for any intentional misuse or misappropriation, by
such Party, its Affiliates, or the employees, consultants, agents or contractors
of such Party or such Party's Affiliates, of the other Party's Confidential
Information.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    
 

    
      15.4    Terms of
Agreement

    

    Except
for any disclosure that is deemed necessary, in the reasonable judgment of the
responsible Party, to comply with national, federal, state or provincial laws or
regulations (including the rules and regulations of any national stock exchange
on which such Party's securities are traded) or disclosure to a Party's
employees, consultants, advisors, agents, contractors, partners, potential
partners, potential acquirers, investors or potential investors under reasonable
conditions of confidentiality, neither Party shall, without the prior written
consent of the other Party, disclose in any manner to any Third Party the terms
and conditions of this Agreement.

    


    
      15.5    Notification of Mandatory
Disclosure

    

    


    
      	
              (a)  

            	
              Notification and
      Consultation In the event that a Party (in such case, the Notifying
      Party) believes it is required by applicable statute or regulation
      (including the rules and regulations of any national stock exchange on
      which such Party's securities are traded), or by judicial or
      administrative process to disclose any part of the other Party's (in such
      case, the Notified Party) Confidential Information which is disclosed to
      it under this Agreement, the Notifying Party
  shall:

            


    

    


    
      	
              (i)  

            	
              promptly
      notify the Notified Party of each such requirement and identify the
      documents so required thereby, so that the Notified Party may seek an
      appropriate protective order or other remedy or waive compliance by the
      Notifying Party with the provisions of this Agreement,
  and

            


    

    


    
      	
              (ii)  

            	
              consult
      with the Notified Party on the advisability of taking legally available
      steps to resist or narrow the scope of such
  requirement.

            


    

    


    
      	
              (b)  

            	
              Limited
      Disclosure If, in the absence of such a protective order or such a
      waiver by the Notified Party of the provisions of this Agreement, the
      Notifying Party is nonetheless required by mandatory applicable law to
      disclose any part of the Notified Party's Confidential Information which
      is disclosed to it under this Agreement, the Notifying Party may disclose
      such Confidential Information without liability under this Agreement,
      except that the Notifying Party shall furnish only that portion of the
      Confidential Information which is legally
  required.

            


    

    


    15.6           No
Licenses

    Except as
expressly provided in ARTICLE
9 hereof, no right or license, either express or implied, is granted
under any intellectual property right or by virtue of the disclosure of
Confidential Information under this Agreement, or otherwise.

    


    15.7           Equitable
Relief

    Each
Party agrees that;

    


    
      	
              (a)  

            	
              the
      other Party and their respective Affiliates would be irreparably injured
      by a material breach of the confidentiality and nonuse provisions of this
      Agreement by the breaching Party or by its employees or the employees of
      its Affiliates, consultants, agents or
  contractors,

            


    

    


    
      	
              (b)  

            	
              that
      monetary remedies would be inadequate to protect the other Party against
      any actual or threatened material breach of the provisions of this ARTICLE 15 by the breaching
      Party or by its employees or the employees of its Affiliates, consultants,
      agents or contractors, and,

            


    

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    
 

    
      	
              (c)  

            	
              without
      prejudice to any other rights and remedies otherwise available to the
      other Party, the breaching Party agrees, upon proof of any such actual or
      threatened material breach, to the granting of equitable relief, including
      injunctive relief and specific performance, in the other Party's favor
      without proof of actual damages. It is further understood and agreed that
      no failure or delay by either Party in exercising any right, power or
      privilege hereunder shall operate as a waiver thereof, nor shall any
      single or partial exercise thereof preclude any other or further exercise
      thereof or the exercise of any other right, power or privilege
      hereunder.

            


    

    


    15.8           Prior
Confidentiality Agreement

    The
Parties acknowledge that the Confidentiality Agreement dated on or about June 5,
2007 shall survive the execution and delivery of this Agreement and shall remain
in full force and effect in accordance with its terms.

    


    ARTICLE
16 PRESS RELEASES; USE OF NAMES

     

    
      16.1    Press
Releases

    

    BioVectra
and Helix shall not originate any publicity, news releases, public statements or
announcements, whether written or oral, relating to this Agreement without the
prior written consent of the other Party, which consent may not be unreasonably
withheld or unduly delayed, provided however, that BioVectra shall not be
prevented from complying with any duty of disclosure it may have pursuant to any
law or regulation or as required by the Regulatory Authorities.

    


    
      16.2    Use of
Names

    

    Either
Party shall not make use of the other Party’s name in any advertising or
promotional material in connection with this Agreement or any related
agreements, without the prior written consent of such Party.

    


    


    ARTICLE
17 TERMINATION & CANCELLATION

    


    
      17.1    Termination 

    

    This
Agreement may be terminated as follows:

    


    
      	
              (a)  

            	
              At the Discretion of
      Helix This Agreement may be terminated in its entirety by Helix
      upon ninety (90) days written notice thereof to BioVectra at Helix’s sole
      discretion.  Any Purchase Order issued by Helix prior to notice
      of Termination shall be completed in full by BioVectra and Helix shall
      compensate BioVectra according to Section 3.1, and Section 17.2
      herein.   

            


    

    


    
      	
              (b)  

            	
               BioVectra Material
      Breach  This
      Agreement may be terminated in its entirety by Helix upon written notice
      thereof to BioVectra in the event of a material breach by BioVectra which,
      if capable of being cured, is not cured


            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    within thirty
(30) days after receipt of written notice from Helix to BioVectra specifying in
reasonable detail the nature of such breach or, if such breach cannot be cured
within such 30-day period but is capable of being cured within a reasonable
time, if BioVectra does not commence and diligently continue actions to cure
such breach. BioVectra shall not render any Services during such cure period
other than those which are necessary to cure such breach, provided that the
breach is capable of being cured within such cure period. In the event such
breach is not cured within such cure period, this Agreement shall terminate as
set forth in Helix's notice of breach and in accordance with the terms of this
ARTICLE
17; provided, however, that this Agreement shall not be terminated
prior to the end of such cure period.  Breach of any of the provisions
of ARTICLE 15 or the Confidentiality
Agreement referred to therein, or of any representation or warranty of BioVectra
contained herein, or any such representation or warranty ceasing to be true,
shall be deemed to constitute a material breach for purposes of this ARTICLE 17 not capable of being
cured, and accordingly, Helix may terminate this Agreement immediately upon
notice in any such event.

     

     

    
      	
              (c)  

            	
              Helix Material
      Breach  This Agreement may be terminated by BioVectra
      upon written notice thereof to Helix in the event of a material breach by
      Helix that is not cured within thirty (30) days after receipt of written
      notice from BioVectra to Helix specifying in reasonable detail the nature
      of such breach. In the event such breach is not cured within such cure
      period, this Agreement shall terminate as set forth in BioVectra's notice
      of breach and in accordance with the terms of this ARTICLE
      17; provided, however, that this Agreement shall not be
      terminated prior to the end of such cure period. Breach of any of the
      provisions of ARTICLE 15 or the
      Confidentiality Agreement referred to therein, or of any representation or
      warranty of Helix contained herein, or any such representation or warranty
      ceasing to be true, shall be deemed to constitute a material breach for
      purposes of this ARTICLE
      17 not capable
      of being cured, and accordingly, BioVectra may terminate this Agreement
      immediately upon notice in any such
event.

            


    

    


    
      	
              (d)  

            	
              Force
      Majeure  A Party shall have the right to terminate this
      Agreement, upon providing written notice thereof to the other Party, if,
      as a result of a Force Majeure Event suffered by such other Party, (i)
      such other Party is unable fully to perform its obligations under this
      Agreement for any consecutive period of sixty (60) days; (ii) it is
      reasonably foreseeable at the time notice of the Force Majeure Event is
      given or is required to be given pursuant to Section 18.2
      that such other Party will be unable fully to perform its obligations
      under this Agreement for any consecutive period of ninety (90) days; or
      (iii) it is reasonably uncertain, (such as in the case of a labour dispute
      that could continue for an indeterminate amount of time) at the time
      notice of the Force Majeure Event is given or is required to be given
      pursuant to Section 18.2, whether such other Party will be able to
      fully to perform its obligations under this Agreement within the next
      following ninety (90) days.

            


    

    


    
      	
              (e)  

            	
              Insolvency
      Either Party may terminate this Agreement upon notice to the other
      Party,

            


    

    


    
      	
              (i)  

            	
              upon
      the institution by or against that other Party of insolvency, receivership
      or bankruptcy proceedings or any other proceedings for the settlement of
      such Party's debts, which proceedings are not dismissed within sixty (60)
      days,

            


    

    
      	 	
               

            
	
               

            	
               

            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    
      	
              (ii)  

            	
              upon
      that other Party making a general assignment for the benefit of
      creditors,  taking the benefit of any statute for bankrupt or
      insolvent debtors, making any proposal, assignment or arrangements with
      its creditors, or taking any steps with a view to readjustment,
      rescheduling or deferral of that Party's indebtedness or suspending making
      payments to that Party's creditors; or

            


       

    

    
      	
              (iii)  

            	
              upon
      that other Party's dissolution or cessation of
  business.

            


    

    


    
      17.2    Consequences of
Termination

    

    


    
      	
              (a)  

            	
              Payment of Amounts Due
        Expiration or termination of this Agreement for any
      reason shall not exempt any Party from paying to any other Party any
      amounts owing to such Party at the time of such expiration or
      termination.

