EXHIBIT
10.17

     

    CONFIDENTIAL
MATERIALS OMITTED AND FILED SEPARATELY WITH THE

    SECURITIES
AND EXCHANGE COMMISSION. ASTERISKS DENOTE OMISSIONS.


      

    AMENDED
AND RESTATED

     

    LICENSE
AND COMMERCIALIZATION AGREEMENT

     

    BY AND
AMONG

     

    IKARIA
DEVELOPMENT SUBSIDIARY ONE LLC

     

    AND

     

    BIOLINERX
LTD.

     

    AND

     

    BIOLINE
INNOVATIONS JERUSALEM L.P.

     

    AUGUST
26, 2009


    
      
         


      

      
         


        
          

        

      

      
         


      

    

     

    Table of
Contents

    
 

    
      
        
          
            
              
                	 	 
      	 
      	
                        Page

                      
	 	 
      	 
      	 
      
	Article
      I  Definitions; Interpretation	
                        1

                      
	 	
                        Section
      1.1

                      	
                        “Affiliate”

                      	
                        2

                      
	 	
                        Section
      1.2

                      	
                        “BGN
      License Agreement”

                      	
                        2

                      
	 	
                        Section
      1.3

                      	
                        “BioLineRx
      Know-How”

                      	
                        2

                      
	 	
                        Section
      1.4

                      	
                        “BioLineRx
      Patent Rights”

                      	
                        2

                      
	 	
                        Section
      1.6

                      	
                        “Business
      Day”

                      	
                        2

                      
	 	
                        Section
      1.7

                      	
                        “Commercialization”
      or “Commercialize”

                      	
                        2

                      
	 	
                        Section
      1.8

                      	
                        “Commercially
      Reasonable Efforts”

                      	
                        2

                      
	 	
                        Section
      1.9

                      	
                        “Confidential
      Information”

                      	
                        2

                      
	 	
                        Section
      1.10

                      	
                        “Control”

                      	
                        3

                      
	 	
                        Section
      1.11

                      	
                        “Cover”
      or “Covered”

                      	
                        3

                      
	 	
                        Section
      1.12

                      	
                        “Development”
      or “Develop”

                      	
                        3

                      
	 	
                        Section
      1.13

                      	
                        “Development
      Term”

                      	
                        3

                      
	 	
                        Section
      1.14

                      	
                        “EU”

                      	
                        3

                      
	 	
                        Section
      1.15

                      	
                        “EU
      Milestone Conditions”

                      	
                        3

                      
	 	
                        Section
      1.16

                      	
                        “Executive
      Officers”

                      	
                        4

                      
	 	
                        Section
      1.17

                      	
                        “FDA”

                      	
                        4

                      
	 	
                        Section
      1.18

                      	
                        “Field”

                      	
                        4

                      
	 	
                        Section
      1.19

                      	
                        “First
      Commercial Sale”

                      	
                        4

                      
	 	
                        Section
      1.20

                      	
                        Intentionally
      Omitted

                      	
                        4

                      
	 	
                        Section
      1.21

                      	
                        Intentionally
      Omitted

                      	
                        4

                      
	 	
                        Section
      1.22

                      	
                        Intentionally
      Omitted

                      	
                        4

                      
	 	
                        Section
      1.23

                      	
                        Intentionally
      Omitted

                      	
                        4

                      
	 	
                        Section
      1.24

                      	
                        Intentionally
      Omitted

                      	
                        4

                      
	 	
                        Section
      1.25

                      	
                        “Know-How”

                      	
                        4

                      
	 	
                        Section
      1.26

                      	
                        “Knowledge”

                      	
                        4

                      
	 	
                        Section
      1.27

                      	
                        “Licensee”

                      	
                        4

                      
	 	
                        Section
      1.28

                      	
                        “Manufacturing”
      or “Manufacture”

                      	
                        4

                      
	 	
                        Section
      1.29

                      	
                        “Net
      Sales”

                      	
                        5

                      
	 	
                        Section
      1.30

                      	
                        “On-Going
      Phase I/II Trial”

                      	
                        6

                      
	 	
                        Section
      1.31

                      	
                        “Other
      On-Going Trials”

                      	
                        
                          6

                        

                      
	 	
                        Section
      1.32

                      	
                        “Party”;
      “Parties”

                      	
                        
                          6

                        

                      
	 	
                        Section
      1.33

                      	
                        “Patent
      Rights”

                      	
                        
                          6

                        

                      
	 	
                        Section
      1.34

                      	
                        “Person”

                      	
                        
                          6

                        

                      
	 	
                        Section
      1.35

                      	
                        “Pivotal
      Clinical Trial”

                      	
                        
                          6

                        

                      
	 	
                        Section
      1.36

                      	
                        “Primary
      Indication”

                      	
                        
                          6

                        

                      
	 	
                        Section
      1.37

                      	
                        “Product”

                      	
                        
                          6

                        

                      
	 	
                        Section
      1.38

                      	
                        “Regulatory
      Approval”

                      	
                        6

                      
	 	
                        Section
      1.39

                      	
                        “Regulatory
      Authority”

                      	
                        7

                      
	 	
                        Section
      1.40

                      	
                        “Royalty
      Term”

                      	
                        
                          7

                        

                      
	 	
                        Section
      1.41

                      	
                        “Sublicensed
      IP”

                      	
                        
                          7

                        

                      
	 	
                        Section
      1.42

                      	
                        “Successful
      Completion”

                      	
                        
                          7

                        

                      
	 	
                        Section
      1.43

                      	
                        “Territory”

                      	
                        
                          7

                        

                      


              

            

          

        

      

    


    
      
         


      

      
        i

        
          

        

      

      
         


      

    

    


    Table of
Contents

    


    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    	 	 
      	 
      	
                                            Page

                                          
	 	 
      	 
      	 
      
	 	
                                            Section
      1.44

                                          	
                                            “Third
      Party”

                                          	
                                            8

                                          
	 	
                                            Section
      1.45

                                          	
                                            “Valid
      Claim”

                                          	
                                            
                                              8

                                            

                                          
	 	
                                            Section
      1.46

                                          	
                                            Additional
      Definitions

                                          	
                                            
                                              8

                                            

                                          
	 	
                                            Section
      1.47

                                          	
                                            Interpretation

                                          	
                                            9

                                          
	 	 
	Article
      II  Grant of Rights	
                                            10

                                          
	 	
                                            Section
      2.1

                                          	
                                            BioLineRx
      License Grant to Ikaria; Consent of OCS

                                          	
                                            
                                              10

                                            

                                          
	 	
                                            Section
      2.2

                                          	
                                            Non-Competition

                                          	
                                            
                                              10

                                            

                                          
	 	
                                            Section
      2.3

                                          	
                                            Existing
      Product Agreements

                                          	
                                            
                                              10

                                            

                                          
	 	
                                            Section
      2.4

                                          	
                                            Intentionally
      Omitted

                                          	
                                            
                                              10

                                            

                                          
	 	
                                            Section
      2.5

                                          	
                                            Section
      365(n) of the Bankruptcy Code

                                          	
                                            
                                              11

                                            

                                          
	 	
                                            Section
      2.6

                                          	
                                            Retained
      Rights

                                          	
                                            
                                              11

                                            

                                          
	 	 
	Article
      III  Development; Manufacturing; Commercialization	
                                            
                                              11

                                            

                                          
	 	
                                            Section
      3.1

                                          	
                                            General

                                          	
                                            
                                              11

                                            

                                          
	 	
                                            Section
      3.2

                                          	
                                            Joint
      Development Committee.

                                          	
                                            12

                                          
	 	
                                            Section
      3.3

                                          	
                                            On-Going
      Trials

                                          	
                                            13

                                          
	 	
                                            Section
      3.4

                                          	
                                            Regulatory
      Matters

                                          	
                                            
                                              13

                                            

                                          
	 	
                                            Section
      3.5

                                          	
                                            Technology
      Exchange.

                                          	
                                            
                                              13

                                            

                                          
	 	
                                            Section
      3.6

                                          	
                                            Manufacturing

                                          	
                                            14

                                          
	 	
                                            Section
      3.7

                                          	
                                            Commercialization

                                          	
                                            15

                                          
	 	
                                            Section
      3.8

                                          	
                                            Efforts

                                          	
                                            15

                                          
	 	 
	Article
      IV  Financial Provisions	
                                            16

                                          
	 	
                                            Section
      4.1

                                          	
                                            Milestone
      Payments.

                                          	
                                            
                                              16

                                            

                                          
	 	
                                            Section
      4.2

                                          	
                                            Royalties
      on Net Sales of Products

                                          	
                                            17

                                          
	 	
                                            Section
      4.3

                                          	
                                            Reports
      and Accounting.

                                          	
                                            18

                                          
	 	
                                            Section
      4.4

                                          	
                                            Currency
      Amounts

                                          	
                                            19

                                          
	 	
                                            Section
      4.5

                                          	
                                            Currency
      Exchange

                                          	
                                            
                                              19

                                            

                                          
	 	
                                            Section
      4.6

                                          	
                                            Tax
      Withholding

                                          	
                                            
                                              19

                                            

                                          
	 	
                                            Section
      4.7

                                          	
                                            Upfront
      Payments Received Under Sublicenses

                                          	
                                            
                                              19

                                            

                                          
	 	 
	Article
      V  Intellectual Property Ownership, Protection and Related
      Matters	
                                            
                                              19

                                            

                                          
	 	
                                            Section
      5.1

                                          	
                                            Ownership
      of Inventions.

                                          	
                                            
                                              19

                                            

                                          
	 	
                                            Section
      5.2

                                          	
                                            Prosecution
      and Maintenance of Patent Rights.

                                          	
                                            20

                                          
	 	
                                            Section
      5.3

                                          	
                                            Third
      Party Infringement.

                                          	
                                            21

                                          
	 	 
	Article
      VI  Confidentiality; Non-Solicitation; Standstill	
                                            24

                                          
	 	
                                            Section
      6.1

                                          	
                                            Confidential
      Information

                                          	
                                            
                                              24

                                            

                                          
	 	
                                            Section
      6.2

                                          	
                                            Disclosures
      to Employees, Consultants, Advisors, Etc

                                          	
                                            
                                              25

                                            

                                          
	 	
                                            Section
      6.3

                                          	
                                            Non-Solicitation

                                          	
                                            
                                              25

                                            

                                          
	 	
                                            Section
      6.4

                                          	
                                            Standstill

                                          	
                                            
                                              25

                                            

                                          
	 	
                                            Section
      6.5

                                          	
                                            Term

                                          	
                                            
                                              26

                                            

                                          


                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

    

    


    
      
        
        

      

      
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    Table of
Contents

    


    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              	 	 
      	 
      	
                                      Page

                                    
	 	 
      	 
      	 
      
	 	
                                      Section
      6.6

                                    	
                                      Publicity

                                    	
                                      
                                        26

                                      

                                    
	 	
                                      Section
      6.7

                                    	
                                      Publications

                                    	
                                      
                                        26

                                      

                                    
	 	 
	Article
      VII  Representations and Warranties	
                                      27

                                    
	 	
                                      Section
      7.1

                                    	
                                      Representations
      of Authority

                                    	
                                      2

                                    
	 	
                                      Section
      7.2

                                    	
                                      Consents

                                    	
                                      
                                        27

                                      

                                    
	 	
                                      Section
      7.3

                                    	
                                      No
      Conflict

                                    	
                                      
                                        27

                                      

                                    
	 	
                                      Section
      7.4

                                    	
                                      Enforceability

                                    	
                                      
                                        27

                                      

                                    
	 	
                                      Section
      7.5

                                    	
                                      Additional
      BioLineRx Representations

                                    	
                                      
                                        27

                                      

                                    
	 	
                                      Section
      7.6

                                    	
                                      BGN
      License Agreement

                                    	
                                      28

                                    
	 	
                                      Section
      7.7

                                    	
                                      Employee,
      Consultant and Advisor Legal Obligations

                                    	
                                      29

                                    
	 	
                                      Section
      7.8

                                    	
                                      Accuracy
      of Representations and Warranties on Effective Date

                                    	
                                      
                                        29

                                      

                                    
	 	
                                      Section
      7.9

                                    	
                                      No
      Warranties

                                    	
                                      
                                        29

                                      

                                    
	 	 
	Article
      VIII  Term and Termination	
                                      
                                        29

                                      

                                    
	 	
                                      Section
      8.1

                                    	
                                      Term

                                    	
                                      
                                        29

                                      

                                    
	 	
                                      Section
      8.2

                                    	
                                      Termination
      for Material Breach

                                    	
                                      30

                                    
	 	
                                      Section
      8.3

                                    	
                                      Development-Related
      Termination

                                    	
                                      
                                        30

                                      

                                    
	 	
                                      Section
      8.4

                                    	
                                      Effect
      of Certain Terminations and Expiration.

                                    	
                                      
                                        30

                                      

                                    
	 	
                                      Section
      8.5

                                    	
                                      Survival

                                    	
                                      31

                                    
	 	
                                      Section
      8.6

                                    	
                                      Termination
      Prior to Effective Date

                                    	
                                      
                                        31

                                      

                                    
	 	 
	Article
      IX  Dispute Resolution	
                                      
                                        31

                                      

                                    
	 	
                                      Section
      9.1

                                    	
                                      Negotiation

                                    	
                                      
                                        31

                                      

                                    
	 	
                                      Section
      9.2

                                    	
                                      Escalation

                                    	
                                      
                                        31

                                      

                                    
	 	
                                      Section
      9.3

                                    	
                                      Mediation

                                    	
                                      
                                        31

                                      

                                    
	 	
                                      Section
      9.4

                                    	
                                      Litigation

                                    	
                                      32

                                    
	 	
                                      Section
      9.5

                                    	
                                      Equitable
      Relief

                                    	
                                      32

                                    
	 	 
	Article
      X  Miscellaneous Provisions	
                                      
                                        32

                                      

                                    
	 	
                                      Section
      10.1

                                    	
                                      Indemnification.

                                    	
                                      
                                        32

                                      

                                    
	 	
                                      Section
      10.2

                                    	
                                      Governing
      Law

                                    	
                                      
                                        33

                                      

                                    
	 	
                                      Section
      10.3

                                    	
                                      Submission
      to Jurisdiction

                                    	
                                      
                                        33

                                      

                                    
	 	
                                      Section
      10.4

                                    	
                                      Assignment

                                    	
                                      34

                                    
	 	
                                      Section
      10.5

                                    	
                                      Entire
      Agreement; Amendments

                                    	
                                      
                                        34

                                      

                                    
	 	
                                      Section
      10.6

                                    	
                                      Notices.

                                    	
                                      
                                        34

                                      

                                    
	 	
                                      Section
      10.7

                                    	
                                      Force
      Majeure

                                    	
                                      
                                        35

                                      

                                    
	 	
                                      Section
      10.8

                                    	
                                      Independent
      Contractors

                                    	
                                      
                                        35

                                      

                                    
	 	
                                      Section
      10.9

                                    	
                                      Limitations
      of Liability

                                    	
                                      
                                        35

                                      

                                    
	 	
                                      Section
      10.10

                                    	
                                      No
      Implied Waivers; Rights Cumulative

                                    	
                                      36

                                    
	 	
                                      Section
      10.11

                                    	
                                      Severability

                                    	
                                      
                                        36

                                      

                                    
	 	
                                      Section
      10.12

                                    	
                                      Execution
      in Counterparts; Facsimile Signatures

                                    	
                                      
                                        36

                                      

                                    


                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

    


    
      
         


      

      
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    Table of
Contents

    


    
      
        
          
            	 
      	 
      	
                    Page

                  
	 
      	 
      	 
      
	
                    Schedules

                  	 
      	 
      
	
                    Schedule
      1.30

                  	
                    Protocol
      for On-Going Phase I/II Trial

                  	
                    38

                  
	
                    Schedule
      1.31

                  	
                    Descriptions
      of Other On-Going Trials

                  	
                    39

                  
	
                    Schedule
      1.35

                  	
                    Outline
      of Initial Pivotal Clinical Trial

                  	
                    40

                  
	
                    Schedule
      1.42(a)

                  	
                    Independent
      Safety Monitoring Board Charter

                  	
                    41

                  
	
                    Schedule
      2.3

                  	
                    Existing
      Product Agreements

                  	
                    46

                  
	
                    Schedule
      3.1

                  	
                    Initial
      Development Plan

                  	
                    47

                  
	
                    Schedule
      3.3

                  	
                    Independent
      Safety Monitoring Board

                  	 
      
	
                    Schedule
      3.7

                  	
                    Preliminary
      Commercialization Plan

                  	
                    48

                  
	
                    Schedule
      4.3(a)

                  	
                    Wire
      Transfer Information

                  	
                    49

                  
	 
      	 
      	 
      
	
                    Exhibits

                  	 
      	 
      
	
                    Exhibit
      A

                  	
                    Technology
      Exchange Plan

                  	
                    50

                  
	
                    Exhibit
      B

                  	
                    BioLineRx
      Patent Rights

                  	
                    51

                  


          

        

      

    

    

      
        
           


        

        
          iv

          
            

          

        

        
           


        

      

    

     

    AMENDED AND
RESTATED

    LICENSE AND
COMMERCIALIZATION AGREEMENT

     

    This
Amended and Restated License and Commercialization Agreement (the “Agreement”) is
entered into this 26th day of
August, 2009, by and among Ikaria Development Subsidiary One
LLC, a Delaware limited liability company having a principal place of
business at 6 State Route 173, Clinton, NJ 08809, USA (“Ikaria”), BioLineRx Ltd., a corporation
organized and existing under the laws of the State of Israel and having a
principal place of business at 19 Hartum Street, P.O. Box 45158, Jerusalem
91450, Israel (“BioLineRx Ltd.”), and
BioLine Innovations Jerusalem
L.P., a limited partnership organized and existing under the laws of the
State of Israel and having a principal place of business at 19 Hartum Street,
P.O. Box 45158, Jerusalem 91450, Israel (“BioLine Innovations”; together with
BioLineRx Ltd., “BioLineRx”).

     

    INTRODUCTION

     

    WHEREAS,
BioLineRx owns or controls certain intellectual property rights covering a
liquid polymer composed of Sodium Alginate and Ca-D-Gluconate (designated by
BioLineRx as “BL-1040”);

     

    WHEREAS,
BioLineRx is currently developing the Product (as defined below) as a medical
device for the direct treatment of cardiac tissue following acute myocardial
infarction;

     

    WHEREAS,
BioLineRx is concluding the safety and clinical trials of the Product that were
initiated by BioLineRx prior to the Effective Date (as defined
below);

     

    WHEREAS,
BioLineRx desires to grant to Ikaria the worldwide exclusive rights to Develop,
Manufacture, and Commercialize Products (as such capitalized terms are defined
below); and

     

    WHEREAS,
Ikaria desires to obtain such exclusive rights in accordance with the terms and
conditions of this Agreement.

     

    NOW,
THEREFORE, BioLineRx and Ikaria agree as follows:

     

    Article
I

    Definitions;
Interpretation

     

    When used
in this Agreement, each of the following capitalized terms has the meaning set
forth in this Article I:

     

    Section
1.1     “Affiliate” shall
mean, with respect to a Party, any Person that controls, is controlled by, or is
under common control with such Party.  For purposes of this Section
1.1, “control” shall refer to (a) in the case of a Person that is a corporate
entity, direct or indirect ownership of more than fifty percent (50%) of the
stock, shares or membership units having the right to vote for the election of a
majority of the directors of such Person, and (b) in the case of a Person that
is an entity, but is not a corporate entity, the possession, directly or
indirectly, of the power to direct, or cause the direction of, the management or
policies of such Person, whether through the ownership of voting securities, by
contract or otherwise.

    


    
      
        
           


        

        
          1

          
            

          

        

        
           


        

      

    

    


    Section
1.2     “BGN License
Agreement” shall mean that certain License Agreement, dated January 10,
2005, as amended, by and among BioLine Jerusalem L.P. and B.G. Negev
Technologies and Applications Ltd. (“BGN”) on behalf of
Ben Gurion University.

     

    Section
1.3     “BioLineRx Know-How”
shall mean all Know-How that is (a) necessary or useful for the Development,
Manufacture, or Commercialization of any Product and (b) either (i) is
Controlled by BioLineRx as of the Effective Date or (ii) BioLineRx comes to
Control during the term of this Agreement.

     

    Section
1.4     “BioLineRx Patent
Rights” shall mean Patent Rights that claim or disclose BioLineRx
Know-How, including the Patent Rights listed in Exhibit
B.

     

    Section
1.5     “BioLineRx Intellectual
Property” shall mean BioLineRx Patent Rights (including Patent Rights in
the Sublicensed IP), and BioLineRx Know-How (including Know-How in the
Sublicensed IP).

     

    Section
1.6     “Business Day” shall
mean a day that is not a Saturday, a Sunday or a day on which banking
institutions in New York, New York, USA are authorized by law to remain
closed.

     

    Section
1.7     “Commercialization” or
“Commercialize”
shall mean any activities directed to marketing, promoting, distributing,
importing, exporting, or selling a product.

     

    Section
1.8     “Commercially Reasonable
Efforts” shall mean the efforts, expertise and resources normally used by
a Party to Develop, Manufacture and Commercialize a product owned by it or to
which it has rights, which is of similar market potential at a similar stage in
its development or product life, taking into account issues of safety and
efficacy, product profile, difficulty in developing the product, competitiveness
of the marketplace for the product, the proprietary position of the product, the
regulatory structure involved, the availability and level of reimbursement for
such treatment by Third Party payors or health insurance plans, the potential
total profitability of the applicable product(s) marketed or to be marketed and
other relevant factors affecting the cost, risk and timing of Development and
the total potential reward to be obtained if a product is Commercialized. The
Parties agree that Commercially Reasonable Efforts shall require a Party to
expend efforts, expertise and resources that such Party would normally expend to
Develop, use, Manufacture and Commercialize a product owned by it or to which it
has rights, taking into account the foregoing factors.

     

    Section
1.9     “Confidential
Information” shall mean, with respect to a disclosing Party, all Know-How
or other information (whether or not patentable) regarding such Party’s
technology, products, business information or objectives (whether disclosed
before or after the Effective Date) that is of a confidential and proprietary
nature, including reports and audits under Section 4.3, the Development Plan,
the Commercialization Plan, the terms of this Agreement, and all proprietary
tangible materials (and data and information associated therewith) of such
Party.  Notwithstanding the foregoing, Confidential Information shall
not include Know-How or other information that:

    


    
      
        
           


        

        
          2

          
            

          

        

        
           


        

      

    

    


    (a)      was
rightfully known or used by the receiving Party or its Affiliates without an
obligation of confidentiality prior to its date of disclosure to the receiving
Party as demonstrated by contemporaneous written records; or

     

    (b)      either
before or after the date of the disclosure to the receiving Party is lawfully
disclosed to the receiving Party or its Affiliates by sources other than the
disclosing Party rightfully in possession of such information and not bound by
confidentiality obligations to the disclosing Party; or

     

    (c)      either
before or after the date of the disclosure to the receiving Party or its
Affiliates is or becomes published or otherwise is or becomes part of the public
domain through no breach hereof on the part of the receiving Party or its
Affiliates; or

     

    (d)      is
independently developed by or for the receiving Party or its Affiliates without
reference to or use of the Confidential Information of the disclosing Party as
demonstrated by contemporaneous written records.

     

    Section
1.10     “Control” shall mean
the legal authority or right of a Party or its Affiliates to grant a license or
sublicense of intellectual property rights to the other Party, or to provide
tangible material to or otherwise disclose proprietary or trade secret
information to such other Party, without breaching the terms of any agreement
with a Third Party.  For the avoidance of doubt, BioLineRx Controls
the Sublicensed IP.

     

    Section
1.11     “Cover” or “Covered” shall mean,
with respect to a Patent Right and a product, that, in the absence of ownership
of (with a retained right to exploit), or a license granted under, a Valid Claim
included in such Patent Right, the Manufacture, Development, Commercialization,
use, sale, import, or offer for sale, as applicable, of such product would
infringe such Valid Claim in the country where such activity
occurs.

     

    Section
1.12     “Development” or
“Develop” shall
mean development activities, including test method development and stability
testing, toxicology, formulation, optimization, quality assurance/quality
control development, statistical analysis, clinical studies, regulatory affairs,
product approval, and registration.

     

    Section
1.13     “Development Term”
shall mean the term of development of Products by Ikaria.

     

    Section
1.14     “EU” shall mean the
European Union and all the member states thereof, as it may be comprised from
time to time.

     

    Section
1.15     “EU Milestone
Conditions” shall mean (a) satisfaction of all requirements for [***], (b) [***]
set forth therein, and
(c) [***].

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          3

          
            

          

        

        
           


        

      

    

    


    Section
1.16     “Executive Officers”
shall mean the Chief Executive Officer of Ikaria (or a senior executive officer
of Ikaria designated by Ikaria) and the Chief Executive Officer of BioLineRx (or
a senior executive officer of BioLineRx designated by BioLineRx).

     

    Section
1.17     “FDA” shall mean the
United States Food and Drug Administration or any successor agency
thereof.

     

    Section
1.18     “Field” shall mean any
and all uses described or claimed in the BioLineRx Patent Rights.

     

    Section
1.19     “First Commercial
Sale” shall mean, with respect to a Product in a country, the first
commercial sale of such Product by Ikaria, its Affiliates, distributors, agents
or Licensees in such country.  Sales for clinical trial purposes or
compassionate or similar use shall not be considered to constitute a First
Commercial Sale.

     

    Section
1.20     Intentionally Omitted

     

    Section
1.21     Intentionally Omitted

     

    Section
1.22     Intentionally Omitted

     

    Section
1.23     Intentionally Omitted.

     

    Section
1.24     Intentionally Omitted.“

     

    Section
1.25     “Know-How” shall mean
any tangible or intangible know-how, expertise, information, inventions,
discoveries, documents and other works of authorship, copyrights, trade secrets,
data, or materials, whether proprietary or not, including ideas, concepts,
formulas, methods, procedures, designs, technologies, compositions, plans,
applications, technical data, data generated in clinical trials, samples,
chemical compounds and biological materials and all derivatives, modifications
and improvements thereof.

     

    Section
1.26     “Knowledge” shall
mean, with respect to a Party, the Party’s actual knowledge together with any
knowledge of any of the Party’s officers or director-level employees, that a
Person in such party’s position would be expected to obtain given the exercise
of reasonably prudent scientific and business diligence in accordance with the
standards of companies of such Party’s size in such Party’s
industry.

     

    Section
1.27     “Licensee” shall mean
any Person to whom Ikaria licenses its rights under this Agreement in the manner
provided in Section 2.1, including any Third Party contractors.

     

    Section
1.28     “Manufacturing” or
“Manufacture”
shall mean any activities associated with the production, manufacture, supply,
processing, filling, packaging, labeling, shipping, or storage of a product or
any components thereof, including process and formulation development, process
validation, stability testing, manufacturing scale-up, development and
commercial manufacture and analytical development, product characterization,
quality assurance and quality control development, testing, and
release.

    


    
      
        
           


        

        
          4

          
            

          

        

        
           


        

      

    

    


    Section
1.29     “Net Sales” shall
mean, with respect to a Product, the gross amounts billed by Ikaria, its
Affiliates, or Licensees in respect of sales of such Product by Ikaria and its
Affiliates or Licensees to unrelated Third Parties, in each case less the
following deductions:

     

    (a)      Trade,
cash, or quantity discounts (including amounts incurred in connection with
government mandated rebate programs) actually allowed and taken with respect to
such sales;

     

    (b)      Tariffs,
duties, excises, sales taxes or other taxes imposed upon and paid with respect
to the production, sale, delivery, or use of the Product (excluding national,
state, or local taxes based on income);

     

    (c)      Amounts
repaid or credited by reason of billing corrections, rejections, defects,
recalls, or returns (due to spoilage, damage, expiration of useful life or
otherwise) or because of chargebacks, refunds or retroactive price reductions
and allowances for wastage replacement and bad debts;

     

    (d)      Portions
of invoices sales amounts included in Net Sales in prior periods that are
actually written off by Ikaria, its Affiliates, or licenses as uncollectible;
and

     

    (e)      Postage,
freight, shipping, insurance, and other transportation related charges incurred
in shipping a Product to Third Parties.

     

    Such
amounts shall be determined from the books and records of Ikaria, its
Affiliates, or Licensees, maintained in accordance with generally accepted
accounting principles, consistently applied.  For the avoidance of
doubt, in no event will fines, penalties or other monetary damages assessed
against Ikaria, its Affiliates or Licensees by any governmental authority for
violation of any applicable law, result in an appropriate deduction to Net
Sales.

     

    If one or
more Products is sold as part of a Combination Product (as defined below), the
Net Sales from the Combination Product, for the purposes of determining royalty
payments, shall be determined by multiplying the Net Sales (as determined above)
of the Combination Product, during the applicable royalty reporting period, by
the fraction, A/(A+B), where A is the average sale price of the Product(s) when
sold separately in finished form and B is the average sale price of the other
components included in the Combination Product when sold separately in finished
form, in each case in the applicable country during the applicable royalty
reporting period or, if sales of both the Product(s) and the other components
did not occur in such country in such period, then in the most recent royalty
reporting period in which sales of both occurred.  If such average
sale price cannot be determined for both the Product(s) and all other components
included in such Combination Product, Net Sales for the purposes of determining
royalty payments shall be calculated by multiplying the Net Sales of the
Combination Product by the fraction of C/(C+D) where C is the fair market value
of the Product(s) and D is the fair market value of all other components
included in the Combination Product.  In such event, the Parties shall
negotiate in good faith to arrive at a determination of the respective fair
market values of the Product(s) and all other components included in the
Combination Product.  If the Parties are unable to agree on such
determination within sixty (60) days, then such matter shall be resolved as
provided in Article IX.

    


    
      
        
           


        

        
          5

          
            

          

        

        
           


        

      

    

    


    As used
above, the term “Combination Product”
means any therapeutic medical product that includes both (i) one or more
Product(s) and (ii) other component(s).

     

    Section
1.30     “On-Going Phase I/II
Trial” shall mean that certain clinical trial of a Product that was
initiated by BioLineRx prior to and that is ongoing as of the Effective Date,
the protocol for which is attached hereto as Schedule
1.30.