            


    

    


    
      	
              (b)  

            	
              Payment for Partial
      Services Within 30 days of termination of this Agreement pursuant
      to sections 17.1(b), (c), (d), or (e), Helix shall pay BioVectra that
      portion of the price set forth in Schedule C equal to the portion of
      Services provided up to the time of such termination and not previously
      paid by Helix (excluding the cost of Raw Materials which are dealt with
      separately in section 17.2(d)), provided that in no event shall
      such proportionate price, plus the cost of any Raw Materials purchased
      under section 17.2(d), exceed the full price
      set out in Schedule C in respect of which such Services were
      rendered.

            


    

    


    
      	
              (c)  

            	
              Cumulative
      Remedies Except as expressly stated otherwise herein, a Party’s
      right to terminate this Agreement, and any other remedies under this
      Agreement, are cumulative, and nothing in this Agreement shall prevent any
      Party, in the case of a breach (after expiration of any applicable cure
      period and notice periods), from terminating this Agreement pursuant to
      Section 17.1
      and pursuing all other rights and remedies such Party may otherwise have
      at law or in equity in respect of such
breach.

            


    

    


    
      	
              (d)  

            	
              Raw Materials
      Upon expiration of this Agreement or termination by Helix pursuant to
      Section 17.1(b)(BioVectra material
      breach) or 17.1(e) (Insolvency of BioVectra) or
      Section 17.1 (d) (Force Majeure), Helix may elect (but shall have no
      obligation) to purchase from BioVectra, at BioVectra's Actual &
      Reasonable Costs and Expenses plus 10%, all remaining usable Raw Materials
      acquired and paid for by BioVectra for the manufacture of Product under
      this Agreement, and not previously paid for by Helix, and which cannot be
      used for other BioVectra clients in full within 90 days.  Upon
      termination of this Agreement by Helix pursuant to Section 17.1(a) (At the Discretion of Helix) or
      by BioVectra pursuant to Section 17.1(c)
      (Helix Material Breach) or 17.1(e) (Helix
      Insolvency), Helix shall purchase from BioVectra, at BioVectra's Actual
      & Reasonable Costs and Expenses plus 10%, all remaining Raw Materials
      acquired and paid for by BioVectra, but not previously paid for by Helix
      or included in the price payable by Helix under section 17.2(b), for the manufacture
      of Product under this Agreement and which cannot be used for other
      BioVectra clients, except as may be necessary for completion of any
      portion of Services hereunder that are not immediately
      terminated.

            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      	
              (e)  

            	
              Return of Materials
      and of Helix Confidential Information; Upon expiration or
      termination of this Agreement, unless otherwise directed by Helix,
      BioVectra shall promptly:

            


    

    


    
      
        	
                (i) 

              	
                 return
      or, at Helix's election, destroy all quantities of the Product, with any
      such destruction to be certified in writing to Helix by an authorized
      BioVectra officer,

              


      

    

    


    
      
        	
                (ii) 

              	
                 return
      all Helix Confidential Information to Helix, except for a single copy
      and/or sample which may be retained for documentation purposes only and
      which shall remain subject to the obligations of non-use and
      confidentiality set forth in this
Agreement,

              


      

    

    


    
      
        	
                (iii) 

              	
                 return
      to Helix all retention and reserve samples being held by BioVectra,
      provided that BioVectra may retain one set of such samples for
      documentation and regulatory purposes only;
and

              


      

    

    


    
      
        	
                (iv) 

              	
                 
      return
      to Helix all remaining interferon alpha-2b previously provided by Helix to
      BioVectra.

              


      

    

    


    Helix
shall pay BioVectra for all Actual & Reasonable Costs and Expenses incurred
by BioVectra in carrying out BioVectra’s obligations under this Section 17.2(e),  unless this Agreement has been
terminated pursuant to Section 17.1(b), in which event all such costs shall be
for BioVectra’s account.

    


    
      	
              (f)  

            	
              Return of BioVectra
      Confidential Information Upon expiration or termination of this
      Agreement, Helix shall promptly return all BioVectra Confidential
      Information to BioVectra, except for a reasonable number of copies to be
      retained by Helix to exercise its rights under this Agreement in relation
      to such BioVectra Confidential Information, but which shall otherwise
      remain subject to the obligations of non-use and confidentiality set forth
      in this Agreement.

            


    

    


    
      	
              (g)  

            	
              Accrued Rights
      Except as otherwise expressly set forth herein, any termination or
      expiration of this Agreement shall be without prejudice to any right which
      shall have accrued to the benefit of either Party and shall not relieve
      either Party of any obligation which has accrued prior to the effective
      date of such termination or expiration, which obligations shall remain in
      full force and effect for the period provided therein or, if no period is
      provided therein, then such obligations shall remain in full force and
      effect indefinitely.

            


    

    


    
      17.3    Surviving
Rights

    

    All terms
of this Agreement, which by their nature are intended to survive termination of
this Agreement, shall survive termination of this Agreement.

    


    
      17.4    Cancellation of
Services

    

    Helix
may, upon written notice, cancel a Purchase Order for which it previously
notified BioVectra to provide Services, and BioVectra shall cease providing
Services in relation to such Purchase Order as of the effective date of such
cancellation.   Within 30 days of providing notice of
cancellation, Helix will pay to BioVectra that portion of the price set forth in
the relevant Purchase Order equal to the portion of Services provided by
BioVectra in respect of the cancelled Purchase Order  prior to the
effective date of such notice, plus;

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      	
              (a)  

            	
              BioVectra’s
      actual cost any services commenced by BioVectra under the Cancelled
      Purchase Order  which cannot be reasonable stopped or
      terminated;  and

            


    

    


    
      	
              (b)  

            	
              The
      cost of remaining usable Raw Materials specifically obtained by BioVectra
      for purposes of the cancelled Purchase Order  the cost of which
      has not been included in the portion of Services payable by Helix,
      provided that in no event, except for the following sentence, shall such
      combined payment exceed, in the aggregate, the price set out in the
      cancelled Purchase
Order  .

            


    

    


     All
remaining usable Raw Materials obtained by BioVectra for purposes of the
cancelled Purchase Order and paid for by Helix, shall become the property of
Helix upon the effective date of Helix’s notice of cancellation and shall be
returned to Helix or otherwise dealt with, at the expense of Helix, as Helix may
direct.

    


    ARTICLE
18 FORCE MAJEURE

    


    
      18.1    Effects of Force
Majeure

    

    No Party
shall be in breach of this Agreement if there is any failure of performance
under this Agreement (except for payment of any amounts due under this
Agreement) occasioned by any reason beyond the control and without the fault or
negligence of the Party affected thereby, including, without limitation, an act
of God, fire, act of government or state, war, civil commotion, insurrection,
embargo, an infectious virus which cannot be detected by testing and which
causes a shutdown for a substantial period of a large portion of the BioVectra
Facility due to contamination despite commercially reasonable efforts by
BioVectra to prevent such occurrence, prevention from or hindrance in obtaining
energy or other utilities, a market-wide shortage of Raw Materials or other
necessary components, labor disputes (excluding any disputes that may arise at
BioVectra) of whatever nature, or any other reason beyond the control and
without the fault or negligence of the Party affected thereby (a “Force Majeure
Event”). Such excuse shall continue as long as the Force Majeure Event
continues, and any estimated completion date affected by such Force Majeure
event shall be extended accordingly. Upon cessation of such Force Majeure Event,
the affected Party shall promptly resume performance under this Agreement as
soon as it is commercially reasonable for the Party to do so.

    


    
      18.2    Notice of Force
Majeure;
Obligations of Parties During Force  Majeure
Event

    

    Each
Party agrees to give the other Party prompt written notice of the occurrence of
any Force Majeure Event, the nature thereof, and the extent to which the
affected Party will be unable to fully perform its obligations under this
Agreement. Each Party further agrees to use commercially reasonable efforts to
correct the Force Majeure Event as quickly as practicable and to give the other
Party prompt written notice when it is again fully able to perform such
obligations.  In the event that the Force Majeure cannot be corrected
quickly, the parties will work together to ensure that the Services will carry
forward to the extent practicable, even if this means transfer of materials to
another facility on a temporary or permanent basis.  Any proceeds
received from Business interruption or similar insurance will be applied to this
action.

    


    
      18.3    Termination

    

    This
Agreement may be terminated as a result of a Force Majeure Event in accordance
with Section 18.1 hereof.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    


    ARTICLE
19 ASSIGNMENT; TRANSFER

    


    
      19.1    Assignment

    

    This
Agreement shall be binding upon the successors and assigns of the Parties and
the name of a Party appearing herein shall be deemed to include the names of its
successors and assigns. Neither Party may assign its interest under this
Agreement without the prior written consent of the other Party, such consent not
to be unreasonably withheld; provided, however, either Party may assign its
interest under this Agreement, without the prior written consent of the other,
(a) to an Affiliate or (b) to a successor of the business by reason of merger,
sale of all or substantially all of its assets or other form of acquisition. Any
permitted assignment of this Agreement by either Party will be conditioned upon
that Party's permitted assignee agreeing in writing to comply with all the terms
and restrictions contained in this Agreement. Any purported assignment without a
required consent shall be void. No assignment shall relieve any Party of
responsibility for the performance of any obligation that accrued prior to the
effective date of such assignment.


    


    ARTICLE
20 MISCELLANEOUS

    


    
      20.1    Notices

    

    Any
notice required or permitted to be given under this Agreement by any Party shall
be in writing and shall be (a) delivered personally, (b) sent by registered
mail, return receipt requested, postage prepaid, (c) sent by a
nationally-recognized courier service guaranteeing next-day or second day
delivery, charges prepaid, or (d) delivered by facsimile (with the original
promptly sent by any of the foregoing manners), to the addresses or facsimile
numbers of the other Parties set forth below, or at such other addresses as may
from time to time be furnished by similar notice by any Party. The effective
date of any notice under this Agreement, other than a termination notice
pursuant to ARTICLE
17, shall be the date of receipt by the receiving Party.