     

    Section
1.31     “Other On-Going
Trials” shall mean those pre-clinical and CMC trials (other than the
On-Going Phase I/II Trial) that were initiated by BioLineRx prior to, and that
are ongoing as of, the Effective Date, descriptions of which are attached hereto
as Schedule
1.31.

     

    Section
1.32     “Party” shall mean
BioLineRx or Ikaria; “Parties” shall mean BioLineRx and Ikaria.

     

    Section
1.33     “Patent Rights” shall
mean United States and foreign patents and patent applications (including
provisional applications) and all substitutions, divisionals, continuations,
continuations-in-part, reissuances, reexaminations, registrations, renewals,
confirmations, supplementary protection certificates and extensions
thereof.

     

    Section
1.34     “Person” shall mean
any natural person or any corporation, company, partnership, joint venture,
firm, university, other entity, governmental authority, or subdivision
thereof.

     

    Section
1.35     “Pivotal Clinical
Trial” shall mean a randomized, controlled clinical trial of a Product
designed to demonstrate statistically significant clinical efficacy and safety
in human patients (in conjunction with performance of a therapeutic procedure)
pursuant to a clinical study agreed with the FDA, which trial the FDA accepts as
a pivotal clinical trial necessary for Regulatory Approval of such
Product.  An outline of the structure of the initial Pivotal Clinical
Trial is attached as Schedule
1.35.

     

    Section
1.36     “Primary Indication”
shall mean the diagnosis, prevention, mitigation, or treatment of injury to
myocardial tissue via the administration of a Product to a human
patient.

     

    Section
1.37     “Product” shall mean a
liquid polymer composed of Sodium Alginate and Ca-D-Gluconate (designated by
BioLineRx as “BL-1040”), or any back-ups or second-generation polymers or
polymer combinations thereof that is Developed under the Development
Program.

     

    Section
1.38     “Regulatory Approval”
shall mean, with respect to a jurisdiction, the approval of the applicable
Regulatory Authority required to market and sell a Product in such
jurisdiction.  For clarity, Regulatory Approval for a Product shall
occur:

     

    (a)       in
the United States, on the date when the FDA approves a Premarket Approval (PMA)
application;

     

    (b)      in
Europe, on the date when such Product may first be placed on the market as a
medical device (as such terms are defined in Art. 1 Paragraphs 2(a) and (h) of
Directive 93/42/EEC, as amended) bearing the CE marking according to Art. 17 of
Directive 93/42/EEC, as amended, in any member state of the EU; and

    


    
      
        
           


        

        
          6

          
            

          

        

        
           


        

      

    

    


    (c)      in
Japan, on the date when the Ministry of Health approves a marketing
authorization.

     

    Section
1.39     “Regulatory Authority”
shall mean any national (e.g., the FDA),
supra-national or other regulatory agency or governmental entity involved in the
granting of Regulatory Approval for, or in the regulation of human clinical
studies of, therapeutic medical devices.

     

    Section
1.40     “Royalty Term” shall
mean, with respect to a Product in a country of the Territory, the period of
time commencing on the First Commercial Sale of such Product in such country and
ending upon the earlier of (a) the expiration of the last-to-expire Valid Claim
in the BioLineRx Patent Rights that Covers the sale or use of such Product in
the Field in such country, or (b) the date of a judicial determination from
which no appeal can be taken of invalidity of a set of claims in the BioLineRx
Patent Rights that Cover the sale or use of such Product in the Field in such
country and that are asserted through litigation (whether in an infringement
action, a declaratory judgment action, or otherwise) to exclude a Third Party
from selling or using a product in the Field in such country.

     

    Section
1.41     “Sublicensed IP” shall
mean that portion of the BioLineRx Intellectual Property licensed to BioLineRx
pursuant to the BGN License Agreement.

     

    Section
1.42     “Successful
Completion” shall mean:

     

    (a)      with
respect to the On-Going Phase I/II Trial, no treatment-related safety findings
during the treatment period and the six (6) month follow up period, that were
considered by the Independent Safety Monitoring Board for the On-Going Phase
I/II Trial (in accordance with and subject to the Independent Safety Monitoring
Board Charter attached hereto as Schedule 1.42(a)) to be of sufficient concern
to discontinue the On-Going Phase I/II Trial;

     

    (b)      with
respect to the Interim Analysis of the Pivotal Clinical Trial/Phase IIb Proof of
Concept, safety and efficacy data from completion of all patients at the [***]
follow up demonstrates more than a [***]probability of meeting pre-specified
endpoints at [***] in the Pivotal Clinical Trial, and no apparent safety signal
in the treatment group for the entire cohort at all times;

     

    (c)      with
respect to the Pivotal Clinical Trial for the Primary Indication, safety and
efficacy data from completion of all patients at the [***] follow up meets the
primary endpoint and demonstrates a positive benefit-to-risk ratio to enable FDA
submission; and

     

    (d)      with
respect to all other clinical trials of a Product, that the JDC has determined
that the final results of such clinical trial have achieved the success criteria
established by the JDC with respect to such clinical trial.

     

    Section
1.43     “Territory” shall mean
the entire world.

     

    [***]
Redacted pursuant to a confidential treatment request

    


    
      
        
           


        

        
          7

          
            

          

        

        
           


        

      

    

    


    Section
1.44     “Third Party” shall
mean any Person other than a Party or any of its Affiliates or
Licensees.

     

    Section
1.45     “Valid Claim” shall
mean a claim of any issued, unexpired patent that has not been revoked or held
unenforceable or invalid by a decision of a court or governmental agency of
competent jurisdiction from which no appeal can be taken, or with respect to
which an appeal is not taken within the time allowed for appeal, and that has
not been disclaimed or admitted to be invalid or unenforceable through reissue,
reexamination, disclaimer, or otherwise.

     

    Section
1.46     Additional
Definitions.  Each of the following terms is defined in the
section of this Agreement indicated below:

     

    
      
        	
                Term

              	
                Section

              
	 
      	 
      
	
                “Agreement”

              	
                Preamble

              
	
                “Bankruptcy
      Code”

              	
                Section
      2.5

              
	
                “BGN”

              	
                Section
      1.2

              
	
                “BioLineRx”

              	
                Preamble

              
	 
      	 
      
	
                “BL-1040”

              	
                Section
      1.37

              
	
                “Breaching
      Party”

              	
                Section
      8.2

              
	
                “Combination
      Product”

              	
                Section
      1.29

              
	
                “Commercialization
      Plan”

              	
                Section
      3.7

              
	
                “Competitive
      Infringement”

              	
                Section
      5.3(a)

              
	
                “Effective
      Date”

              	
                Section
      2.1

              
	
                “Existing Product
      Agreements”

              	
                Section
      2.3

              
	
                “Ikaria”

              	
                Preamble

              
	 
      	 
      
	
                “Development
      Plan”

              	
                Section
      3.1

              
	
                “Development
      Program”

              	
                Section
      3.1

              
	
                “Force Majeure
      Event”

              	
                Section
      10.7

              
	
                “Indemnified
      Party”

              	
                Section
      10.1(c)

              
	
                “Indemnifying
      Party”

              	
                Section
      10.1(c)

              
	
                “Invalidity
      Claim”

              	
                Section
      5.3(d)

              
	
                “Joint Development
      Committee” or “JDC”

              	
                Section
      3.2

              
	 
      	 
      
	
                “Joint Manufacturing
      Committee” or “JMC”

              	
                Section
      3.6(c)

              
	
                “Lead
      Party”

              	
                Section
      5.3(e)

              
	
                “Losses”

              	
                Section
      10.1(a)

              
	
                “New
      Indication”

              	
                Section
      2.4

              
	
                “New Indication
      Invention”

              	
                Section
      5.1(a)

              
	
                “Non-Breaching
      Party”

              	
                Section
      8.2

              
	
                “OCS”

              	
                Section
      2.1

              
	
                “SEC”

              	
                Section
      6.1

              
	
                “Severed
      Clause”

              	
                Section
      10.11

              
	 
      	 
      
	
                “Technology
      Exchange”

              	
                Section
      3.5

              


      

    

    


    
      
        
        

      

      
        8

        
          

        

      

      
        
        

      

       

    

    
      
        	
                Term

              	
                Section

              
	 
      	 
      
	
                “Technology Exchange
      Plan”

              	
                Section
      3.5

              
	
                “Third Party
      Payment”

              	
                Section
      4.2(b)

              
	 
      	 
      


      

    

    Section
1.47     Interpretation.  Whenever
the context may require, any pronoun shall include the corresponding masculine,
feminine, and neuter forms.  The words “include”, “includes” and
“including” shall be deemed to be followed by the phrase “without limitation”.
The word “will” shall be construed to have the same meaning and effect as the
word “shall”.  The word “or” shall be construed to have the same
meaning and effect as “and/or”.  This Agreement has been prepared
jointly with the assistance of counsel and shall not be strictly construed
against either Party.  The captions or headings of the sections or
other subdivisions hereof are inserted only as a matter of convenience or for
reference and shall have no effect on the meaning of the provisions
hereof.  Unless the context requires otherwise, (a) any definition of
or reference to any agreement, instrument, or other document herein shall be
construed as referring to such agreement, instrument, or other document as from
time to time amended, supplemented, or otherwise modified (subject to any
restrictions on such amendments, supplements, or modifications set forth herein
or therein), (b) any reference to any laws herein shall be construed as
referring to any law, statute, rule, regulation, ordinance, or other
pronouncement having the effect of law of any federal, national, multinational,
state, provincial, county, city, or other political subdivision, domestic or
foreign, as they from time to time may be enacted, repealed, or amended, (c) any
reference herein to any Person shall be construed to include the Person’s
successors and assigns, (d) the words “herein”, “hereof”, and “hereunder”, and
words of similar import, shall be construed to refer to this Agreement in its
entirety and not to any particular provision hereof, (e) any reference herein to
the words “mutually agree” or “mutual written agreement” shall not impose any
obligation on either Party to agree to any terms relating thereto or to engage
in discussions relating to such terms except as such Party may determine in such
Party’s sole discretion, and (f) all references herein to Articles, Sections,
Exhibits, or Schedules shall be construed to refer to Articles, Sections,
Exhibits, and Schedules of this Agreement.

    


    
      
        
           


        

        
          9

          
            

          

        

        
           


        

      

    

    


    Article
II

    Grant of
Rights

     

    Section
2.1       BioLineRx License Grant to
Ikaria; Consent of OCS.  Subject to the terms and conditions of
this Agreement, including the consent of the Office of the Chief Scientist of
the State of Israel (“OCS”), BioLineRx
hereby grants to Ikaria the exclusive, royalty-bearing right and license in the
Territory under the BioLineRx Intellectual Property (including, for clarity, a
sublicense under the Sublicensed IP) to Develop, Manufacture and Commercialize
Products for use in the Field.  Subject to the consent of BioLineRx,
which consent shall not be unreasonably withheld, conditioned or delayed, the
foregoing license includes the right to grant sublicenses under the BioLineRx
Intellectual Property, provided that, with respect to
sublicenses granted under the Sublicensed IP, Ikaria shall (a) grant such
sublicenses only for consideration and at arm’s-length transactions, and (b)
grant such sublicenses only pursuant to written agreements that contain such
terms and conditions as may be required for Ikaria to comply with this
Agreement.  BioLineRx shall use its best efforts to obtain the written
consent of the OCS to this Agreement within [***] days after August 26th, 2009,
which consent must be in a form that is satisfactory to each
Party.  If the OCS has still not provided such consent during such
[***] days, Ikaria shall have the right to require BioLineRx to continue to use
best efforts to obtain such consent within the subsequent [***] day
period.  In addition, (i) Ikaria shall have the right to have a
representative present at all interactions between BioLineRx’s representatives
and the OCS relating to such consent, (ii) BioLineRx shall (A) provide Ikaria
with a reasonable opportunity to review and approve the request for consent
submitted to the OCS and (B) keep Ikaria fully informed as to the progress of
such request for consent and shall consult with Ikaria in good faith with
respect thereto, (iii) BioLineRx shall not engage in any activities or
discussions with any Third Party relating to the subject matter of this
Agreement, including pursuing any other transactions relating to the BioLineRx
Intellectual Property, without Ikaria’s consent, and (iv) Ikaria shall have the
right, prior to the Effective Date, to unilaterally modify this Agreement to
comply with the specific, formal, written requests of the OCS, provided that such
modifications have no detrimental financial impact on BioLineRx under this
Agreement.  Notwithstanding BioLineRx’s obligation to exercise best
efforts to obtain the consent from the OCS as described above, BioLineRx shall
not be required to (y) agree to any request by the OCS that would require
BioLineRx to pay to the OCS an aggregate amount of more than [***] or (z) obtain
a consent based on the characterization of this Agreement as a “transfer of
know-how outside of Israel” under Section 19B of the Israeli Law for the
Encouragement of Industrial Research & Development,
1984.  Notwithstanding anything herein to the contrary, subject to
Section 8.6, the provisions of this Agreement other than this Section 2.1,
Section 2.2, Article VII, Section 8.6 and Article X shall not be effective until
such consent has been obtained and each Party has delivered the certificate set
forth in Section 7.8 (the “Effective
Date”).


     

    Section
2.2       Non-Competition.  During
the term of this Agreement, BioLineRx shall not, within the Territory, directly
or indirectly (including through its Affiliates), conduct research or discovery
activities, Develop, Manufacture (except as set forth in Section 3.6),
Commercialize, or grant any rights or options or provide assistance to any Third
Party to conduct research or discovery activities, Develop, Manufacture (except
as set forth in Section 3.6) or Commercialize, (a) the Product or (b) any
compound, substance, polymer, or product (whether pharmaceutical or device in
nature) the method of action or effect of which is similar to any
Product.

     

    Section
2.3       Existing Product
Agreements.  BioLineRx hereby agrees that, upon the written
request of Ikaria, BioLineRx shall assign to Ikaria each of the agreements
listed in Schedule
2.3 attached hereto (the “Existing Product
Agreements”), and all of its rights, title, and interest
therein.  BioLineRx shall cooperate with Ikaria, including by
executing and recording documents, as may be necessary to effectuate such
assignments and the exercise by Ikaria of its rights under the Existing Product
Agreements.

     

    Section
2.4       Intentionally
Omitted.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          10

          
            

          

        

        
           


        

      

    

    


    Section
2.5       Section 365(n) of the
Bankruptcy Code.  All rights and licenses granted under or
pursuant to any Section of this Agreement, including under this Article II and
with respect to any BioLineRx Intellectual Property subject to Technology
Exchange under Section 3.5, are rights to “intellectual property” (as defined in
Section 101(35A) of Title 11 of the United States Code (such Title, the “Bankruptcy
Code”)).  Each of Ikaria and BioLineRx hereby acknowledges
“embodiments” of such intellectual property for purposes of Section 365(n) of
the Bankruptcy Code shall include (a) copies of research data, (b) laboratory
samples, (c) product samples, (d) formulas, (e) laboratory notes and notebooks,
(f) data and results related to clinical studies, (g) regulatory filings and
approvals, (h) rights of reference in respect of regulatory filings and
approvals, (i) research data and results, and (j) marketing, advertising, and
promotional materials, in each case, that relate to such intellectual
property.  Each Party shall retain and may fully exercise all of its
rights and elections under the Bankruptcy Code or analogous legislation in any
other jurisdiction.  Upon the institution by or against BioLineRx of
any assignment for the benefit of creditors, composition, or any bankruptcy,
reorganization, arrangement, insolvency, or similar proceedings under the laws
of any jurisdiction, Ikaria shall further be entitled to a complete duplicate
of, or complete access to, as appropriate, any such intellectual property
(including embodiments thereof), and such intellectual property and embodiments,
if not already in its possession, shall be promptly delivered to Ikaria, unless
BioLineRx elects to continue, and continues, to perform all of its obligations
under this Agreement.

     

    Section
2.6       Retained
Rights.  Except as otherwise specifically provided for in this
Agreement, each Party retains all rights and licenses to exploit its own
intellectual property.

     

    Article
III

    Development; Manufacturing;
Commercialization

     

    Section
3.1               General.  Ikaria
shall be solely responsible for conducting and funding all Development
activities pursuant to the Development Plan, and shall have the sole right to
Develop, Manufacture, and Commercialize Products in the Field in the
Territory.  Subject to its obligations under Section 3.8, Ikaria shall
prepare a non-binding plan (the “Development Plan”)
for the Development of Product(s) (the “Development
Program”).  The Development Plan shall include an estimated
budget setting forth Ikaria’s anticipated development costs.  Ikaria
shall provide BioLineRx with a copy of its then-current Development Plan at
least [***] per year, but no later than [***]days following the beginning of
each year.  The initial Development Plan is attached hereto as
Schedule 3.1, which shall be non-binding, including any timelines or milestones
that may be included therein.  In addition, Ikaria shall, within [***]
days after the Effective Date, provide BioLineRx with a revised draft protocol
for the Interim Analysis of the Pivotal Clinical Trial/Phase IIb Proof of
Concept and the Pivotal Clinical Trial, after taking into account any comments
BioLineRx may wish to provide based on the initial draft of the protocol
attached hereto as Schedule 1.35, that would include modifications designed to
maximize the likelihood of obtaining reasonable reimbursement for one or more
Products in any one or more of the following countries: [***].  Upon
the Successful Completion of the Interim Analysis of the Pivotal Clinical
Trial/Phase IIb Proof of Concept, or, failing that, upon the Successful
Completion of the Pivotal Clinical Trial, Ikaria shall, within [***] days
thereafter, submit a formal written request for a reimbursement price for one or
more Product(s) to the applicable governmental agency in one or more of the
following countries: [***].

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          11

          
            

          

        

        
           


        

      

    

    


    Section
3.2       Joint Development
Committee.

     

    (a)      The
Parties shall establish a Joint Development Committee (the “Joint Development
Committee” or “JDC”), comprised of
[***] representatives of Ikaria and [***] representatives of BioLineRx, to
oversee the Development of Products.  Each Party shall make its
initial designation of its representatives not later than [***] days after the
Effective Date.  Each Party may change any one or more of its
representatives to the Joint Development Committee at any time upon notice to
the other Party.

     

    (b)      The
JDC shall meet at least [***] during the Development Term or more or less
frequently as the JDC may agree.  The JDC may meet in person or by
means of a telephone or video conference call.  One meeting of the JDC
per year shall be held in person at Ikaria’s headquarters in Clinton, NJ and one
meeting of the JDC per year shall be held in person at BioLineRx’s headquarters
in Israel, provided, that the Parties’ representatives may participate in
person, via telephone, or video conference in their discretion.  Each
Party shall use reasonable efforts to cause its representatives to attend the
meetings of the JDC.  If a representative of a Party is unable to
attend a meeting, such Party may designate an alternate to attend such meeting
in place of the absent representative.  Each Party shall bear its own
costs with respect to its participation on the JDC.  Prior to every
meeting of the JDC, Ikaria will provide to the JDC detailed reports describing
Ikaria’s current clinical and development activities and plans.

     

    (c)      The
JDC shall be the vehicle by which BioLineRx may offer insight and guidance to
Ikaria with respect to (i) establishing the Development Plan setting forth the
Development Program’s objectives and the activities to be conducted, (ii)
reviewing and updating the Development Plan from time to time, (iii) monitoring
the progress and results of the Development Program, (iv) determining future
Development Program activities, including Development activities relating to
Manufacturing, to be conducted during the Development Term, and (v) establishing
success criteria for the clinical trials (other than those for which success
criteria are set forth in this Agreement), and determining whether the results
of such clinical trials have achieved the applicable success
criteria.

     

    (d)      The
JDC shall only act unanimously, with each Party given one (1) vote regardless of
the number of representatives.  If, however, the JDC is unable to
reach agreement with respect to any matter within [***] days, the matter shall
be referred to the Parties’ respective Executive Officers for
resolution.  If the Executive Officers are not able to resolve any
such matter by consensus within [***] days following referral, Ikaria’s
Executive Officer shall have the right to decide the matter taking into account
Ikaria’s obligation to use Commercially Reasonable Efforts under Section
3.8.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          12

          
            

          

        

        
           


        

      

    

    


    Notwithstanding
anything in this Section 3.2, neither Party shall have a unilateral right to
resolve any dispute involving the breach or alleged breach of this Agreement, to
amend or modify this Agreement or the Parties’ respective rights and obligations
hereunder or, except as expressly provided in this Section 3.2, any Development
Plan or the Parties’ respective rights and obligations thereunder.

     

    Section
3.3       On-Going
Trials.  BioLineRx shall retain control of, bear all costs
relating to the On-Going Phase I/II Trial and the Other On-Going Trials, and
shall exercise Commercially Reasonable Efforts to continue and complete the
On-Going Phase I/II Trial and the Other On-Going Trials, which shall be managed
by BioLineRx.  BioLineRx may modify the On-Going Phase I/II Trial and
the Other On-Going Trials, including any changes to the protocols therefor, only
with the prior written consent of Ikaria, which consent shall not be
unreasonably withheld, conditioned or delayed.

     

    Section
3.4       Regulatory
Matters.  Ikaria shall prepare and submit all filings with
Regulatory Authorities relating to Products, which filings shall be in Ikaria’s
name, provided
that Ikaria
shall provide BioLineRx [***] days prior notice to enable BioLineRx to review
and provide any comments on such submissions.  With respect to
regulatory matters concerning Products, BioLineRx shall cooperate with Ikaria in
the preparation and support of each application for Regulatory Approval and
shall provide Ikaria with such reasonable assistance as Ikaria may
request.  For example, upon Ikaria’s request, BioLineRx shall describe
the materials in sufficient and reasonable detail as requested by Ikaria, the
Manufacturing techniques and other appropriate characteristics of Products (and
the components thereof), and provide Ikaria with such other information related
to the Products, including materials, chemistry, Manufacturing, technical
dossier and controls data, batch records, analytical and quality control, device
master files (if applicable), data from the On-Going Phase I/II Trial or Other
On-Going Trials, or other information as Ikaria may reasonably
request.

     

    Section
3.5       Technology
Exchange.

     

    (a)      As
soon as reasonably practicable after Ikaria’s written request, BioLineRx shall
complete the activities assigned to BioLineRx as set forth on the technology
exchange plan attached hereto as Exhibit A (the “Technology Exchange
Plan”), to effect the transfer to Ikaria (or Ikaria’s designee(s)) of all
embodiments of and information relating to BioLineRx Intellectual Property
reasonably necessary for the exercise of Ikaria’s rights under the license
granted pursuant to Section 2.1, including the Manufacturing of Products (“Technology
Exchange”).  BioLineRx shall make available to Ikaria (or
Ikaria’s designee(s)) such number of technical personnel as may be set forth in
the Technology Exchange Plan to answer any questions or provide instruction as
reasonably requested by Ikaria (or Ikaria’s designee(s)) concerning the items
delivered pursuant to this Section 3.5, in connection with the
Development,  Manufacture and Commercialization of Products
hereunder.  Each Party shall bear its own costs with respect to the
Technology Exchange.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          13

          
            

          

        

        
           


        

      

    

    


    (b)      The
Joint Development Committee shall be responsible for coordinating the technology
exchange activities under the Technology Transfer Plan.  Each Party
shall cooperate with the other Party in such other Party’s conduct of technology
exchange activities under the Technology Exchange Plan.

     

    (c)      If
Ikaria desires that BioLineRx provide technology exchange services beyond the
scope of the Technology Exchange Plan, BioLineRx shall provide such services on
terms to be agreed upon in good faith by the Parties.  Notwithstanding
the foregoing, BioLineRx shall provide Ikaria with reasonable access to
BioLineRx’s employees and consultants involved prior to the Effective Date and
during the term of this Agreement with the Development of any
Product.

     

    Section
3.6       Manufacturing.

     

    (a)      Ikaria
shall be solely responsible for the Manufacture of Products for Development or
for Commercialization in the Field in the Territory, which Ikaria may conduct
itself or through Affiliates or Licensees.

     

    (b)      BioLineRx
Ltd. shall have the option (either directly or through an Affiliate),
exercisable in its sole discretion no later than [***] months prior to the date
on which Ikaria intends to file for Regulatory Approval in the U.S., to
Manufacture Product pursuant to the terms of a supply agreement to be negotiated
in good faith by the Parties, provided that (i) BioLineRx
may exercise the foregoing option only to the extent that it has the
demonstrated ability to manufacture the Product, including compliance with cGMP
and all applicable laws and regulations, including those of the FDA and EMEA,
(ii) BioLineRx shall bear all expenses required to establish and qualify the
BioLineRx manufacturing site, including the costs of scale-up batches, process
validation batches and stability batches, (iii) BioLineRx shall not be entitled
to assign such option or to utilize subcontract manufacturing, and (iv) neither
Party shall have any obligation to enter into such agreement unless all of the
terms and conditions thereof are acceptable to both Parties.  If
BioLineRx Ltd. exercises such option and the Parties enter into a supply
agreement, (x) Ikaria shall be required to purchase no less than twenty
percent (20%) of its requirements for the Product from BioLineRx, and (y)
the per unit price for the Product shall be the [***], provided that the price shall
not exceed [***]%) of the Net Sales price per unit of Product; provided, further, that if BioLineRx at
any time shall fail to supply Product on time or such supply is otherwise
disrupted, the minimum purchase requirement set forth in the preceding clause
(x) shall no longer apply.  Any clinical supply provided to Ikaria by
BioLineRx would be provided at cost.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          14

          
            

          

        

        
           


        

      

    

    


    (c)      The
Parties will discuss the most efficient structure for the Manufacture and supply
of Product for Development and Commercialization purposes.  If the
Parties determine that coordination in Manufacturing is appropriate, the Parties
will establish a Joint Manufacturing Committee (the “Joint Manufacturing
Committee” or “JMC”) to coordinate
Manufacturing efforts.  If established, the JMC would be comprised of
[***] representatives of Ikaria and [***] representatives of BioLineRx, to
oversee the Manufacturing of Products.  Each Party would make its
initial designation of its representatives not later than [***] days after the
Parties agreed to establish the JMC.  Each Party shall designate as
its representatives individuals who have the requisite experience and knowledge
to discuss the Manufacturing of Products.  Each Party would be
permitted to change any one or more of its representatives to the JMC at any
time upon notice to the other Party.

     

    (d)      The
JMC would meet at least [***] or more or less frequently as the JMC may
agree.  The location of such meetings shall be as mutually agreed by
the Parties.  The JMC may also meet by means of a telephone or video
conference call.  Each Party shall use reasonable efforts to cause its
representatives to attend the meetings of the JMC.  If a
representative of a Party is unable to attend a meeting, such Party may
designate an alternate to attend such meeting in place of the absent
representative.  Each Party would bear its own costs with respect to
its participation on the JMC.

     

    (e)      The
JMC would only act unanimously.  If, however, the JMC is unable to
reach agreement with respect to any matter within [***] days, the matter shall
be referred to the Parties’ respective Executive Officers for
resolution.  If the Executive Officers are not able to resolve any
such matter by consensus within [***] days following referral, Ikaria’s
Executive Officer shall have the right to decide the matter taking into account
Ikaria’s obligation to use Commercially Reasonable Efforts under Section
3.8.

     

    Section
3.7       Commercialization.  Ikaria
shall be solely responsible for conducting, itself or through Affiliates or
Licensees, the Commercialization of Products in the Field in the Territory,
including (a) contracting with customers and booking sales, (b) setting the
price and terms and conditions under which a Product may be sold to customers,
and (c) handling of managed care accounts, and, subject to Section 1.29, Section
4.2(b), Section 5.2(d), Section 5.3(e) and Section 10.1(b), as between the
Parties, Ikaria shall bear all costs associated therewith.  Ikaria
shall produce and update from time to time a comprehensive Commercialization
plan (the “Commercialization
Plan”), which shall include plans for Commercializing Product in each
major market in which Ikaria does not then have a presence.  The
Commercialization Plan shall include a preliminary timeline for the initial
Commercialization of Products, which is intended as a planning and informational
tool and shall not constitute a binding obligation on Ikaria, and shall be
subject to adjustment by Ikaria from time to time, provided, that, Ikaria shall
provide BioLineRx with prior written notice of any material proposed change to a
timeline.  The most recent preliminary Commercialization Plan is
attached hereto as Schedule
3.7.

     

    Section
3.8       Efforts.  Ikaria
shall use Commercially Reasonable Efforts, either itself or through Affiliates
or Licensees, (a) to Develop at least one Product in the Territory and (b) to
Commercialize at least one Product in the Territory.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
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    Article
IV

    Financial
Provisions

     

    Section
4.1       Milestone
Payments.

     

    (a)      Development and Regulatory
Milestones.  With respect to each of the following milestones,
Ikaria shall pay BioLineRx the corresponding payment set forth below within
[***] days after the achievement by Ikaria, its Affiliates or Licensees of such
milestone:

    


    
      
        
          	
                  MILESTONE

                	 	
                  PAYMENT

                	 
	 
      	 	 	 
	
                  1.Effective
      Date

                	 	$	7,000,000	 
	 
      	 	 	 	 
	
                  2.Successful
      Completion of On-Going Phase I/II Trial

                	 	$	10,000,000	 
	 
      	 	 	 	 
	
                  3.[***]

                	 	 	 	 
	 
      	 	 	 	 
	
                  4.[***]

                	 	 	 	 
	 
      	 	 	 	 
	
                  5.[***]

                	 	 	 	 
	 
      	 	 	 	 
	
                  6.[***]

                	 	 	 	 
	 
      	 	 	 	 
	
                  Total
      Development and Regulatory Milestone Payments

                	 	$	132,500,000	 


        

      

    

     

    (b)           Commercialization
Milestones.  Ikaria shall pay each of the following milestone
payments to BioLineRx within [***] days after the achievement of such
milestone:

     

    
      
        
          	
                  MILESTONE

                	 	
                  PAYMENT

                	 
	 
      	 	 	 
	
                  7.      Annual
      Net Sales in Territory exceed $[***] in a Calendar Year

                	 	$	[***	]
	 
      	 	 	 	 
	
                  8.Annual
      Net Sales in Territory exceed $[***] in a Calendar Year

                	 	$	[***	]
	 
      	 	 	 	 
	
                  9.Annual
      Net Sales in Territory exceed $[***] in a Calendar Year

                	 	$	[***	]


        

      

    

     

    Each of
the milestones set forth in Section 4.1(a) and Section 4.1(b) shall be paid only
once regardless of the number of Products that achieve such
milestone.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
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    Section
4.2       Royalties on Net Sales of
Products.  During the Royalty Term applicable to each Product,
and subject to adjustment as set forth in Section 4.2(b), Ikaria shall pay to
BioLineRx royalties on a Product-by-Product basis, with the amount of such
royalties calculated as a percentage of Net Sales in a calendar year for such
Product as set forth below:

     

    
      
        	
                Net
      Sales

              	
                Royalty

              
	
                Up
      to [***]

              	 
      
	
                [***]

              	 
      
	
                [***]

              	 
      


      

    

     

    (a)      Royalties Payable Only
Once.  The obligation to pay royalties is imposed only once
with respect to Net Sales of the same unit of a Product.