    


    Helix
BioPharma Corp.

    3-305
Industrial Parkway S.

    Aurora,
ON

    Canada,
L4G 6X7

    Attn John
Docherty

    Fax #
(905) 841-2244

    


    BioVectra
Inc.

    16
McCarville Street,

    Charlottetown,
Prince Edward Island,

    C1E 2A6,
Canada

    Attn
President & CEO

    Fax #
902-566-2498

    


    


    
      20.2    Applicable
Law

                
This Agreement shall be construed, interpreted and enforced in accordance with
the laws in force in the Province of Ontario.

    

    


    
      20.3    Headings

            
All headings in this Agreement are for convenience of reference only and shall
not affect the interpretation of this Agreement.

    

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      20.4    Exhibits

    

    All
exhibits referred to herein form an integral part of this Agreement and are
incorporated into this Agreement by such reference.

    


    
      20.5    Severability

    

    Each
Party hereby expressly agrees that:

    
      	
              (a)  

            	
              it
      has no intention to violate any public policy, statutory or common laws,
      rules, regulations, treaty or decision of any government agency or
      executive body thereof of any country or community or association of
      countries;

            


    

    


    
      	
              (b)  

            	
              that
      if any word, sentence, paragraph, clause or combination thereof in this
      Agreement is found by a court or executive body with judicial powers
      having jurisdiction over this Agreement or any Party hereto, in a final
      unappealed order, to be in violation of any such provisions in any country
      or community or association of countries, such words, sentences,
      paragraphs, clauses or combination shall be inoperative in such country or
      community or association of countries and the remainder of this Agreement
      shall remain binding upon the Parties, so long as enforcement of the
      remainder does not violate the Parties overall intentions in this
      transaction.

            


    

    


    
      20.6    Independent
Contractors

    

    Each of
the Parties is an independent contractor and nothing herein contained shall be
deemed to constitute the relationship of partners, joint venturers, nor of
principal and agent between the Parties. Neither Party shall hold itself out to
Third Parties as purporting to act on behalf of, or serving as the agent of, the
other Party.

    


    
      20.7    Waiver

    

    No waiver
of any term, provision or condition of this Agreement whether by conduct or
otherwise in any one or more instances shall be deemed to be or construed as a
further or continuing waiver of any such term, provision or condition or of any
other term, provision or condition of this Agreement.   The
failure of either Party to assert a right hereunder or to insist upon compliance
with any term or condition of this Agreement shall not constitute a waiver of
that right or excuse a similar subsequent failure to perform any such term or
condition by the other Party.

    


    
      20.8    Counterparts

    

    This
Agreement and any amendment hereto may be executed in any number of
counterparts, each of which shall for all purposes be deemed an original and all
of which shall constitute the same instrument. This Agreement shall be effective
upon full execution by facsimile or original, and a facsimile signature shall be
deemed to be and shall be as effective as an original signature.

    


    
      20.9    Entirety;
Amendments

    

    This
Agreement, including any exhibits attached hereto and referenced herein,
constitutes the full understanding of the Parties and a complete and exclusive
statement of the terms of their agreement with respect to the specific subject
matter hereof, and no terms, conditions, understandings or agreements purporting
to modify or vary the terms thereof shall be binding unless it is hereafter made
in writing and signed by each of the Parties. No modification to this Agreement
shall be effected by the acknowledgment or acceptance of any purchase order or
shipping instruction forms or similar documents containing terms or conditions
at variance with or in addition to those set forth herein. This Agreement may be
amended and supplemented only by a written instrument signed by each of the
Parties.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      20.10    Preference

    

    The terms
of this Agreement shall prevail in the event of a conflict between this
Agreement and any  Schedule hereto.

    


    
      20.11    Limitation on
Damages

    

    Except
for (i) the parties’ obligations under ARTICLE
13 or any breach of
such obligations; or (ii) a breach of the obligations of a party under ARTICLE
15, in no event shall either Party be liable to the other Party for
incidental, special, punitive, exemplary or consequential damages, including,
but not limited to, any claim for damages based upon lost profits.

    


    
      20.12    Time

    

    Time is
of the essence of this Agreement.

    


    


    


    


    IN
WITNESS WHEREOF, the Parties have caused this Agreement to be executed as of the
Effective Date.

    


    
      	
              HELIX
      BIOPHARMA CORP.

            	 
      	
              BIOVECTRA
      INC.

            
	 
      	 
      	 
      	 
      	 
      
	 
      	 
      	 
      	 
      	 
      
	
              Per:

            	
              /s/
      John Docherty

            	 
      	
              Per:

            	
              /s/
      Ronald J. Keefe

            
	 
      	
              John
      Docherty

              Director
      and President

               

            	 
      	 
      	
              Ronald
      J. Keefe

              President
      & CEO

            
	
              Per:

            	 
      	 
      	 
      	 
      
	 
      	
              [Name]

              [Title]

            	 
      	 
      	 
      


    

    


    


    Schedule
A – Stage 2 Production Schedules

    


    Schedule
B – Quality Assurance Agreement

    


    Schedule
C – Purchase Order - Payment Schedules

    


    Schedule
D - Equipment List and Prices

    


    


    


    


    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    


     

     

    
 

    


    Schedule
A


    


    


    


    


    


    


    


    PROPOSAL
FOR STAGE 2 PRODUCTION OF L-DOS47

    February
19, 2007

     

     

     

    

     

     

     

     

     

     

     

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    1.
INTRODUCTION

    


    BioVectra
extends its appreciation to Helix Biopharma for their consideration of BioVectra
as a contract manufacturer for the implementation and production of
L-DOS47.   BioVectra has been servicing the needs of the
biopharmaceutical market for over 30 years. Based on an assessment of the
process knowledge BioVectra has gained to date, and its experience in producing
clinical trial requirements, the following proposal is given as a working
document for Helix to consider and evaluate against its own independent
determinations of requirements.

    


    Should
you have any comments or questions regarding this proposal, please do not
hesitate to contact our team. Inquiries should be directed as
follows:

    


    Primary
Customer
contact:                 Amanda
Sauer    , Project/Product Manager

                           
BioVectra

    16 McCarville St.

    Charlottetown, PE

    C1E 2A6

    (866) 883-2872 ext 6227
Office

    (902) 628-2045 Fax

    email: sball@biovectra.com

    


    Secondary
Customer Contact:          
Tibor Breining, Director of Research

    BioVectra

    16 McCarville St.

    Charlottetown, PE

    C1E 2A6

    (866) 883-2872 ext 6260
Office

    (902) 628-2045 Fax

    email: tbreinin@biovectra.com

    


    Primary
Technical
Contact:                Scott
Doncaster, Director of Manufacturing

    BioVectra

    11 Aviation Avenue

    Charlottetown, PE

    C1E 2E6

    (866) 883-2872 ext 6330
Office

    (902) 566 6126 Direct

    (902) 892-0632 Fax

    email: sdoncaster@biovectra.com

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    2.
SCOPE OF PROPOSAL

    


    2.1
Overview of Deliverables

    


    This
stage of the L-DOS47 project will be used to optimize certain process
conditions, meet current and future regulatory requirements and provide for 3 ×
50 grams of L-DOS47 Conjugate for toxicological studies and phase I clinical
trials.

    


    3.
CELL BANK STRATEGY

    


    3.1
Deliverables

    


    The
research cell bank (“RCB”) that has been used for the project to date at
BioVectra will be used for the first and/or second 50 gram lot in this next
stage of the project. BioVectra needs to establish the baseline traceability and
lineage of the current RCB. The current RCB can be used for this stage based on
the availability of pertinent technical details surrounding the origin of the
cell bank. In order to meet the current and future regulatory requirements for
this process BioVectra will require the documentation listed in Appendix A from Helix to
support this strategy (this information can be provided as copies of original
records). BioVectra is preparing the process to be future compliant with
ICHQ5B.

    


    Once the
documentation of the RCB has been reviewed and evaluated BioVectra will use a
single vial of the RCB as the working cell bank (“WCB”) for this portion of the
L-DOS47 development activities. These activities are summarized
below

    


    
      	
              I.  

            	
              Determination
      of the Limit for Cell Age for
Production

            


    

    
      	
              II.  

            	
              Microbiological
      purity trial of the cell bank

            


    

    
      	
              III.  

            	
              Reproducibility
      trial of the cell bank

            


    

    
      	
              IV.  

            	
              Limited
      Characterization of the cell bank for use in the production
      runs

            


    

    


    For the
remaining 50 gram lots of L-DOS47 a Master Cell Bank (“MCB”) will be prepared
and characterized. The work to produce the MCB will need to occur concurrent to
the preliminary work outlined in this proposal. BioVectra will utilize their
partner CRO to prepare and test the cGMP MCB. This proposal includes the cost to
prepare 100 vials of the MCB and perform the characterization tests itemized
below. The vial stock will be stored at BioVectra as well as an alternate
controlled site. The cost for this storage is included in the
proposal.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    Master
Cell Bank Characterization tests:

    
      	
              ·  

            	
              Purity
      via differential agars

            


    

    
      	
              ·  

            	
              Microbial
      ID by comparative sequence

            


    

    
      	
              ·  

            	
              Analysis
      of genomic DNA

            


    

    
      	
              ·  

            	
              Viability
      of Bacterial suspensions

            


    

    
      	
              ·  

            	
              Mytomycin
      C

            


    

    
      	
              ·  

            	
              Retention
      of selectable markers

            


    

    
      	
              ·  

            	
              Retention
      of recombinant construct

            


    

    
      	
              ·  

            	
              DNA
      sequencing

            


    

    
      	
              ·  

            	
              Analysis
      of gene copy number by PCR

            


    

    
      	
              ·  

            	
              Restriction
      endonuclease analysis – confirmatory
assay

            


    

    


    3.1.1
Determination of the Limit for Cell Age for Production

    This is a
requirement by ICH5B as well as a pertinent study performed to ensure that the
cell line will carry the plasmid through to the age required for the production
fermentor.  The limit for in vitro cell age for
production will be derived from production cells expanded under pilot-scale
conditions to mimic the production in vitro cell age or
beyond.  This will be accomplished by expanding the cell line from
vial to shake flask to 30L fermentor and again to the 30L fermentor (using
equivalent inoculum) to mimic the future production age in the 500 L fermentor.
This study has also been referred to as a plasmid stability test.