     

    (b)      Royalty Reductions for Third
Party Payments.  Ikaria shall use Commercially Reasonable
Efforts to avoid any Third Party Payments.  Ikaria shall provide
BioLineRx written notice within [***] days of its receipt of any request or
demand that Ikaria, its Affiliates or any Licensee obtain a license or immunity
from suit from any Third Party in order for Ikaria, its Affiliates, or any
Licensee to exercise or use the rights granted to Ikaria herein.  If
Ikaria is required to obtain a license or immunity from suit from any Third
Party in order for Ikaria, its Affiliates, or any Licensee to exercise or use
the rights granted to Ikaria herein, and Ikaria, its Affiliates, or any Licensee
pays any Third Party any up-front fee, milestone, royalty, or other payment
(each, a “Third Party
Payment”) in connection with such license or immunity from suit, Ikaria
shall have the right to set off against any amounts payable to BioLineRx under
this Article IV [***]%) of any Third Party Payments provided that in no event will
the royalty paid to BioLineRx on Net Sales in the applicable country fall below
[***]%).  If the amount of Third Party Payments that Ikaria is
entitled to set off exceeds the amount otherwise payable to BioLineRx at any
given time, or is limited by the foregoing [***]%), Ikaria shall be entitled to
carry over the excess for set off against amounts payable to BioLineRx in
subsequent periods until Ikaria has been credited for the full amount it is
entitled to set off.  Prior to paying any Third Party Payment, the
Parties shall obtain an analysis from their respective counsel in respect of the
validity of the claim of any Third Party seeking Third Party
Payments.  If the Parties are unable to agree on an assessment of the
claim, the Parties shall jointly engage mutually acceptable independent patent
counsel not regularly employed by either Party to assess such
claims.  Ikaria shall substitute the decision of such independent
patent counsel for that of its own counsel with respect to deciding whether to
obtain a license or immunity from suit from any Third Party in order for Ikaria,
its Affiliates, or any Licensee to exercise or use the rights granted to Ikaria
herein.

     

    (c)      Duration of
Payments.  The amounts payable to BioLineRx under Section 4.2
shall be paid on a Product-by-Product and country-by-country basis until the
expiration of the Royalty Term for such Product in such country.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          17

          
            

          

        

        
           


        

      

    

    


    (d)      Price
Concessions.  Ikaria shall not, and shall ensure that its
Affiliates and Licensees do not, sell or distribute the Product at a discount
(including in the form of government mandated rebates) (with or without
consideration) in return substantially for (i) concessions or consideration
received in transactions involving products or services other than the Product
or (ii) concessions from any government or governmental authority relating to
products or services other than the Product.

     

    Section
4.3       Reports and
Accounting.

     

    (a)      Reports;
Payments.  Ikaria shall deliver to BioLineRx, within [***] days
after the end of each calendar quarter, reasonably detailed written accountings
of Net Sales of Products that are subject to payment obligations to BioLineRx
for such calendar quarter.  Such quarterly reports shall indicate (i)
gross sales and Net Sales on a country-by-country basis, (ii) the calculation of
payment amounts owed to BioLineRx from such gross sales and Net Sales, and (iii)
any amounts set off pursuant to Section 4.2(b) against payments owed to
BioLineRx.  When Ikaria delivers such accounting to BioLineRx, Ikaria
shall also deliver all amounts due under Section 4.2 to BioLineRx for the
calendar quarter.  All payments shall be made by wire transfer to the
account specified in Schedule
4.3(a).

     

    (b)      Audits by
BioLineRx.  Ikaria shall keep, and shall require its Affiliates
and Licensees to keep, complete and accurate records of the most recent [***]
years relating to gross sales and Net Sales and all information relevant under
Section 4.1 and Section 4.2.  For the sole purpose of verifying
amounts payable to BioLineRx, BioLineRx shall have the right no more than [***]
per calendar year, at BioLineRx’s expense, to engage independent accountants to
review such records in the location(s) where such records are maintained by
Ikaria, its Affiliates, and its Licensees upon reasonable notice and during
regular business hours.  Prior to any review conducted pursuant to
this Section 4.3(b), BioLineRx’s accountants shall have entered into a written
agreement with Ikaria limiting the use of such records to verification of the
accuracy of payments due under this Agreement and prohibiting the disclosure of
any information contained in such records to a Third Party and to BioLineRx for
a purpose other than as set forth in this Section 4.3(b).  The right
to audit any royalty report or quarterly report or payment shall extend for
[***] years from the end of the calendar year in which such royalty report or
quarterly report was delivered or such payment made.  Results of such
review shall be made available to Ikaria.  If the review reflects an
underpayment to BioLineRx, such underpayment shall be promptly remitted to
BioLineRx.  Likewise, if the review reflects an overpayment, Ikaria
shall be entitled to reduce any subsequent payments by the amount of the
overpayment.  If the underpayment to BioLineRx is equal to or greater
than [***] %) of the amount that was otherwise due, BioLineRx shall be entitled
to have Ikaria reimburse BioLineRx’s reasonable out-of-pocket costs of such
review.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          18

          
            

          

        

        
           


        

      

    

    


    Section
4.4       Currency
Amounts.  All dollar ($) amounts specified in this Agreement
are United States Dollar amounts.

     

    Section
4.5       Currency
Exchange.  With respect to sales of Products invoiced in U.S.
Dollars and other amounts received or paid by Ikaria, its Affiliates or
Licensees in U.S. Dollars, such amounts and the amounts payable hereunder shall
be expressed in U.S. Dollars.  With respect to sales of Products
invoiced in a currency other than U.S. Dollars and other amounts received or
paid by Ikaria, its Affiliates or Licensees in a currency other than U.S.
Dollars, such amounts and the amounts payable hereunder shall be expressed in
their U.S. Dollar equivalent calculated using the applicable rate of exchange
reported by The Wall Street
Journal (Eastern U.S. edition) on the last Business Day of the calendar
quarter to
which the report under Section 4.3(a) relates.  All payments hereunder
shall be made in U.S. Dollars.

     

    Section
4.6       Tax
Withholding.  The Parties shall use all reasonable and legal
efforts to reduce tax withholding on payments made to BioLineRx.  The
Parties agree to cooperate in good faith to provide one another with such
documents and certifications as are reasonably necessary to enable Ikaria to
minimize any withholding tax obligations.  Ikaria shall promptly
provide to BioLineRx documentation of the payment of any withholding taxes that
are paid pursuant to this Section 4.6, including copies of receipts or other
evidence reasonably required and sufficient to allow BioLineRx to document such
tax withholdings adequately for purposes of claiming foreign tax credits and
similar benefits.

     

    Section
4.7       Upfront Payments Received
Under Sublicenses.  If Ikaria receives an upfront payment
consideration under a sublicense granted to a Third Party under this Agreement,
Ikaria shall pay to BioLineRx ten percent (10%)of any such payment within 30
days after actual receipt thereof from the Third Party.

     

    Article
V

    Intellectual Property
Ownership, Protection and Related Matters

     

    Section
5.1       Ownership of
Inventions.

     

    (a)      Intentionally
Omitted.

     

    (b)      Intentionally
Omitted.

     

    (c)      Inventorship.  Questions
of inventorship shall be resolved in accordance with United States patent
laws.  In the event of a dispute regarding inventorship, if the
Parties are unable to resolve the dispute, the Parties shall jointly engage
mutually acceptable independent patent counsel not regularly employed by either
Party to resolve such dispute.  The decision of such independent
patent counsel shall be binding on the Parties with respect to the issue of
inventorship.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          19

          
            

          

        

        
           


        

      

    

    


    (d)      Further Actions and
Assignments.  Each Party shall take all further actions and
execute all assignments requested by the other Party and reasonably necessary or
desirable to vest in the other Party the ownership rights set forth in this
Section 5.1.

     

    Section
5.2       Prosecution and Maintenance
of Patent Rights.

     

    (a)      Intentionally
Omitted.

     

    (b)      BioLineRx Intellectual
Property.  Upon the Effective Date, Ikaria shall assume
responsibility for the management of the preparation, filing prosecution and
maintenance of any and all patent applications, including any interference
proceedings related thereto, included in the BioLineRx Intellectual Property
(including, for clarity, the Sublicensed IP, BioLineRx Patent Rights and patents
and patent applications that claim or disclose BioLineRx Know-How).

     

    (c)      BioLineRx Step-in
Right.  If Ikaria, on a country-by-country basis, declines to
file and prosecute, or elects not to take actions necessary to avoid abandonment
of, any patent applications or maintain any patent in any country, in each case
for which it has responsibility under Section 5.2(a) or Section 5.2(b), it shall
give BioLineRx reasonable notice to this effect sufficiently in advance to
permit BioLineRx to undertake such filing and prosecution without a loss of
rights, and thereafter BioLineRx may, upon written notice to Ikaria, file and
prosecute such patent applications and maintain such patents in such
country.  If BioLineRx files, prosecutes or maintains any such patent
application or patent in such country and any resulting Valid Claim of BioLineRx
Patent Rights constitutes the only BioLineRx Patent Rights Covering the Product
in such country (i.e., there are no other
BioLineRx Patent Rights Covering the Product in such country),
[***].

     

    If BioLineRx exercises the foregoing
step-in right following the election by Ikaria to abandon all existing BioLineRx
Patent Rights in a given country, Ikaria shall, within [***] days following
BioLineRx’s written request, notify BioLineRx in writing whether Ikaria intends
to Commercialize a Product in the Field in such country.  If Ikaria
notifies BioLineRx that Ikaria has no intent to Commercialize a Product in the
Field in such country, BioLineRx may, upon written notice to Ikaria within [***]
days of receipt of Ikaria’s notice of lack of intent, exercise a right to
directly Commercialize a Product in the Field in such country.  If
BioLineRx provides Ikaria with such notice:[***]

     

    (d)      Costs and
Expenses.  Ikaria shall pay the costs and expenses of
preparing, filing, prosecuting, and maintaining the Patent Rights covered by
Section 5.2(a) or Section 5.2(b), [***].

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          20

          
            

          

        

        
           


        

      

    

    


    (e)      Cooperation Between
Parties.  Each Party agrees to cooperate with the other with
respect to the preparation, filing, prosecution and maintenance of Patent Rights
pursuant to this Section 5.2, including the execution of all such documents and
instruments and the performance of such acts as may be reasonably necessary in
order to permit the other Party to continue any preparation, filing, prosecution
or maintenance of such Patent Rights, including Patent Rights that such Party
has elected not to pursue, as provided for in subsections (a), (b) and (c)
above.  In addition, the filing, prosecuting and maintaining Party in
subsections (a), (b) and (c) above shall promptly forward to the other Party
copies of any substantive correspondence and actions prepared for or received
from the U.S. Patent and Trademark Office or any foreign patent office that may
materially affect the Patent Rights being prosecuted or
maintained.  The other Party’s patent counsel may provide comments to
the filing, prosecuting and maintaining Party.  If any comments by the
other Party’s patent counsel are provided in sufficient time for the filing,
prosecuting and maintaining Party to reflect such comments in its correspondence
or response, and such comments are reasonably directed to maximizing the
coverage of the claims of the Patent Rights being prosecuted or maintained, the
filing, prosecuting and maintaining Party shall reflect such comments in its
correspondence or response, if its patent counsel deems it prudent to do
so.

     

    (f)       Coordination with BioLineRx
pursuant to the Sublicensed IP.  With respect to any
Sublicensed IP which Ikaria is responsible for filing, prosecuting, and
maintaining, Ikaria shall:

     

    (i)       consult
with BioLineRx regarding the preparation, filing, and prosecution of all patent
applications, and the maintenance of all patents, included within such
Sublicensed IP, including the content, timing, and jurisdiction of the filing of
such patent applications and their prosecution, and other details and overall
global strategy pertaining to the procurement and maintenance of Patent Rights
in such Sublicensed IP, and shall file, prosecute, and maintain all such Patent
Rights through a law or patent attorney firm selected by Ikaria and approved by
BioLineRx (and  BioLineRx shall exercise its rights under the BGN
License Agreement as may be necessary to obtain BGN’s approval);
and

     

    (ii)      provide
BioLineRx with copies of all patent applications that claim or disclose such
Sublicensed IP, and BioLineRx shall exercise its rights under the BGN License
Agreement to ensure that BGN cooperates in a timely manner with Ikaria’s efforts
to register such Patent Rights, including by causing BGN to execute any
documents as may be required for such purpose.

     

    BioLineRx
shall take all actions required to remain in compliance with the BGN License
Agreement in connection with the foregoing.

     

    Section
5.3       Third Party
Infringement.

     

    (a)      Notice.  Each
Party shall promptly report in writing to the other Party during the term of
this Agreement any (i) known or suspected infringement of any of the BioLineRx
Patent Rights or (ii) unauthorized use of any of the BioLineRx Know-How of which
such Party becomes aware, including, in the case of either clause (i) or clause
(ii) involving, or that may reasonably lead to, the Development, Manufacture,
use or Commercialization of a product or product candidate that is or may be
competitive with a Product in the Field (“Competitive
Infringement”), and shall provide the other Party with all available
evidence supporting such infringement, suspected infringement, unauthorized use
or suspected unauthorized use.

    


    
      
        
           


        

        
          21

          
            

          

        

        
           


        

      

    

    


    (b)      BioLineRx Intellectual
Property; Step-in Rights.