    


    At this
point the production cells will be examined using different dilutions on both
selective and non-selective agars to determine the purity and plasmid retention
of the production cells at this stage. Viability can also be determined at this
point. It is recommended to expand the cell age past the planned production age
to justify expansion of cell line to a later age (i.e. larger scale) that might
be required in the future of the L-DOS47 development.  The expression
construct of the production cells at this cell age will also be analyzed at this
point. The protein coding sequence of the expression construct in the production
cells will be verified by nucleic acid testing or analysis of the final protein
product. This will provide assurance that at the next planned production scale
(500L) the cell line has the ability to produce comparable results as those
established at the 20L scale (or age). Through this study, BioVectra will be
able to establish an acceptable level of plasmid loss or protein titer that can
be applied as an acceptance specification for later development
batches.

    


    Site                                cGMP
API Facility

    Fermentor                    Shake
flasks, 30L - 30 L (22L)

    Time                        
     2 weeks

    Documentation            Protocol
for the study

    
      Deliverables        
Report
for Cell Age Determination for Production Cells and Laboratory notebook
references

    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    3.1.2
Microbiological and Reproducibility Trial

    To assure
the microbiologic purity of the cell bank that will be used for the production
of the clinical material, a trial must be performed to check for external
contamination. Using the culture in production for determination of the limit
for cell age (3.1.1) a sample will be taken for a microbiological trial (“MT”)
prior to the addition of the inducer. External contamination will be checked
using different agar medium plates (with and without antibiotics). Colony
characteristics will be verified to determine purity at this cell age, which
will indicate purity of the originating cell bank.

    


    Using the
same fermentation culture the reproducibility of the cell bank will be
determined. The end point is similar to the limit for cell age except that the
titer of the AFAIK2 is of specific interest. A sample will be taken at the end
of the fermentation in the 30 L fermentor and taken to a certain point in the
downstream process to determine titer. A target titer specification can then be
applied to the cell bank, based on the titer obtained in the reproducibility
trial. We have previously used a target titer that is approximately 50% of the
typical production titer.

    


    Site                                cGMP
API Facility

    Fermentor                    Shake
flasks, 30L - 30 L (22L)

    Time                              2
weeks

    Documentation            Protocol
for the study

    Deliverables                 Results
reported in a Certificate of Conformance for the RCB

    


    3.1.3
Limited Characterization of the RCB

    Depending
on the detail of the documentation provided by Helix in Appendix A, a limited amount
of testing will be performed to provide additional data for the RCB that will be
used for the production scale work. This work will be performed as pre-bank
confirmatory testing prior to the creation of the MCB and not as a release test
for the RCB. These tests will include,

    


    
      	
              I.  

            	
              Induction
      of Bacterial virus from E.coli using Mytomycin C. This
      will determine if the cell bank is lysogenic in nature or contaminated
      with phage.

            


    

    
      	
              II.  

            	
              Determination
      of purity in differential agars

            


    

    
      	
              III.  

            	
              Microbial
      ID by comparative sequence analysis

            


    

    


    This
testing will be performed by BioVectra’s partner CRO and the cost is included in
this proposal. Helix will be provided with a summary and copies of the primary
data for review.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    4.
PRE-PILOT SCALE DEVELOPMENT

    


    4.1
Option A

    


    The use
of a different protein source is an option at this point in the development of
the AFAIK2 fermentation. If investigation of an alternate protein is
desired,  prior to scaling the fermentation to the next stage a
certain number of activities will need to be undertaken to assure the process
for the production of AFAIK2 at the 500L scale will support the current stage of
the project. These activities are summarized below,

    


    
      	
              I.  

            	
              Replacement
      of the LB media with another protein source at shake
  flask

            


    

    
      	
              II.  

            	
              Testing
      of a new agar medium

            


    

    
      	
              III.  

            	
              New
      media test fermentation at 30L fermentor
scale

            


    

     

    4.1.1
LB Media Replacement

    Previous
investigations using a chemically defined media did not meet yield expectations,
a study will be undertaken to test new animal free media protein sources at the
shake flask scale. The determining factor for choosing a new media component
will be relative growth rate as compared to the control LB media. At the present
time HySoy, Yeast extract, HiVeg, HiPep, HiYeast, Amisoy and Celton are being
looked at as replacement media.

    


    Site                                cGMP
API Facility

    Fermentor                    Shake
flasks

    Time                              2
weeks

    Documentation            Research
protocol

    Deliverables                 Lab
Development Report/Lab Notebook documentation

    


    4.1.2
Agar Plate Testing

    Concurrent
with the work to replace the protein source in the fermentation media, the same
change will be implemented in the agar preparation protocol.

    


    Site                                cGMP
API Facility

    Time                              2
weeks

    Documentation            Research
protocol

    Deliverables                 Lab
Development Report/Lab Notebook documentation

    


    4.1.3
Pilot Fermentation(s) Utilizing New Protein Source

    To
confirm the results obtained at the shake flask stage, a pilot scale
fermentation of the AFAIK2 will be performed at a 30L fermentor scale. These
runs will also serve as technical transfer runs to qualify a disk stack
centrifuge to be used in the process for cell separation as well as further
optimize and scale up the use of the microfluidizer for cell lysis. The
downstream processing will be taken to such a point where BioVectra can confirm
comparable AFAIK2 purity to the batches prepared using LB media. Additional
improvements for the DSP portion of the process can be studied using these runs
to supply product (i.e. addition of protease inhibitors). The fermentation
parameters confirmed in this batch will be used to prepare the protocols and
batch records for the 500 L scale.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    Site                                cGMP
API Facility

    Fermentor                    30
L (22L working)

    Centrifuge                   Westfalia
Whisperfuge

    Microfluidizer             Microfluidics
M-110EH

    Time                               8
weeks

    Documentation            Approved
protocol

    Deliverables                 Lab
Development Report/Lab Notebook documentation

    


    4.2
Option B

    


    The use
of the chemically defined R media requires additional development and
optimization of the titer and purification yield for the AFAIK2. This is based
upon the results of the two 20L fermentation trials performed to date. Prior to
scaling the fermentation to the next stage there are a certain number of
activities that must be undertaken to assure the process for the production of
AFAIK2 at the 500L scale will support the current stage of the project. These
activities are summarized below,

    


    
      	
              I.  

            	
              Repeat
      the R media shake flask experiments

            


    

    
      	
              II.  

            	
              R
      media test fermentation at 20-30L fermentor
  scale

            


    

    
      	
              III.  

            	
              Purification
      of AFAIK2 to confirm yield from 20-30L
scale.

            


    

    


    4.2.1
Pilot Fermentation(s) Utilizing R Media

    To
confirm the results obtained at the shake flask stage, a pilot scale
fermentation of the AFAIK2 will be performed at a 30L fermentor scale. These
runs will also serve as technical transfer runs to qualify a disk stack
centrifuge to be used in the process for cell separation as well as further
optimize and scale up the use of the microfluidizer for cell lysis. The
downstream processing will be taken to such a point where BioVectra can confirm
comparable AFAIK2 purity to the batches prepared using LB media. Additional
improvements for the DSP portion of the process can be studied using these runs
to supply product (i.e. addition of protease inhibitors). The fermentation
parameters confirmed in this batch will be used to prepare the protocols and
batch records for the 500 L scale.

    


    Site                                cGMP
API Facility

    Fermentor                  
 30 L (22L working)

    Centrifuge                   Westfalia
Whisperfuge

    Microfluidizer             Microfluidics
M-110EH

    Time                               8
weeks

    Documentation            Approved
Protocol

    Deliverables                 Lab
Development Report/Lab Notebook documentation

     

    `

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    5.
PREPARATION OF 3 × 50g OF CONJUGATE

    


    After the
successful completion of the pilot scale fermentations and the generation of
batch records for the 500-1000L fermentor, the production of the 3 × 50 g
material will be initiated. The following deliverables are attached to this
stage of the project:

    


    
      	
              I.  

            	
              Preparation
      of Crude Urease

            


    

    
      	
              II.  

            	
              Preparation
      of Purified Urease

            


    

    
      	
              III.  

            	
              Fermentation
      of AFAIK2 at 500-1000L scale

            


    

    
      	
              IV.  

            	
              DSP
      for AFAIK2

            


    

    
      	
              V.  

            	
              Conjugation
      of Urease to AFAIK2

            


    

    


    5.1
Preparation of Crude Urease

    


    A minimum
of 810 MU of Urease (U-080) will be prepared using the new equipment purchased
to create an animal free process train that is specific to this process. The 810
MU of U-080 will generate 150 grams of Purified Urease. The U-080 will be
prepared using the current batch records, protocols and acceptance criteria.
cGMP review will be added to the current release criteria for the U-080. Prior
to, or concurrent with, the production of the crude urease, the Jack Bean
supplier qualification will be completed.

    Additional
testing of the Jack Beans (ie. Pesticide screening) will be conducted for the
materials being used in these production batches. The batches will be prepared
and lyophilized concurrent with the pilot AFAIK2 work plan to ensure supply for
the 3 × 50 g conjugate.

    


    Site                                cGMP
API Facility

    Equipment                    “Animal
Free” process train

    Time                              3
weeks

    Documentation            Approved
Batch Records

    Deliverables                 540
MU of U-080

    


    5.2
Preparation of Purified Urease

    


    A total
of 150 grams of Purified Urease will be prepared based on the optimized methods
reported by Byron Wentzell in “AFAIK2-Urease Conjugation, Process Optimization
and scale-up, November 2007”. Unless the equipment used throughout the process
is to be dedicated, cleaning procedures will have to be developed. The
effectiveness of the cleaning and sanitizing procedures for the column resin and
UF unit will have to be tested.  Both the resin and UF membranes will
be used multiple times and reusability will have to be demonstrated as well as
the effectiveness of the growth-inhibiting storage solutions.  This
will involve microbial and endotoxin testing using LAL test kit.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    Site                                cGMP
API Facility

    Equipment                     New/Existing

    
      Time              
6
weeks

    

    
      Documentation    Approved
Batch Records to prepare product against approved target
specifications

    

    Deliverables                 405
MU (150 grams) of Purified Urease

    


    5.3   L-DOS-47
Engineering Batch #1

    


    5.3.1
Fermentation

    Upon
completion of the 30L trial, and concurrent with the work to prepare the
purified Urease, the first 500-1000 L Engineering batch will commence. The 50
gram conjugate deliverable will require 25 grams of purified AFAIK2. Pending yields this may
require 2 × 500 L batches to be performed or a single batch performed at the
required volume in a 1000 L fermentor. A new continuous centrifuge and
microfluidizer will be qualified for the process at this stage. The fermentation
will be performed using preliminary batch records to ensure the accepted
protocol is followed; additional testing of samples or data collection can be
recorded in laboratory notebooks.

    


    Site                                cGMP
API Facility

    Fermentor
(s)              30
L (22L working)

                   500
L (350 L working)

    Time                              7
days

    Documentation            Draft
Batch records, draft QC methods and notebooks

    Deliverables      
          Completed batch
records, QC reports and Development report

    


    5.3.2
Purification of the AFAIK2

    Downstream
processing of the AFAIK2 will be completed based on the process as optimized by
BioVectra. Unless the equipment used throughout the process is to be dedicated,
cleaning procedures will have to be developed. The effectiveness of the cleaning
and sanitizing procedures for the column resins will be demonstrated during the
engineering batches.  The resins will be used multiple times and
reusability will have to be demonstrated as well as the effectiveness of the
growth-inhibiting storage solutions.  This will involve microbial and
endotoxin testing using LAL test kit.

    


    Site                                cGMP
API Facility

    Equipment                     Various
(columns, tanks)

    Time                               15
days

    Documentation             Draft
Batch records, draft QC methods and notebooks

    
      Deliverables         
25 grams
AFAIK2 Completed batch records, QC reports and Development
report

    

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    5.3.3
Conjugation

    The
AFAIK2 product from the first engineering batch will be conjugated with 50 grams
of high purity urease. The final product will be prepared in a stabilized buffer
solution, the nature of the ingredients to be provided by Helix. The conjugated
product will be available for use by Helix as well as be available to complete
the qualification for the majority of the release tests, with others as FIO
since the stability of the product prior to conjugation has not been
established. The product will also be used for packaging trials of the bulk drug
substance in the selected packaging container for shipment to the
formulator.

    


    Site                                cGMP
API Facility, Class 100K clean room

    Time                              2
days

    
      Documentation    Preliminary
batch records and notebooks to prepare product against target specifications,
draft QC test methods and procedures.

    

    
      Deliverables        
50 grams
L-DOS47 , Completed batch records, QC reports Development report, Draft
Certificate of analysis

    

    


    5.4   L-DOS-47
Engineering Batch #2

    


    5.4.1
Fermentation

    After the
completion of the first L-DOS47 engineering batch and review of the production
process, the second 500-1000 L engineering batch will commence. The 50 gram
conjugate deliverable will require 25 grams of purified AFAIK2. Pending yields from the
first Engineering batch this may require 2 × 500 L batches to be performed or a
single batch performed at the required volume in a 1000 L fermentor. The
fermentation will be performed using batch records revised from the first
engineering batch to ensure the accepted protocol is followed; additional
testing of samples or data collection can be recorded in laboratory
notebooks.

    


    Site                                cGMP
API Facility

    Fermentor
(s)               30
L (22L working)

                500-1000
L (350-650 L working)

    Time                               7
days

    Documentation             Batch
records and notebooks

    Deliverables                 
Completed batch records, QC reports and Development report

    


    5.4.2
Purification of AFAIK2

    Downstream
processing of AFAIK2 will be completed based on the process as optimized by
BioVectra. The effectiveness of the cleaning and sanitizing procedures for the
column resins will be demonstrated during the engineering
batches.  The resins will be used multiple times and reusability will
have to be demonstrated as well as the effectiveness of the growth-inhibiting
storage solutions.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    Site                                cGMP
API Facility

    Equipment                     Various
(columns, tanks)

    Time                               15
days

    Documentation              Batch
records, QC methods and notebooks

    
      Deliverables          25 grams
AFAIK2, Completed batch records, QC reports and Development
report

    

    


    5.4.3
Conjugation

    The
AFAIK2 product from the second engineering batch will be conjugated with 50
grams of high purity urease. The final product will be prepared in a stabilized
buffer solution, the nature of the ingredients to be provided by Helix. It is
BioVectra’s understanding that the second engineering batch will be used as the
toxicological batch. As such this batch will be used for the early stability
study, as the batch prior to the clinical batch and a portion of this batch will
allocated accordingly. The final product will be released against the same tests
as proposed for the future clinical batch.

    


    Site                                cGMP
API Facility, Class 100K clean room

    Time                              2
days

    
      Documentation    Batch
records and notebooks to prepare product against target specifications, QC test
methods and procedures.

    

    
      Deliverables       
50 grams
L-DOS47, Completed batch records, QC reports Development report, Certificate of
analysis

    

    


    5.5   L-DOS-47
Clinical Batch

    


    5.5.1
Fermentation

    After the
completion and review of the L-DOS47 Engineering batches, the 500-1000 L
Clinical batch will commence. The 50 gram conjugate deliverable will require 25
grams of purified AFAIK2. Pending yields this may
require 2 × 500 L batches to be performed or a single batch performed at the
required volume in a 1000 L fermentor. The fermentation will be performed using
batch records revised from the engineering batches to ensure the accepted
protocol is followed; additional testing of samples or data collection can be
recorded in laboratory notebooks.

    


    Site                                cGMP
API Facility

    Fermentor
(s)               30
L (22L working)

                    500-1000
L (350-650 L working)

    Time                               7
days

    Documentation             Batch
records, QC test methods and procedures.

    Deliverables                  Completed
batch records, QC reports and Development report

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    5.5.2
Purification of AFAIK2 and Conjugation

    Downstream
processing of AFAIK2 will be completed based on the process optimized by the
engineering batches. The AFAIK2 product from this batch will be conjugated with
50 grams of high purity urease. The product from this batch will be used for
Clinical studies. The final product will be prepared in a stabilized buffer
solution, the nature of the ingredients to be provided by Helix. This batch will
be filled by BioVectra to the final bulk packaging container and sampled
accordingly for release. Stability samples will be required from this batch. The
final product will be released against the same criteria as developed for the
second engineering batch.

    


    Site                                cGMP
API Facility, Class 100K clean room

    Centrifuge                   Westfalia

    Microfluidizer          
  Microfluidics

    Time                              17
days

    
      Documentation     Batch
records and notebooks to prepare product against target specifications, QC test
methods and procedures.

    

    
      Deliverables        
50 grams
L-DOS47, Completed batch records, QC reports Development report, Certificate of
analysis

    

    


    6.
TARGET SPECIFICATIONS

    


    6.1
Target Specifications for Purified Urease

     

    * * *

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    6.2
Target Specifications for AFAIK2

     

     

    
      * * *

       

    

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    6.3
Target Release Specifications for the L-DOS47 Conjugate

     

     

    
      * * *

       

    

    


    7.
ANALYTICAL METHODS, QC PROCEDURES

    


    The
analytical methods are described in the tables outlined in Section 7. Each of
these tests will be qualified by preparing a protocol, undergoing experiments
and writing a report. In addition, the following tasks will be
completed:

    


    Raw Materials Qualification:
5-7 raw materials including QC documentation

    


    Cleaning Validation: Method
validation protocol, experiments, Method Validation Report

    


    Column Cleaning Validations:
Method validation protocol, experiments, Method
Validation Report

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    Time                      Analytical
methods qualification: 3 months

    
      	
               
      

            	
              Raw
      material qualification: 3 weeks

            


    

    Cleaning
validations: 2 months

    
      	
              Documentation

            	
              Notebooks

            


    

    
      	
              Deliverables

            	
              Completed
      QC documents, Certificate of Analysis, Validation Protocols and
      Reports

            


    

    


    8.
STABILITY

     

    We will
establish stability indicating test methods for the urease, antibody and L-DOS47
conjugate derived from forced degradation studies. Stability testing will be
carried out at pre-defined time points following a written stability test
protocol. After completion the results will be summarized in a stability test
report. Stability studies will be carried out for the second engineering batch
and the clinical batch. Intermediate stability will be investigated on purified
urease and AFAIK2 for six months with time points at 0, 1, 3, and 6 months.
Stability of the API conjugate will be investigated over two years with time
points at 0, 6, 12 and 24 months. BioVectra has proposed possible testing
methods in section 6 (highlighted with an asterix).