     

    (i)       Ikaria
shall have the first right, but not the obligation, to initiate a suit or take
other appropriate action that either Party reasonably believes is required to
protect BioLineRx Intellectual Property from Competitive
Infringement.  Ikaria shall give BioLineRx sufficient advance notice
of its intent to file any such suit or take any such action, and the reasons
therefor, and shall provide BioLineRx with an opportunity to make suggestions
and comments regarding such suit or action.  Thereafter, Ikaria shall
keep BioLineRx informed, and shall from time to time consult with BioLineRx
regarding the status of any such suit or action and shall provide BioLineRx with
copies of all material documents (i.e., complaints, answers,
counterclaims, material motions, orders of the court, memoranda of law and legal
briefs, interrogatory responses, depositions, material pre-trial filings, expert
reports, affidavits filed in court, transcripts of hearings and trial testimony,
trial exhibits and notices of appeal) filed in, or otherwise relating to, such
suit or action.  Any recovery obtained as a result of any proceeding
pursuant to this subsection (b)(i), by settlement or otherwise, shall be applied
in the following order of priority: (A) first, each Party shall be reimbursed,
on a pro rata basis, for all costs incurred by such Party in connection with
such suit; and (B) second, [***]

     

    (ii)      If
Ikaria chooses not to initiate a suit or take other appropriate action under
subsection (b)(i) above to protect BioLineRx Intellectual Property from
Competitive Infringement, Ikaria will so notify BioLineRx of its intention, in
which case BioLineRx shall have the right to initiate such suit or take such
other appropriate action.  BioLineRx shall give Ikaria sufficient
advance notice of its intent to file any such suit or take any such action, and
the reasons therefor, and shall provide Ikaria with an opportunity to make
suggestions and comments regarding such suit or action.  Thereafter,
BioLineRx shall keep Ikaria informed, and shall from time to time consult with
Ikaria regarding the status of any such suit or action and shall provide Ikaria
with copies of all material documents (i.e., complaints, answers,
counterclaims, material motions, orders of the court, memoranda of law and legal
briefs, interrogatory responses, depositions, material pre-trial filings, expert
reports, affidavits filed in court, transcripts of hearings and trial testimony,
trial exhibits and notices of appeal) filed in, or otherwise relating to, such
suit or action.  Any recovery obtained as a result of any proceeding
pursuant to this subsection (b)(ii), by settlement or otherwise, shall be
applied in the following order of priority: (A) first, each Party shall be
reimbursed, on a pro rata basis, for all costs incurred by such Party in
connection with such suit; and (B) second, any remainder shall be shared [***]%
for BioLineRx and [***] % for Ikaria.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
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    (iii)     If
BioLineRx chooses not to initiate a suit or take other appropriate action under
subsection (b)(ii) above to protect Sublicensed IP from Competitive Infringement
and BGN exercises its rights under the BGN License Agreement to prosecute,
prevent, or terminate such Competitive Infringement, any amount received by
BioLineRx in connection therewith, whether by settlement or otherwise,
[***].

     

    (c)      Claimed
Infringement.  If a Party becomes aware of any claim that the
Development, Manufacture, or Commercialization of Products for use in the Field
in the Territory infringes Patent Rights or any other intellectual property
rights of any Third Party, such Party shall promptly notify the other
Party.  In any such instance, Ikaria shall have the exclusive right to
settle such claim.

     

    (d)      Patent Invalidity
Claim.  If a Third Party at any time asserts a claim that any
BioLineRx Patent Rights is invalid or otherwise unenforceable (an “Invalidity Claim”),
whether (i) as a defense in an infringement action brought by Ikaria or
BioLineRx pursuant to subsection (b) above, or (ii) in an action brought against
Ikaria or BioLineRx referred to in subsection (c) above, or (iii) otherwise, the
Parties shall cooperate with each other in preparing and formulating a response
to such Invalidity Claim.  Neither Party shall settle or compromise
any Invalidity Claim without the consent of the other Party, which consent shall
not be unreasonably withheld, conditioned or delayed.

     

    (e)      Conduct of Certain Actions;
Costs.  Ikaria shall have the sole and exclusive right to
select counsel for any suit initiated by it referenced in subsection (b)(i)
above or against it referenced in subsection (c) above, and BioLineRx shall have
the sole and exclusive right to select counsel for any suit initiated by it
referenced in subsection (b)(ii) above.  If required under applicable
law in order for a Party (the “Lead Party”) to
initiate or maintain such suit, the other Party shall join as a party to the
suit.  Such other Party shall offer reasonable assistance to the Lead
Party in connection therewith at no charge to the Lead Party except for
reimbursement of such other Party’s reasonable out-of-pocket expenses incurred
in rendering such assistance.  The Lead Party shall assume and pay all
of its own out-of-pocket costs incurred in connection with any litigation or
proceedings referenced in the first sentence of this subsection (e), including
the fees and expenses of the counsel selected by it.  Subject to
applicable law, the other Party shall have the right to participate and be
represented in any such suit by its own counsel at its own expense.

     

    (f)       Coordination with
BGN.  With respect to any suit to protect Sublicensed IP from
infringement for which Ikaria is the Lead Party, notwithstanding anything to the
contrary in this Section 5.3:

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
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    (i)       if
required under applicable law in order for Ikaria to initiate or maintain such
suit, BioLineRx shall (A) exercise its rights under the BGN License Agreement to
cause BGN to join as a party to such suit, (B) exercise its rights under the BGN
License Agreement to obtain BGN’s approval of counsel selected by Ikaria to
represent Ikaria and BGN in such suit, and (C) [***];

     

    (ii)      Ikaria
shall not compromise or settle such suit without the prior written consent of
BGN, which consent BioLineRx shall exercise its rights under the BGN License
Agreement to obtain; and

     

    (iii)     any
recovery obtained by Ikaria as a result of such suit, by settlement or
otherwise, shall be applied in the following order of priority: (A) first, each
Party shall be reimbursed, on a pro rata basis, for all costs incurred by such
Party in connection with such suit (for clarity, BioLineRx shall be reimbursed
for any costs of BGN paid by BioLineRx in accordance with clause (i)(C) above);
(B) second, [***]%) of any remainder shall paid to BioLineRx for remittance to
BGN as provided in Section 10.1.2 of the BGN License Agreement ; and (C) third,
the remaining [***]%) shall be retained by Ikaria; [***].

     

    Article
VI

    Confidentiality;
Non-Solicitation; Standstill

     

    Section
6.1       Confidential
Information.  Each Party agrees that all Confidential
Information disclosed to it or its Affiliates by the other Party (a) shall not
be used by the receiving Party or its Affiliates except to fulfill its
obligations or exercise its rights under this Agreement, (b) shall be maintained
in confidence by the receiving Party and its Affiliates, and (c) shall not be
disclosed by the receiving Party or its Affiliates to any Third Party who is not
a consultant of, or an advisor to, the receiving Party or its Affiliates without
the prior written consent of the disclosing Party, which consent the disclosing
Party may withhold in its sole discretion.  Notwithstanding the
foregoing, either Party may disclose Confidential Information of the other Party
if such Party is required to make such disclosure by applicable law, regulation
or legal process, including by Israeli securities laws, the rules or regulations
of the United States Securities and Exchange Commission (the “SEC”) or any similar
regulatory agency in a country other than the United States or of any stock
exchange, including the Tel Aviv Stock Exchange, in which event such Party shall
provide prior notice of such intended disclosure to such other Party, if
possible under the circumstances, and shall disclose only such Confidential
Information of the other Party as is required to be disclosed.  If
this Agreement shall be included in any report, statement or other document
filed by either Party or an Affiliate of either Party pursuant to the preceding
sentence, such Party shall use, or shall cause its Affiliate, as the case may
be, to use, reasonable efforts to obtain confidential treatment from the SEC,
similar regulatory agency or stock exchange of any financial information or
other information of a competitive or confidential nature, and shall include in
such confidentiality request such provisions of this Agreement as may be
reasonably requested by the other Party.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
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    Section
6.2       Disclosures to Employees,
Consultants, Advisors, Etc.  Each Party agrees that it and its
Affiliates shall provide Confidential Information received from the other Party
only to the receiving Party’s respective employees, consultants, advisors,
Licensees and potential Licensees, and to the employees, consultants and
advisors of the receiving Party’s Affiliates, who have a need to know such
Confidential Information to assist the receiving Party in fulfilling its
obligations under this Agreement and only under conditions of confidentiality
and non-use at least as stringent as the conditions imposed by this Agreement,
provided that BioLineRx and
Ikaria shall each remain responsible for any failure by its and its Affiliates’
respective employees, consultants, advisors, Licensees and potential Licensees
to treat such information and materials as required under Section
6.1.  For clarity, (a) Ikaria is permitted to disclose Confidential
Information to actual or potential Licensees, acquirors or financing sources;
and (b) BioLineRx is permitted to disclose this Agreement and the Development
Plan to BGN, solely to the extent required under the BGN License Agreement;
provided that any such
disclosure subjects the receiving Third Party to conditions of confidentiality
and non-use at least as stringent as the conditions imposed by this
Agreement.

     

    Section
6.3       Non-Solicitation.  During
the term of this Agreement and continuing for [***] months after the termination
of this Agreement, neither Party shall directly or indirectly, for its own
account or for the account of others, urge, induce, entice, or in any manner
whatsoever solicit any employee directly involved in the activities conducted
pursuant to this Agreement to leave the employment of the other Party or any of
its Affiliates.  For purposes of the foregoing, “urge”, “induce”,
“entice” or “solicit” shall not be deemed to mean: (a) circumstances where an
employee of a Party initiates contact with the other Party or any of its
Affiliates with regard to possible employment; or (b) general solicitations of
employment not specifically targeted at employees of a Party or any of its
Affiliates, including responses to general advertisements.

     

    Section
6.4       Standstill.  Neither
Ikaria nor any of its Affiliates shall directly or indirectly, for its own
account or for the account of others, acquire more than [***]%) of the equity or
debt securities of BioLineRx, or urge, induce, entice or solicit any Third Party
to acquire the equity or debt securities of BioLineRx, in either case without
the consent of BioLineRx, which may be withheld in its sole
discretion.  The obligations of Ikaria under this Section 6.4 shall
terminate in the event that (a) any Third Party initiates a tender or exchange
offer, or otherwise publicly proposes or agrees to acquire, a majority of the
equity or debt securities of BioLineRx (provided that the restrictions set forth
in this Section 6.4 shall be reinstated in the event that such tender or
exchange offer, or proposal, is terminated or withdrawn), (b) it is publicly
disclosed that voting securities representing at least [***] of the total voting
power of BioLineRx have been acquired by any one or more Third Parties, (c)
BioLineRx publicly announces that it intends to seek a Third Party acquirer
(provided that the restrictions set forth in this Section 6.4 shall be
reinstated in the event that BioLineRx publicly announces that it no longer is
seeking a Third Party acquirer and so notifies Ikaria in writing), (d) BioLineRx
enters into any agreement to merge with, or sell or dispose of [***] or more of
its assets or securities, or (e) this Agreement is terminated pursuant to
Article VIII.  BioLineRx shall provide Ikaria with prompt written
notice of the occurrence of any of the foregoing events to the extent permitted
under applicable law.  For clarity, the acquisition by any employee
benefit plan of Ikaria or its Affiliates in any diversified index, mutual or
pension fund, which fund in turn holds BioLineRx securities, shall not be deemed
a breach of this Section 6.4.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
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    Section
6.5       Term.  All
obligations of confidentiality imposed under this Article VI shall survive until
the date that is [***] years after the expiration or termination of this
Agreement.

     

    Section
6.6       Publicity.  During
the term of this Agreement, the content of any press release or public
announcement relating to this Agreement or a Product shall be mutually approved
by the Parties, except that (a) a Party may issue such press release or public
announcement if the contents of such press release or public announcement have
previously been made public other than through a breach of this Agreement by the
issuing Party, (b) a Party may issue such a press release or public announcement
if it is advised by counsel that such press release or public announcement is
required by applicable law, regulation or legal process, including by Israeli
securities laws, the rules or regulations of the SEC or any similar regulatory
agency in a country other than the United States or of any stock exchange,
including the Tel Aviv Stock Exchange, and (c) Ikaria shall remain free to issue
press releases and public announcements regarding the Development,
Manufacturing, Commercialization and use of Products in the Field, provided that Ikaria shall
provide BioLineRx with advance notice of at least [***] days prior to public
disclosure of such releases and announcements or such shorter period as required
to comply with any applicable law.  In addition, BioLineRx shall
reasonably implement any changes that Ikaria may recommend with respect to any
filing to be made in accordance with the rules or regulations of the SEC or any
similar regulatory agency in a country other than the United States or of any
stock exchange, including the Tel Aviv Stock Exchange; provided that such Ikaria
shall only have the right to comment upon portions of such filings that directly
related to Ikaria or this Agreement.  Nothing in the foregoing shall
require BioLineRx to implement any change that Ikaria may recommend that is not
consistent with the rules or regulations of the Israel Securities Authority, Tel
Aviv Stock Exchange, the rules or regulations of the SEC, or any similar
regulatory agency in a country other than the United States or Israel, as
advised in writing by BioLineRx’s legal counsel.  BioLineRx’s legal
counsel will provide Ikaria confirmation of such advise.

     

    Section
6.7       Publications.  The
results of the Development Program may be published by a Party as part of a
scientific presentation or publication only after scientific review by and
approval of the Joint Development Committee unless the other Party, acting
reasonably, disapproves of the presentation or publication in writing within
[***] days after receipt of the presentation or publication.  Either
Party may require that such Party’s Confidential Information be redacted from
such presentation or publication and may reasonably require that other
information also be redacted.  In addition, at the request of either
Party, the date of submission for presentation or publication shall be delayed
for a period of time sufficiently long to permit a Party to seek appropriate
patent protection.  Other than as provided for herein, BioLineRx shall
not make any publication regarding any Product or containing any Confidential
Information of Ikaria without the prior written consent of
Ikaria.  Notwithstanding the foregoing, to the extent necessary or
appropriate as determined in Ikaria’s discretion, Ikaria may disclose
information otherwise covered by this Section 6.7 in documents filed with the
SEC.

     

    [***]
Redacted pursuant to a confidential treatment request.

     

    
      
        
        

      

      
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    Article
VII

    Representations and
Warranties

     

    Section
7.1       Representations of
Authority.  BioLineRx and Ikaria each represents and warrants
to the other Party that, except for the consent of the OCS, it has full
corporate right, power and authority to enter into this Agreement and to perform
its respective obligations under this Agreement and that it has the right to
grant to the other Party the rights and licenses granted pursuant to this
Agreement.

     

    Section
7.2       Consents.  BioLineRx
and Ikaria each represents and warrants to the other Party that, except for the
consent of the OCS, all necessary consents, approvals and authorizations of all
government authorities and other Persons required to be obtained by it as of the
date hereof in connection with the execution, delivery and performance of this
Agreement have been obtained.

     

    Section
7.3       No
Conflict.  BioLineRx and Ikaria each represents and warrants to
the other Party that, notwithstanding anything to the contrary in this
Agreement, except for the consent of the OCS, the execution and delivery of this
Agreement, the performance of such Party’s obligations in the conduct of the
collaboration and the licenses and rights to be granted pursuant to this
Agreement (a) do not conflict with or violate any requirement of applicable laws
or regulations existing as of the date hereof and (b) do not conflict with,
violate, breach or constitute a default under any contractual obligations of
such Party or any of its Affiliates existing as of the date hereof.

     

    Section
7.4       Enforceability.  BioLineRx
and Ikaria each represents and warrants to the other Party that this Agreement
is a legal and valid obligation binding upon it and is enforceable against it in
accordance with its terms.

     

    Section
7.5       Additional BioLineRx
Representations.  BioLineRx represents and warrants to Ikaria
that:

     

    (a)      BioLineRx
has the right to grant the licenses granted to Ikaria on the terms set forth in
this Agreement;

     

    (b)      BioLineRx
is not engaged with any Third Party in any Development efforts directed to
Products in the Field in the Territory other than with respect to the On-Going
Phase I/II Trial, the Other On-Going Trials or the Existing Product
Agreements;

     

    (c)      BioLineRx
has provided Ikaria with true and complete copies of each of the Existing
Product Agreements, each of which is in full force and effect in accordance with
its terms as of the date hereof, and has obtained all consents necessary for the
assignment to Ikaria of each of the Existing Product Agreements hereunder, and,
following such assignment, Ikaria shall have the legal right to exercise all
rights of BioLineRx that existed thereunder immediately prior to such
assignment;

    


    
      
        
           


        

        
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    (d)      to
BioLineRx’s Knowledge, the BioLineRx Patent Rights listed in Exhibit B are valid
and enforceable and constitute all of the Patent Rights necessary or useful for
Ikaria to fully exercise and enforce its rights hereunder;

     

    (e)      to
BioLineRx’s Knowledge, the BioLineRx Patent Rights are not being infringed and
the BioLineRx Know-How is not being misappropriated by any Third
Party;

     

    (f)       BioLineRx
owns the entire right, title and interest in and to the BioLineRx Intellectual
Property (other than the Sublicensed IP) free and clear of any liens, charges,
claims and encumbrances, and no other Person has any claim of ownership or right
to obtain compensation with respect to such BioLineRx Intellectual
Property;

     

    (g)      to
BioLineRx’s Knowledge, the Products developed in the Development Program and the
Development, Manufacture and Commercialization of such Products will not
infringe or misappropriate any intellectual property rights not licensed to
Ikaria hereunder; and

     

    (h)      BioLineRx
has not received and has no Knowledge of any claim or demand of any Person
pertaining to, or any proceeding which is pending or threatened that asserts,
the invalidity, misuse or unenforceability of the BioLineRx Patent Rights or
that challenges BioLineRx’s ownership of the BioLineRx Intellectual Property or
that makes any adverse claim with respect thereto, and, to the Knowledge of
BioLineRx, there is no basis for any such claim, demand or
proceeding.

     

    Section
7.6       BGN License
Agreement.  BioLineRx represents, warrants and covenants to
Ikaria that:

     

    (a)      BioLineRx
has provided Ikaria with a true and complete copy of the BGN License Agreement,
which is in full force and effect in accordance with its terms as of the date
hereof;

     

    (b)      BioLineRx
shall obtain and provide to Ikaria within ten (10) days of execution of this
Agreement a written statement from BGN certifying that the terms of this
Agreement are consistent with those of the BGN License Agreement, including in
the context of Section 13.4.1(c) thereof;

     

    (c)      BioLineRx
has (i) achieved by its designated performance date each Milestone (as that term
is defined in the BGN License Agreement) having a designated performance date on
or before the date hereof, or obtained a waiver in respect thereof, and (ii)
neither (A) committed any material breach of the its obligations under the BGN
License Agreement nor (B) received any notice from BGN of any alleged material
breach thereof by BioLineRx or of any Failure (as that term is defined
therein);

     

    (d)      BioLineRx
shall upon receipt by BioLineRx promptly provide Ikaria with a copy of any
notice from BGN described in the foregoing clause (c)(ii)(B);

    


    
      
        
           


        

        
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    (e)      BioLineRx
shall not terminate, amend, supplement or otherwise modify the BGN License
Agreement without Ikaria’s prior written consent;

     

    (f)       the
rights and obligations of BioLine Jerusalem L.P. under the BGN License Agreement
have been assigned and delegated, or otherwise transferred, to
BioLineRx;

     

    (g)      as
between BioLineRx and Ikaria, BioLineRx shall be responsible for any and all
payments to be made under the BGN License Agreement;

     

    (h)      in
the event of any termination of the BGN License Agreement, BioLineRx shall, at
Ikaria’s request, provide all reasonable assistance to Ikaria in Ikaria’s
efforts to obtain from BGN an exclusive license to the Sublicensed IP, including
through enforcement of the provisions of Sections 5.2.3 and 13.4.1(c) of the BGN
License Agreement.

     

    Section
7.7       Employee, Consultant and
Advisor Legal Obligations.  BioLineRx and Ikaria each
represents and warrants that each of its and its Affiliates’ employees,
consultants and advisors who is or will be involved in performing any
obligations hereunder has executed or will have executed an agreement or have an
existing obligation under law requiring assignment to such Party of all
intellectual property made during the course of and as the result of his, her or
its association with such Party or such Affiliate, and obligating such employee,
consultant or advisor to maintain the confidentiality of Confidential
Information to the extent required under Article VI.  BioLineRx and
Ikaria each represents and warrants that, to its Knowledge, none of its or its
Affiliates’ employees, consultants or advisors who is or will be involved in
performing any obligations hereunder is, as a result of the nature of such
obligations to be performed by the Parties, in violation of any covenant in any
contract relating to non-disclosure of proprietary information, non-competition
or non-solicitation.

     

    Section
7.8       Accuracy of Representations
and Warranties on Effective Date.  The representations and
warranties of each of the Parties set forth in the preceding sections of this
Article VII remain true and accurate on and as of the Effective
Date.  Each Party shall promptly following receipt of acceptable
consent from the OCS deliver to the other Party a certificate to such effect
executed by its Chief Executive Officer.

     

    Section
7.9       No
Warranties.  EXCEPT AS OTHERWISE EXPRESSLY SET FORTH IN THIS
AGREEMENT, THE PARTIES MAKE NO REPRESENTATIONS AND EXTEND NO WARRANTIES OF ANY
KIND, EITHER EXPRESS OR IMPLIED, INCLUDING THAT ANY PRODUCTS WILL BE
ECONOMICALLY OR TECHNICALLY UTILIZABLE, THAT ANY SALES OF ANY PRODUCTS WILL
OCCUR, THAT THE DEVELOPMENT PROGRAM ACTIVITIES WILL BE COMPLETED IN THE EXPECTED
TIMEFRAME, OR THAT ANY PRODUCT WILL BE FREE OF ANY THIRD PARTY
RIGHTS.

     

    Article
VIII

    Term and
Termination

     

    Section
8.1       Term.  The
term of this Agreement shall begin on the Effective Date, may be terminated as
set forth in this Article VIII, and shall expire on a Product-by-Product and
country-by-country basis upon the date of expiration of the Royalty Term for
such Product in such country, and shall expire in its entirety upon the
last-to-expire Royalty Term, unless earlier terminated as set forth in this
Article VIII.

    


    
      
        
           


        

        
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    Section
8.2       Termination for Material
Breach.  Upon any breach of a material provision of this
Agreement by a Party (the “Breaching Party”),
the other Party (the “Non-Breaching Party”)
may terminate this Agreement by providing ninety (90) days written notice to the
Breaching Party specifying the material breach.  The termination shall
become effective at the end of the notice period unless the Breaching Party
cures such breach during such notice period.  Ikaria may terminate
this Agreement pursuant to this Section 8.2 immediately upon any termination of
the BGN License Agreement.

     

    Section
8.3       Development-Related
Termination.  Ikaria shall have the right to terminate this
Agreement upon sixty (60) days prior written notice, if Ikaria at any time
determines, in its sole judgment, that the results of the Development Program do
not warrant further Development of Products.

     

    Section
8.4       Effect of Certain
Terminations and Expiration.

     

    (a)      If
this Agreement is terminated by Ikaria under Section 8.2:

     

    (i)       The
licenses granted by BioLineRx to Ikaria under Section 2.1 and, notwithstanding
any other provision in this Agreement to the contrary, Ikaria’s obligations
under Section 4.2, shall survive;

     

    (ii)      Section
2.2 shall survive until Ikaria is no longer obligated to pay royalties to
BioLineRx under Section 4.2; and

     

    (iii)     Section
5.1 and Section 5.3 shall survive.

     

    (b)      If
this Agreement is terminated by either BioLineRx under Section 8.2, or by Ikaria
under Section 8.3, the licenses granted under Section 2.1 shall terminate as of
the effective date of such termination; provided, however, that Ikaria,
its Affiliates, and its Licensees shall be afforded a commercially reasonable
period of time (but no less than [***] months) to sell off any then existing or
in process stocks of the Products, subject to the terms and conditions of this
Agreement, including the payment of royalties thereon.

     

    (c)      Upon
any termination or expiration of this Agreement, each Party shall return to the
other Party any tangible property owned by the other Party, including any books
and records and Confidential Information, in accordance with the reasonable
instructions given by the other Party, with any shipping costs to be borne by
the other Party, provided, however, that a Party may
retain a copy of any regulatory records it is required to maintain in accordance
with applicable law.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
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    Section
8.5       Survival.  In
the event of any expiration or termination of this Agreement, (a) all financial
obligations under Article IV and Article V owed as of the effective date of such
expiration or termination shall remain in effect, including such obligations
that have accrued, but have not been invoiced, as of such effective date, and
(b) the obligations set forth in Section 5.1, Article VI, Article IX and Article
X, and all other terms, provisions, representations, rights and obligations
contained in this Agreement that by their express terms survive expiration or
termination of this Agreement (including Section 8.4 and this Section 8.5),
shall survive and all other terms, provisions, representations, rights and
obligations contained in this Agreement shall terminate.

     

    Section
8.6       Termination Prior to
Effective Date.  Notwithstanding anything to the contrary in
this Article VIII, Ikaria may terminate this Agreement prior to the Effective
Date, with no liability to BioLineRx, if the OCS does not consent to the
Agreement in a form reasonably satisfactory to both Parties within forty-five
(45) days after the execution of this Agreement.  The provisions of
Article X (except for Section 10.1(a)) and this Section 8.6 shall survive such
termination, and all other terms, provisions, representations, rights and
obligations contained in this Agreement shall terminate.

     

    Article
IX

    Dispute
Resolution

     

    Section
9.1       Negotiation.  Any
controversy, claim or dispute arising out of or relating to this Agreement shall
be settled, if possible, through good faith negotiations between the
Parties.

     

    Section
9.2       Escalation.  If
the Parties are unable to settle any dispute after good faith negotiations
pursuant to Section 9.1 after [***] days, such dispute (except for any matter
that by its express terms shall be resolved as provided in this Agreement,
including any matter arising under Section 3.2 or Section 3.6) shall be referred
to the Executive Officers to be resolved by negotiation in good faith as soon as
is practicable but in no event later than [***] days after
referral.

     

    Section
9.3       Mediation.  Solely
with respect to a dispute as to whether Ikaria has breached its obligations to
use Commercially Reasonable Efforts as set forth in Section 3.8, if the
Executive Officers are unable to settle such dispute after good faith
negotiations pursuant to Section 9.2 within [***] days after referral to the
Executive Officers, the Parties shall, within [***] days thereof, engage a
mutually agreeable Third Party mediator on a non-binding basis to assist the
Parties in determining whether such a breach has occurred.  The
Parties agree that they will participate in good faith in an effort to resolve
the dispute in an informal, inexpensive and expeditious manner and that any
mediator selected shall agree to render any judgments in a timely manner, but no
later than [***] days after the mediator is selected.  All expenses of
the mediator will be shared equally by the Parties.

     

     [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
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    Section
9.4       Litigation.  If
the Executive Officers are unable to settle any dispute after good faith
negotiations pursuant to Section 9.2 (other than a dispute as to whether Ikaria
has breached its obligations to use Commercially Reasonable Efforts as set forth
in Section 3.8) within [***] days after referral, or if the Parties continue to
dispute whether Ikaria has breached its obligations to use Commercially
Reasonable Efforts as set forth in Section 3.8 following mediation pursuant to
Section 9.3, then either Party may seek resolution of the dispute (except for
any matter that by its express terms shall be resolved as provided in this
Agreement, including any matter arising under Section 3.2 or Section 3.6)
through remedies available at law or in equity from any court of competent
jurisdiction as set forth in Section 10.3.

     

    Section
9.5       Equitable
Relief.  Each Party acknowledges and agrees that the other
Party would be damaged irreparably if any of the provisions of Article II,
Article V and Article VI are not performed in accordance with their specific
terms or otherwise are breached.  Accordingly, each Party agrees that
the other Party shall be entitled to an injunction or other equitable relief to
prevent breaches of such provisions, to preserve status quo, and to enforce
specifically such provisions in any action instituted in any court having
jurisdiction over the Parties and the matter, in addition to any other remedy to
which it may be entitled, at law or in equity.

     

    Article
X

    Miscellaneous
Provisions

     

    Section
10.1     Indemnification.

     

    (a)      By
Ikaria.  Ikaria agrees to defend BioLineRx, its Affiliates and
their respective directors, officers, employees and agents at Ikaria’s cost and
expense, and shall indemnify and hold harmless BioLineRx and its Affiliates and
their respective directors, officers, employees and agents from and against any
liabilities, losses, costs, damages, fees or expenses (collectively, “Losses”) arising out
of any Third Party claim to the extent relating to (i) any breach by Ikaria
of any of its representations, warranties or obligations pursuant to this
Agreement, or (ii) personal injury, property damage, product liability or
other damage resulting from the Development, Manufacture, use or
Commercialization of a Product by Ikaria or its Affiliates or Licensees,
excluding any claim for which BioLineRx indemnifies Ikaria under subsection (b)
below.

     

    (b)      By
BioLineRx.  BioLineRx agrees to defend Ikaria, its Affiliates
and their respective directors, officers, employees and agents at BioLineRx’s
cost and expense, and shall indemnify and hold harmless Ikaria and its
Affiliates and their respective directors, officers, employees and agents from
and against any Losses arising out of any Third Party claim to the extent
relating to (i) any breach by BioLineRx of any of its representations,
warranties or obligations pursuant to this Agreement, (ii) personal injury,
property damage or other damage resulting from the conduct of the On-Going Phase
I/II Trial or the Other On-Going Trials by or on behalf of BioLineRx or its
Affiliates, (iii) the BGN Agreement, or (iv) any allegation that the practice of
the BioLineRx Intellectual Property rights in the Development Program infringes
or misappropriates any Third Party intellectual property rights, to the extent
BioLineRx had Knowledge that such practice would infringe or misappropriate such
Third Party intellectual property rights on or before the Effective
Date.

    


    
      
        
           


        

        
          32

          
            

          

        

        
           


        

      

    

    


    (c)      Claims for
Indemnification.  A Person entitled to indemnification under
this Section 10.1 (an “Indemnified Party”)
shall give prompt written notification to the Party from whom indemnification is
sought (the “Indemnifying Party”)
of the commencement of any action, suit or proceeding relating to a Third Party
claim for which indemnification may be sought or, if earlier, upon the assertion
of any such claim by a Third Party (it being understood and agreed, however,
that the failure by an Indemnified Party to give notice of a Third Party claim
as provided in this Section 10.1(c) shall not relieve the Indemnifying Party of
its indemnification obligation under this Agreement except and only to the
extent that such Indemnifying Party is actually damaged as a result of such
failure to give notice).  Within [***] days after delivery of such
notification, the Indemnifying Party may, upon written notice thereof to the
Indemnified Party, assume control of the defense of such action, suit,
proceeding or claim with counsel reasonably satisfactory to the Indemnified
Party.  If the Indemnifying Party does not assume control of such
defense, the Indemnified Party shall control such defense.  The Party
not controlling such defense may participate therein at its own
expense.  The Party controlling such defense shall keep the other
Party advised of the status of such action, suit, proceeding or claim and the
defense thereof and shall consider recommendations made by the other Party with
respect thereto.  The Indemnified Party shall not agree to any
settlement of such action, suit, proceeding or claim without the prior written
consent of the Indemnifying Party, which consent the Indemnifying Party shall
not unreasonably withhold, condition or delay.  The Indemnifying Party
shall not agree, without the prior written consent of the Indemnified Party,
which consent the Indemnified Party shall not unreasonably withhold, condition
or delay, to any settlement of such action, suit, proceeding or claim or consent
to any judgment in respect thereof that does not include a complete and
unconditional release of the Indemnified Party from all liability with respect
thereto or that imposes any liability or obligation on the Indemnified
Party.