    


    
      	
              Time

            	
              Degradation
      study/Stability protocol – 5 weeks

            


    

    
      	
              Documentation

            	
              Notebooks

            


    

    
      	
              Deliverables

            	
              Forced
      degradation protocols and reports, Stability protocol
      proposals

            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    9.
PROJECT TIMELINE

     

    
      * * *

       

    

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    10.
QUOTATION

    


    This
proposal has been written outlining the project scope and deliverables beginning
with optimization of certain process conditions, through to an engineering batch
and delivery of 3 × 50 g of L-DOS47 for toxicological and clinical studies. The
deliverables have been outlined in the quotation below along with the expected
delivery date.


    


    Quotation
HB19C01

    


    
      	
              Deliverables

            	
              Pricing
      (CDN)

            	
              Date

            
	
              Resins
      and Capital Charge

            	
               $                   
      * * *

            	
              * * *

            
	
              Process
      Development Report Initiation

            	
               $                    *
      * *         

            	
              * *
      *

            
	
              Process
      Development Report Completion

            	
               $                   
      * * *

            	
              * *
      *

            
	
              Completion
      of MCB

            	
               $                    *
      * *

            	
              
                * *
      *

              

            
	
              U-080
      (lot #1)

            	
               $                   
      * * *

            	
              
                * *
      *

              

            
	
              U-080
      (lot #2)

            	
               $                   
      * * *

            	
              
                * *
      *

              

            
	
              U-080
      (lot #3)

            	
               $                   
      * * *

            	
              
                * *
      *

              

            
	
              AFAIK2
      (lot #1)*

            	
               $                   
      * * *

            	
              
                * *
      * 

              

            
	
              AFAIK2
      (lot #2)*

            	
               $                   
      * * *

            	
              
                * *
      * 

              

            
	
              AFAIK2
      (lot #3)*

            	
               $                   
      * * *

            	
              
                * *
      * 

              

            
	
              Analytical
      Methods Report

            	
               $        * * * 
      

            	
              
                * *
      *

              

            
	
              L-DOS47
      (lot #1)

            	
               $        * *
      *   

            	
              
                * *
      *

              

            
	
              L-DOS47
      (lot #2)

            	
               $            * *
      *   

            	
              
                * *
      * 

              

            
	
              L-DOS47
      (lot #3)

            	
               $        * *
      *   

            	
              
                * *
      *

              

            
	
               TOTAL

            	
               $           
      * * *

            	
              * *
      *  

            


    

    Terms
for all product shipment FOB Charlottetown, Prince Edward Island,
Canada

    *Release
of HP Urease via appearance, specific activity, purity A (SEC), purity B
(SDS-PAGE) and pH/conductivity; release of AFAIK2 via appearance, solubility in
water, colour of solution, water content, pH of 5mg/mL solution, protein content
assay, purity A (SEC), purity B (RP-HPLC), purity C (SDS-PAGE), free cysteine,
and, antibiotic residue (HPLC)

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    


    APPENDIX
A

    To
support the development of L-DOS47, BioVectra will require the items listed
below,

    


    
      	
              A.  

            	
              The
      origin of the nucleotide sequence coding for the AFAIK2. Include the
      identification and source of the cell from which the nucleotide sequence
      was originally obtained.

            


    

    
      	
              B.  

            	
              The
      methods used to prepare the DNA coding for the
  AFAIK2.

            


    

    
      	
              C.  

            	
              The
      steps in the assembly of the expression construct should be described in
      detail. This description should include the source and function of the
      component parts of the expression construct. (e.g. origins of replication,
      antibiotic resistance, promoters,
etc..)

            


    

    
      	
              D.  

            	
              Provide
      a detailed component map and a complete annotated sequence of the
      plasmid.

            


    

    
      	
              E.  

            	
              The
      nucleotide sequence of the coding region of the gene of interest and
      associated flanking regions inserted into the vector, up to and including
      the junctions of insertion.

            


    

    
      	
              F.  

            	
              If
      the construct has been verified by sequencing, we will require a copy of
      the records verifying the sequence.

            


    

    
      	
              G.  

            	
              A
      description of the method of transfer of the expression construct into the
      host cell.

            


    

    
      	
              H.  

            	
              The
      methods used to amplify the expression construct and criteria used to
      select the cell clone for production should be described in
      detail.

            


    

    
      	
              I.  

            	
              A
      sample of the purified plasmid if
possible.

            


    

     

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    


    SCHEDULE
B

    


    


    QUALITY
ASSURANCE AGREEMENT

    


    


    This
Quality Assurance Agreement is between

    


    Helix BioPharma Corp., having
its principal offices located at

    305
Industrial Parkway South, Unit 3, Aurora, Ontario, L4G 6X7,

    


    (hereinafter
referred to as “Helix”)

    


    and

    


    BioVectra
Inc.,

    having
offices at 16 McCarville Street, Charlottetown, Prince Edward
Island,

    C1E 2A6,
Canada

    


    (hereinafter
referred to as (“BioVectra”)

    


    This
Quality Assurance Agreement sets out certain responsibilities of the parties
relating to the manufacturing, packaging, testing, and supply of the Products as
defined in the L DOS 47 GMP Process Development, Scale Up and Clinical Supplies
Manufacturing Agreement dated the date hereof between BioVectra and Helix (the
“Manufacturing Agreement”).  This document has been drawn up according
to cGMP regulations and will apply to product manufactured for Helix pursuant to
the Manufacturing Agreement, to which this Quality Assurance Agreement is being
attached as Schedule “B”.  All terms used in this Quality Assurance
Agreement which are defined in the Manufacturing Agreement shall have the
meanings ascribed in the Manufacturing Agreement.

    


    


    Confidentiality

    


    Without
limiting the generality of any confidentiality agreement(s) in effect between
the parties, each party agrees to hold all information furnished, disclosed or
made known to either of them or their respective representatives by the other
party or by the examination of the records of the other or otherwise obtained,
whether such information is furnished, disclosed or made known orally, in
writing or by any other means whatsoever, confidential and shall not disclose,
or permit disclosure of such information.  Each party agrees that it
has no right, title or interest whatsoever in or to the confidential information
of the other and that no right or license in such confidential information is
implied or granted.

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    


    


    Duration of
Agreement

    


    This
Agreement shall commence upon the execution and delivery hereof by the parties
and will terminate at such time as the Manufacturing Agreement is
terminated.

    


    


    Revisions to
Agreement

    


    No
amendment to the terms of this Agreement shall be binding on the parties hereto
unless made in writing and signed by an authorized representative of each of the
parties.

    


     

    Communication

    


    Any
notice required or permitted to be given under this Agreement by any party shall
be in writing and shall be (a) delivered personally, (b) sent by registered
mail, return receipt requested, postage prepaid, (c) sent by a
nationally-recognized courier service guaranteeing next-day or second day
delivery, charges prepaid, or (d) delivered by facsimile (with the original
promptly sent by any of the foregoing manners), to the addresses or facsimile
numbers of the other parties set forth below, or at such other addresses as may
from time to time be furnished by similar notice by any party.

    


    Helix
BioPharma Corp.

    3-305
Industrial Parkway S.

    Aurora,
ON

    Canada,
L4G 6X7

    Attn:
John Docherty

    Fax #
(905) 841-2244

    


    BioVectra
Inc.

    16
McCarville Street,

    Charlottetown,
Prince Edward Island,

    C1E 2A6,
Canada

    Attn:
Jeremy Stiles, Director Quality Assurance and Regulatory Affairs

    Fax #:
902-89200632

    


    


    Standard
Responsibilities

    


    Helix
Specifications prepared by BioVectra shall not be effective until approved by
Helix.

    


    BioVectra
specifications for raw materials shall be effective upon approval by BioVectra
and raw materials released by BioVectra in accordance with BioVectra approved
testing methods.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    
      	
              AREA
      OF RESPONSIBILITY

            	
              BioVectra

            	
              Helix

            
	
              Raw
      Materials:

            	 
      	 
      
	
              · Establish
      & approve specifications (grade, testing parameters, acceptance
      criteria)

            	
              x

            	
              x

            
	
              · Prepare
      BioVectra raw material specifications (grade, testing parameters,
      acceptance criteria) based on Helix requirements

            	
              x

            	
              x

            
	
              · Vendor
      Selection

            	
              x

            	 
      
	
              · Vendor
      Approval
      Qualification

            	
              x

            	 
      
	
              · Procurement
      of excipient raw materials (inactive ingredients)

            	
              x

            	 
      
	
              · Procurement
      of active raw materials

            	
              x

            	 
      
	
              · Inspection,
      testing documents, testing & release/rejection of excipients (inactive
      ingredients).

            	
              x

            	 
      
	
              · Inspection,
      testing documents, testing & release/rejection of
    active

            	
              x

            	
              x

            
	
              · Retention
      of excipient raw material samples

            	
              x

            	 
      
	
              · Retention
      of active raw material samples

            	
              x

            	 
      
	
              Lab
      Testing:

            	 
      	 
      
	
              · Selection
      of lab for testing of raw materials, bulk product & finished
      product

            	
              x

            	
              x

            
	
              · Approval
      of Lab

            	
              x

            	
              X

            
	
              · Test
      method transfer execution – raw materials, bulk & finished product
      analytical methodology

            	
              x

            	 
      
	
              · Review
      & approve test method transfer data for unique raw materials, bulk
      & finished product

            	
              x

            	
              x
      (bulk & fp)

            
	
              Stability:

            	 
      	 
      
	
              · Overall
      responsibility for ensuring stability programs comply with applicable
      regulatory guidance & product filings. 

                 
      Including the suitability of the expiry period to the formulation and
      packaging system

            	
               

              x

            	
               

              x

            
	
              · Generate
      stability protocol

            	
              X

            	
              X

            
	
              · Approve
      stability protocol

            	
              X

            	
              X

            
	
              · Execute
      stability protocol

            	
              X

            	 
      
	
              · Review
      stability results

            	
              X

            	
              X

            
	
              · Trend
      stability data

            	
              X

            	 
      
	
              Manufacturing:

            	 
      	 
      
	
              Master
      Formula

            	
              x

            	 
      
	
              Master
      manufacturing work order preparation

            	
              x

            	
              X

            
	
              Master
      manufacturing work order approval

            	
              x

            	 
      
	
              Manufacturing
      of bulk products per approved product Master Formula and
      procedures

            	
              x

            	 
      
	
              Control,
      review and communicate minor deviation to Helix for verbal/electronic
      approval

            	
              x

            	 
      
	
              Control,
      review & approve major process deviations

            	
              x

            	
              X

            


    

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    
      
        	
                AREA
      OF RESPONSIBILITY

              	
                BioVectra

              	
                Helix

              


      

    

    
      	 	 	 
	
              Establish
      & approve bulk product specifications (testing parameters, acceptance
      criteria)

            	
              x

            	
              X

            
	
              Prepare
      BioVectra bulk product specifications (grade, testing parameters,
      acceptance criteria) based on Helix requirements

            	
              x

            	
              X

            
	
              Bulk
      product test method validation

            	
              x

            	 
      
	
              Provide
      bulk product sampling plan

            	
              x

            	 
      
	
              Bulk
      product sampling

            	
              x

            	 
      
	
              Bulk
      product testing as per approved specification

            	
              x

            	 
      
	
              Review
      of manufacturing batch documents

            	
              x

            	
              X

            
	
              Release/rejection
      of bulk product for filling and packaging at BioVectra

            	
              x

            	
              X

            
	
              Packaging:

            	 
      	 
      
	
              Master
      Packaging Formula / Procedure

            	
              x

            	
              X

            
	
              Master
      packaging work order preparation

            	
              x

            	 
      
	
              Master
      packaging work order approval

            	
              x

            	 
      
	
              Allocation
      method of lot number of the products

            	
              x

            	 
      
	
              Validation:

            	 
      	 
      
	
              Premises
      validation

            	
              x

            	 
      
	
              Equipment
      validation

            	
              x

            	 
      
	
              Preparation
      and approval of cleaning procedures

            	
              x

            	 
      
	
              Cleaning
      validation – residual detergent

            	
              x

            	 
      
	
              Cleaning
      validation – residual API (BioVectra swab, Helix test)

            	
              x

            	
              X

            
	
              Manufacturing process
      validation: overall responsibility for ensuring the validation
      program complies with applicable regulatory guidance & product filings
      as the product registration holder

            	 
      	 
      
	
              · Protocol
      development

            	
              x

            	 
      
	
              · Protocol
      approval

            	
              x

            	
              X

            
	
              · Execution
      of strategy & sampling plan

            	
              x

            	 
      
	
              · Summary
      report development

            	
              x

            	 
      
	
              · Summary
      report approval

            	
              x

            	
              x

            
	
              · Test
      method validation – raw materials & bulk product

            	
              x

            	 
      
	
              Packaging process
      validation: overall responsibility for ensuring the validation
      program complies with applicable regulatory guidance & product filings
      as the product registration holder

            	 
      	 
      
	
              · Protocol
      development

            	
              x

            	 
      
	
              · Protocol
      approval

            	
              x

            	 
      
	
              · Execution
      of strategy & sampling plan

            	
              x

            	 
      
	
              · Summary
      report development

            	
              x

            	 
      
	
              · Summary
      report approval

            	
              x

            	
              x

            
	
              · Test
      method validation – finished product

            	
              x

            	
              x

            


    

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    
      
        	
                AREA
      OF RESPONSIBILITY

              	
                BioVectra

              	
                Helix

              


      

    

    
      	 	 	 
	
              Shipping:

            	 
      	 
      
	
              Notification
      of special storage conditions for intermediate materials and/or finished
      product (Shipping specifications and instructions)

            	
              x

            	 
      
	
              Release/rejection
      of finished goods for shipping to sponsor/customer

            	
              x

            	
              x

            
	
              Selection
      of carrier for shipping and shipping conditions

            	
              x

            	
              x

            
	
              Preparation
      of shipping documents

            	
              x

            	 
      
	
              Arrangement
      of shipping details (e.g. pick up)

            	
              x

            	 
      
	
              Transmittal
      of complete production batch documents

            	
              x

            	 
      
	
              OOS
      Investigations (Bulk/FP/Stability):

            	 
      	 
      
	
              Out
      of specification investigation – phase I

            	
              x

            	 
      
	
              Out
      of specification investigation – phase II (re-sampling /
      re-testing)

            	
              x

            	 
      
	
              Out
      of specification approval / rejection

            	
              x

            	
              x

            
	
              Clinical
      Product Release & Recall:

            	 
      	 
      
	
              Release
      of finished product for clinical distribution

            	
              x

            	
              x

            
	
              Product
      Recall

            	
              x

            	 
      
	
              Participate
      in product recall investigations

            	
              x

            	
              x

            
	
              Retains:

            	 
      	 
      
	
              Retention
      of regulatory retain finished product samples

            	
              x

            	 
      
	
              Retention
      of finished product samples for investigational purposes

            	
              x

            	 
      
	
              Retention
      of batch documents for at least 12 months after the expiry
      date.  Notify Helix prior to destruction of batch
      documents

            	
              x

            	 
      
	
              Investigation
      of clinical complaints with respect to the following:

            	 
      	 
      
	
              · Manufacturing

            	
              x

            	
              x

            
	
              · Packaging

            	
              x

            	
              x

            
	
              · Testing,
      documentation and results

            	
              x

            	
              x

            
	
              · Effectiveness
      of Product

            	 
      	
              x

            
	
              · Adverse
      effects

            	 
      	
              x

            
	
              · Reply
      to complainant

            	 
      	
              x

            
	
              Change
      Control:

            	 
      	 
      
	
              Notification
      of all changes to product & process (e.g. changes in raw/packaging
      materials, manufacturing processes, test methods, etc.)

            	
              x

            	
              x

            
	
              Update
      of relevant documents affected by changes

            	
              x

            	
              x

            
	
              Audits:

            	 
      	 
      
	
              Audit
      of BioVectra facilities

            	
              X

            	
              X

            


    

    


     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    
 

    Approval
Signatures

    


    On behalf
of Helix BioPharma Corp.
and BioVectra Inc. we
agree to the conditions and relative responsibilities as set out in the above
document.

    


    


    


    /s/ John
Docherty                                                                                                                       May
4,
2008          

    HELIX BIOPHARMA
CORP.                                                                                                                                       Date

    John
Docherty

    President


    


    


    


    /s/ Jeremy
Styles                                                                                                                        May
12, 2008          


    BioVectra
Inc.                                                                                                                                         
Date

    Authorized
Signatory

    Jeremy
Styles

    Director
Quality Assurance and Regulatory Affairs


    


    


    


    /s/
Dale
Zajicek                                                                                                                          May
12, 2008            


    BioVectra
Inc.                                                                                                                                                  Date


    Authorized
Signatory

    Dale
Zajicek

    Chief
Operating Officer

    


     

    
 

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    


    SCHEDULE
C

    


    Below is
an outline of the project scope and deliverables beginning with project set up
costs, going into process development work and finally delivery of 3 × 50 g of
L-DOS47 for toxicological and clinical studies. The deliverables have been
outlined along with the pricing and expected delivery date.

    


    


    Purchase Order /
Service  / Price  / Delivery Date :

    


    Project Set Up Costs –
Anticipated Start Date:  April 30, 2008

    


    
      	
              P/O

            	
              Services

            	
              Pricing
      

              (CDN)

            	
              PO
      to Delivery Lead Time

            	
              Anticipated

              Delivery
      Date

            
	 	 	 	 	 
	
              1.1

              1.2

            	
              Consumable
      Requirements

              Equipment
      Requirements

              TOTAL

            	
              ***

              ***

              ***

            	
              
                * *
      *

              

              
                * *
      *

              

            	
              
                * *
      *

              

              
                * *
      *

              

            


    

    


    


    Batch 1  -
Anticipated Start Date:  April 30, 2008

    


    
      	
              P/O

            	
              Services

            	
              Pricing

               (CDN)

            	
              PO
      to Delivery Lead Time

            	
              Anticipated
      Delivery Date

            
	
              2.1

              2.2

              2.3

              2.4

              2.5

              2.6

               

            	
              U-080
      (batch #1)

              Process
      Development Report

              U-080
      (batch #2)

              Completion
      of MCB

              AFAIK2
      (batch #1)*

              L
      DOS 47 (batch #1)

              TOTAL

            	
              ***

              ***

              ***

              ***

              ***

              ***

              ***

               

            	
              
                * *
      *

              

              
                * *
      *

              

              
                * *
      *

              

              
                * *
      *

              

              
                * *
      *

              

              
                * *
      *

              

              
                 

              

            	
              
                * *
      * 

                  * *
      * 

                    * *
      * 

                      * *
      * 

                        * *
      * 

                          * *
      * 

                            
                               

                            

                          

                        

                      

                    

                  

                

              

            


    

    


     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

    Batch 2 – Anticipated Start
Date: July 1, 2008

    


    


    
      	
              P/O

            	
              Services

            	
              Pricing
      

              (CDN)

            	
              PO
      to Delivery

               Lead
      Time

            	
              Anticipated
      Delivery Date

            
	 	 	 	 	 
	
              3.1

              3.2

              3.3

              3.4

            	
              Analytical
      Methods Report

              AFAIKA2
      (batch #2)*

              L-DOS47
      (batch #2)

              TOTAL

            	
              ***

              ***

              ***

              ***

               

            	
              
                * *
      * 

                  * *
      * 

                    * *
      *

                  

                

              

               

               

            	
              
                * *
      * 

                  * *
      * 

                    * *
      *

                  

                

              

            


    

    


    Batch 3 – Anticipated Start
Date: Sept 1, 2008

    


    
      	
              P/O

            	
              Services

            	
              Pricing

              (CDN)

            	
              PO
      to Delivery Lead Time

            	
              Anticipated

              Delivery
      Date

            
	 	 	 	 	 
	
              4.1

              4.2

              4.3

            	
              U-080
      (batch #3)

              AFAIKA2
      (batch #3)*

              L-DOS47
      (batch #3)

              TOTAL

            	
              ***

              ***

              ***

              ***

               

            	
              
                * *
      * 

                  * *
      * 

                    * *
      *

                  

                

              

            	
              
                * *
      * 

                  * *
      * 

                    * *
      *

                  

                

              

            


    

    


    P/O =
Purchase Order

    


    * ***

    


    


    Terms for
all product shipment FCA Charlottetown, Prince Edward Island,
Canada.

    


    30%
payment in advance will be required upon issuance of each purchase order by
Helix BioPharma Corp.  The balance will be due within 30 days after
completion of each deliverable. Provided that;

    


    
      	
              i)  

            	
              the
      Purchase Order number 1.1 shall be due and payable in full on
      signing

            


    

    
      	
              ii)  

            	
              the
      Purchase Order number 1.2 has been paid in full pursuant to the Equipment
      Funding Agreement.

            


    

    


     

    
 

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    


     

    


    THIS EQUIPMENT FUNDING AGREEMENT
is made as of April11, 2008

    (the
“Effective Date”)

    


    BY AND
BETWEEN:

    


    HELIX BIOPHARMA CORP., having
its principal offices located at

    305
Industrial Parkway South, Unit 3, Aurora, Ontario, L4G 6X7

    (hereinafter
referred to as “Helix”)

    


    AND:

    


    BIOVECTRA INC., having offices
located at

    16
McCarville Street, Charlottetown, Prince Edward Island, C1E 2A6,
Canada

    (hereinafter
referred to as “BioVectra”)

    


    (each a
“Party” and together the “Parties”).

    


    


    WHEREAS:

    


    A.           Helix
and BioVectra entered into a Term Sheet dated for reference the 6th day of
December, 2006 pursuant to which Helix and Diagnostic Chemicals Limited (former
corporate name of BioVectra Inc.) agreed to perform process development work on
Helix’s proprietary LDOS-47 product.

    


    B.           BioVectra
successfully completed the work contemplated under the Term Sheet.

    


    C.           The
Parties are currently in the final stages of negotiating a cGMP Process
Development Scale-Up and Clinical Supply Manufacturing Agreement (the
“Manufacturing Agreement”) with respect to the LDOS-47 product.

    


    D.           The
Manufacturing Agreement contemplates that certain equipment will need to be
purchased and / or acquired by BioVectra in order to provide the services as
discussed in and pursuant to the Manufacturing Agreement.

    


    E.           In
order to ensure that work under the Manufacturing Agreement commences as soon as
possible and without interruption, BioVectra has requested that Helix pay to
BioVectra an initial payment per BioVectra’s proposal HB19C01, dated February
19, 2008 to be used to purchase the equipment and to attend to the installation
of the equipment in the BioVectra facility.

    


    F.           The
cost of the equipment and its installation totals *** plus applicable GST (the
“Initial Payment”), all as is more particularly set out in the attached Schedule
D Equipment List.

    


    NOW
THEREFORE BE IT RESOLVED THAT:

    


    1.           In
anticipation of the Parties entering into and executing the Manufacturing
Agreement, Helix hereby agrees to pay to BioVectra the Initial Payment of ***
plus applicable GST for the purpose of acquiring and installing the said
equipment in the BioVectra facility.

    


    2.           BioVectra
acknowledges and agrees that the Initial Payment will be used solely and
exclusively by BioVectra for the purchase and installation of the equipment
listed in Schedule D in the BioVectra facility located at 11 Aviation Avenue,
Charlottetown, PEI.

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    3.           BioVectra
agrees that it will immediately, upon written request from Helix, execute an
assignment agreement pursuant to which the bills of sale, invoices and such
other evidence of title to, all or any piece(s), of the equipment listed on the
attached Schedule D will be assigned directly to Helix. In the event that Helix
wishes to transfer such equipment out of the BioVectra facilities to another
location, Helix would be responsible for all costs associated with
decommissioning, uninstalling and transporting said items.

    


    4.           The
parties acknowledge and agree that upon execution of the Manufacturing
Agreement, this agreement shall terminate and be at an end and the equipment
listed in Schedule D and this Agreement shall become part of the Manufacturing
Agreement and the Initial Payment shall be treated as an invoice payment as
described in the Manufacturing Agreement.  The terms of the
Manufacturing Agreement shall take precedence over any contrary of inconsistent
terms or conditions between this Agreement and the Manufacturing
Agreement.

    


    5.           Any
notice required or permitted to be given under this Agreement by any Party shall
be in writing and shall be (a) delivered personally, (b) sent by registered
mail, return receipt requested, postage prepaid, (c) sent by a
nationally-recognized courier service guaranteeing next-day or second day
delivery, charges prepaid, or (d) delivered by facsimile (with the original
promptly sent by any of the foregoing manners), to the addresses or facsimile
numbers of the other Parties set forth below, or at such other addresses as may
from time to time be furnished by similar notice by any Party. The effective
date of any notice under this Agreement, other than a termination notice shall
be the date of receipt by the receiving Party.

    


    To:                      Helix
BioPharma Corp.

           
3-305 Industrial Parkway S.

               
Aurora, ON, L4G 6X7

               
Attn John Docherty

               
Fax: (905) 841-2244

    


    And
to:              
BioVectra Inc.

                16
McCarville Street,Charlottetown,
Prince Edward Island, C1E 2A6

               
Attn President & CEO

               
Fax: (902) 566-2498

    


    6.           Time
is of the essence of this Agreement.

    


    7.           This
Agreement and any amendment hereto may be executed in any number of
counterparts, each of which shall for all purposes be deemed an original and all
of which shall constitute the same instrument. This Agreement shall be effective
upon full execution by facsimile or original, and a facsimile signature shall be
deemed to be and shall be as effective as an original signature.

    


    


    


    


    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

    


    


    


    


    


    IN
WITNESS WHEREOF, the Parties have caused this Agreement to be executed as of the
Effective Date.

    


    
      	
              HELIX
      BIOPHARMA CORP.

            	 
      	
              BIOVECTRA
      INC.

            
	 
      	 
      	 
      	 
      	 
      
	
              Per:

            	
              /s/
      John Docherty

            	 
      	
              Per:

            	
              /s/
      Ronald J. Keefe

            
	 
      	
              John
      Docherty

              Director
      and President

            	 
      	 
      	
              Ronald
      J. Keefe

              President
      & CEO

            
	
              Per:

            	 
      	 
      	 
      	 
      
	 
      	
              [Name]

              [Title]

            	 
      	 
      	 
      


    

    


     

     

     

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

     

     

    SCHEDULE
D

    


    Equipment
List

    


    
      	
              Equipment

               

            	
              Purpose

            	
              Product
      Use

            	
              Installed
      Cost

            
	
              Part
      I

            	 
      	 
      	 
      
	
              One
      lot of HDPE process containers

            	
              ***

            	
              U-080

            	
              ***

            
	
              Sharples
      Bowl and wet end

            	
              ***

            	
              U-080

            	
              ***

            
	
              Colloid
      Mill and Grinder

            	
              ***

            	
              U-080

            	
              ***

            
	
              Process
      Pumps

            	
              ***

            	
              Mixed

               

            	
              ***

            
	
              Vacuum
      Filter

            	
              ***

            	
              Mixed

            	
              ***

            
	
              100
      L Jacketed Tank

            	
              ***

            	
              Mixed

            	
              ***

            
	
              One
      lot of Mixers and Agitators, upgrade to existing tanks

            	
              ***

            	
              Mixed

            	
              ***

            
	
              Hoses,
      filter housings, misc SS fittings

            	
              ***

            	
              Mixed

            	
              ***

            
	
              Microfluidizer
      M-110 EH

            	
              ***

            	
              L-DOS47

            	
              ***

            
	 
      	 
      	
              Sub-total

            	
              ***

            
	
              Part
      II

            	 
      	 
      	 
      
	
              Sartoflow
      10 Holder

            	
              ***

            	
              L-DOS47

            	
              ***

            
	
              Columns

            	
              ***

            	
              L-DOS47

            	
              ***

            
	
              30
      L 316SS jacketed vessel

            	
              ***

            	
              L-DOS47

            	
              ***

            
	
              Alfa
      Laval Disc Stack Continuous centrifuge skid

            	
              ***

            	
              L-DOS47

            	
              ***

            
	 
      	 
      	 
      	 
      
	 
      	 
      	
              subtotal

            	
              ***

            
	 
      	 
      	 
      	 
      
	 
      	 
      	
              Total
      Part I & II

            	
              ***