     

    Section
10.2     Governing
Law.  This Agreement shall be construed and the respective
rights of the Parties determined in accordance with the laws of the State of New
York, USA (other than any principle of conflict or choice of laws that would
cause the application of the laws of any other jurisdiction).

     

    Section
10.3     Submission to
Jurisdiction.  Each Party (a) submits to the jurisdiction
of any state or federal court sitting in the State of New York, USA in any
action or proceeding arising out of or relating to this Agreement,
(b) agrees that all claims in respect of such action or proceeding may be
heard and determined in any such court, (c) waives any claim of
inconvenient forum or other challenge to venue in such court, and (d) agrees not
to bring any action or proceeding arising out of or relating to this Agreement
in any other court, unless the state or federal courts sitting in the State of
New York decline to exercise jurisdiction over any such action or proceeding or
if those courts lack proper jurisdiction, then any action or proceeding arising
out of or relating to this Agreement may be brought in any other U.S. court of
competent jurisdiction.  Each Party agrees to accept service of any
summons, complaint or other initial pleading made in the manner provided for the
giving of notices in Section 10.6, provided that nothing in this
Section 10.3 shall affect the right of either Party to serve such summons,
complaint or other initial pleading in any other manner permitted by
law.

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          33

          
            

          

        

        
           


        

      

    

    


    Section
10.4     Assignment.  Ikaria
may assign this Agreement or any right hereunder, or delegate any obligation
hereunder, in its sole discretion, to (a) any Affiliate of Ikaria or (b) any
entity acquiring all or substantially all of the assets of Ikaria Holdings, Inc.
and its Affiliates.  All other assignments by Ikaria, including (i) to
any entity acquiring all or substantially all of the assets of Ikaria to which
this Agreement relates or (ii) to any entity with which or into which Ikaria may
consolidate or merge, are subject to BioLineRx’s prior approval, which approval
shall not be unreasonably withheld, conditioned or delayed.  BioLineRx
may assign its right to receive payments hereunder to a Third Party, in its sole
discretion, but BioLineRx shall not otherwise be permitted to assign this
Agreement, in whole or in part, without the prior written consent of Ikaria,
which approval shall not be unreasonably withheld, conditioned or
delayed.  Any assignments in contravention of this Section 10.4 shall
be null and void.

     

    Section
10.5     Entire Agreement;
Amendments.  This Agreement constitutes the entire agreement
between the Parties with respect to the subject matter hereof, and supersedes
all previous arrangements between the Parties with respect to the subject matter
hereof, whether written or oral, except for that certain Mutual Non Disclosure
Agreement between the Parties dated February 25, 2009.  Without
limiting the generality of the foregoing, this Agreement hereby supersedes and
replaces in its entirety the License and Commercialization Agreement by and
among the parties dated as of July 5th,
2009.  To the extent that any provision of this Agreement conflicts
with any provisions of such Mutual Non Disclosure Agreement, the provision of
this Agreement shall control.  Except as set forth in Section 2.1(iv),
any amendment or modification to this Agreement shall be made in writing signed
by both Parties.

     

    Section
10.6     Notices.

     

    Notices
to Ikaria shall be addressed to:

    


    Ikaria
Development Subsidiary One LLC

    6 State
Route 173

    Clinton,
NJ 08809, USA

    Attention:
Chief Executive Officer

    


    with copy
to:

    


    Ikaria
Holdings, Inc.

    6 State
Route 173

    Clinton,
NJ 08809, USA

    Attention:
General Counsel

    


    Notices
to BioLineRx Ltd. shall be addressed to:

    


    BioLineRx
Ltd.

    19 Hartum
Street

    P.O. Box
45158

    Jerusalem
91450, Israel

    Attention:  Chief
Executive Officer

    


    
      
        
           


        

        
          34

          
            

          

        

        
           


        

      

    

    


    with copy
to:

    


    Arent Fox
LLP

    1050
Connecticut Avenue

    Washington,
DC  20036, USA

    Attention:
John Dwyer, Esq.

    


    Notices
to BioLine Innovations Jerusalem L.P. shall be addressed to:

    


    BioLine
Innovations Jerusalem L.P.

    19 Hartum
Street

    P.O. Box
45158

    Jerusalem
91450, Israel

    Attention:  Chief
Executive Officer

    


    with copy
to:

    


    Arent Fox
LLP

    1050
Connecticut Avenue

    Washington,
DC  20036, USA

    Attention:
John Dwyer, Esq.

    


    Any Party
may change its address by giving notice to the other Party in the manner herein
provided.  Any notice required or provided for by the terms of this
Agreement shall be in writing and shall be (a) sent by registered or certified
mail, return receipt requested, postage prepaid, (b) sent via a reputable
international courier service, (c) sent by facsimile transmission, or (d)
personally delivered, in each case properly addressed in accordance with the
paragraph above.  The effective date of notice shall be the actual
date of receipt by the Party receiving the same.

     

    Section
10.7     Force
Majeure.  No failure or omission by a Party in the performance
of any obligation of this Agreement shall be deemed a breach of this Agreement
or create any liability if the same shall arise from any cause or causes beyond
the control of such Party, including the following: acts of God; fire; storm;
flood; earthquake; accident; war; rebellion; insurrection; riot; and invasion
(each such event, a “Force Majeure Event”)
and provided
that such Party
cures such failure or omission resulting from one of the above causes as soon as
is practicable after the occurrence of one or more of the above-mentioned
causes.

     

    Section
10.8     Independent
Contractors.  It is understood and agreed that the relationship
between the Parties hereunder is that of independent contractors and that
nothing in this Agreement shall be construed as authorization for either
BioLineRx or Ikaria to act as agent for the other.

     

    Section
10.9     Limitations of
Liability.  NEITHER PARTY SHALL BE LIABLE FOR ANY INDIRECT,
INCIDENTAL, CONSEQUENTIAL, SPECIAL, EXEMPLARY OR PUNITIVE DAMAGES ARISING OUT OF
THIS AGREEMENT OR THE EXERCISE OF ITS RIGHTS HEREUNDER, OR FOR LOST PROFITS
ARISING FROM OR RELATING TO ANY BREACH OF THIS AGREEMENT, REGARDLESS OF ANY
NOTICE OF SUCH DAMAGES.  NOTHING IN THIS SECTION 10.9 IS INTENDED TO
LIMIT OR RESTRICT (A) THE INDEMNIFICATION RIGHTS OR OBLIGATIONS OF EITHER PARTY
WITH RESPECT TO THIRD PARTY CLAIMS; (B) ANY LOSSES, INCLUDING LOST PROFITS,
ARISING FROM ANY (I) BREACH OF A PARTY’S OBLIGATIONS WITH RESPECT TO THE OTHER
PARTY’S CONFIDENTIAL INFORMATION, (II) BREACH BY BIOLINERX OF THE EXCLUSIVE
RIGHTS GRANTED IN SECTION 2.1 OR THE COVENANT CONTAINED IN SECTION 2.2, OR (III)
USE OF ANY PATENT RIGHTS OR KNOW-HOW LICENSED HEREUNDER BEYOND THE SCOPE OF SUCH
LICENSE; OR (C) ANY LOSSES ARISING AS A RESULT OF A PARTY’S FRAUD, GROSS
NEGLIGENCE OR WILLFUL MISCONDUCT.

    


    
      
        
           


        

        
          35

          
            

          

        

        
           


        

      

    

    


    Section
10.10   No Implied Waivers; Rights
Cumulative.  No failure on the part of BioLineRx or Ikaria to
exercise, and no delay in exercising, any right, power, remedy or privilege
under this Agreement, or provided by statute or at law or in equity or
otherwise, shall impair, prejudice or constitute a waiver of any such right,
power, remedy or privilege or be construed as a waiver of any breach of this
Agreement or as an acquiescence thereto, nor shall any single or partial
exercise of any such right, power, remedy or privilege preclude any further or
other exercise thereof or the exercise of any other right, power, remedy or
privilege.

     

    Section
10.11   Severability.  If,
under applicable law or regulation, any provision of this Agreement is invalid,
incomplete or unenforceable, or otherwise directly or indirectly affects the
validity of any other material provision(s) of this Agreement (such invalid,
incomplete or unenforceable provision, a “Severed Clause”),
this Agreement shall endure except for the Severed Clause.  The
Parties shall consult one another and use reasonable efforts to agree upon a
valid, complete and enforceable provision that is a reasonable substitute for
the Severed Clause in view of the intent of this Agreement.

     

    Section
10.12   Execution in Counterparts;
Facsimile Signatures.  This Agreement may be executed in
counterparts, each of which, when so executed and delivered, shall be deemed to
be an original, and all of which, taken together, shall constitute one and the
same instrument even if both Parties have not executed the same
counterpart.  Signatures provided by facsimile transmission shall be
deemed to be original signatures.

     

    REMAINDER
OF PAGE LEFT EMPTY; NEXT PAGE IS THE SIGNATURE PAGE

    


    
      
        
           


        

        
          36

          
            

          

        

        
           


        

      

    

    


    IN
WITNESS WHEREOF, the Parties have executed this License and Commercialization
Agreement as of the Effective Date.

     

    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    
                                      
                                        
                                          
                                            
                                              	
                                                      IKARIA
      DEVELOPMENT SUBSIDIARY ONE LLC

                                                    	 
	 
      	 
	
                                                      By:

                                                    	
                                                      /s/
      Matthew M. Bennett

                                                    	 
	
                                                      Name:

                                                    	
                                                      Matthew
      M. Bennett

                                                    	 
	
                                                      Title:

                                                    	
                                                      Senior
      Vice President

                                                    	 
	 
      	 
	
                                                      BIOLINERX
      LTD.

                                                    	 
	 
      	 
	
                                                      By:

                                                    	
                                                      /s/
      Morris Laster M.D.

                                                    	 
	
                                                      Name:

                                                    	
                                                      Morris
      Laster M.D.

                                                    	 
	
                                                      Title:

                                                    	
                                                      CEO

                                                    	 
	 
      	 
	
                                                      BIOLINE
      INNOVATIONS JERUSALEM L.P.

                                                      by
      its General Partner, BioLine Innovations Jerusalem, Ltd.

                                                    	 
	 
      	 
	
                                                      By:

                                                    	
                                                      /s/
      Morris Laster M.D.

                                                    	 
	
                                                      Name:

                                                    	
                                                      Morris
      Laster M.D.

                                                    	 
	
                                                      Title:

                                                    	
                                                      Director

                                                    	 


                                            

                                          

                                        

                                      

                                    

                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

    

    


    
      
        
           


        

        
          37

          
            

          

        

        
           


        

      

    

    


    SCHEDULE
1.30

     

    PROTOCOL FOR ON-GOING PHASE
I/II TRIAL

     

    [PROTOCOL IMMEDIATELY
FOLLOWS]

    
 

    
      
        
           


        

        
           


          
            

          

        

        
           


        

      

    

      

     

    
      


      CLINICAL
STUDY


      


      Protocol
No. BL-1040.01

      Version
5.00 Incorporating Amendments 1, 2, 3 and 4

      Safety
and Feasibility

      Final

       

      
        A
Phase I, multi-center, open label study designed to assess the safety and
feasibility of the injectable BL-1040 implant to provide scaffolding to
infarcted myocardial tissue

      

      
         

      

      BioLine
Innovations Jerusalem

       

      Confidentiality
Statement

      


      This
document contains information that is the property of BioLine Innovations
Jerusalem and therefore is provided to you in confidence for review by you, your
staff, an applicable ethics committee/institutional review board and regulatory
authorities. It is understood that this information will not be disclosed to
others without written approval from BioLine Innovations Jerusalem, except to
the extent necessary to obtain informed consent from those persons to whom
BL-1040 may be administered.

       

      
        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment 4


        01
December 2008

      

       

      
        
          
          

        

        
          
          

          
            

          

        

        
          
          

        

      

       

      
        	
                 

              	 	
                Protocol
      BL-1040.01, Version 5.00

                Safety
      and Feasibility study of BL-1040

                Final

              	 	
                CONFIDENTIAL

              


      

       

      
        	
                PROTOCOL
      NUMBER:

              	 	
                BL-1040.01
      Safety and Feasibility

              
	 
      	 	 
      
	
                DATE
      OF PROTOCOL:

              	 	
                Final,
      01 December
      2008

              
	 
      	 	
                Version
      2 incorporating Amendment 1, 07 August 2007

              
	 
      	 	
                Version
      3 incorporating Amendment 2, 03 December 2007

              
	 
      	 	
                Version
      4 incorporating Amendment 3, 17 April 2008

              
	 
      	 	
                Version
      5 incorporating Amendment 4, 27 November 2008

              
	 
      	 	 
      
	
                PROTOCOL
      TITLE:

              	 	
                A
      Phase I, multi-center, open label study designed to assess the safety and
      feasibility of the injectable BL-1040 implant to provide scaffolding to
      infarcted myocardial tissue

              
	 
      	 	 
      
	
                SPONSOR:

              	 	
                BioLine
      Innovations Jerusalem

              


      

      


      Responsible study
personnel:

      


      
        	
                Name:

              	 	
                Prof.
      Moshe Phillip, MD, Vice-President of Medical Affairs, Sr. Clinical
      Advisor

              
	
                Address:

              	 	
                BioLine
      Innovations Jerusalem, 19 Hartum St., POB 45158 Jerusalem, Israel
      91450

              
	 
      	 	 
      
	
                Phone:

              	 	
                +972-2-548-9100

              
	
                Fax:

              	 	
                +972-2-548-9101

              
	
                e-mail:

              	 	
                moshep@
      biolinerx.com

              
	 
      	 	 
      
	
                Name:

              	 	
                Shmuel
      Tuvia, PhD

              
	
                Address:

              	 	
                BioLine
      Innovations Jerusalem, 19 Hartum St., POB 45158 Jerusalem, Israel
      91450

              
	 
      	 	 
      
	
                Phone:

              	 	
                +972-2-548-9100,
      ext. 124

              
	
                Fax:

              	 	
                +972-2-548-9101

              
	
                e-mail:

              	 	
                shmuelt@biolinerx.com

              
	 
      	 	 
      
	
                Name:

              	 	
                Moti
      Gal, Clinical Operations Manager

              
	
                Address:

              	 	
                BioLine
      Innovations Jerusalem, 19 Hartum St., POB 45158 Jerusalem, Israel
      91450

              
	 
      	 	 
      
	
                Phone:

              	 	
                +972-2-548-9100,
      ext. 147

              
	
                Fax:

              	 	
                +972-2-548-9101

              
	
                e-mail:

              	 	
                motig@biolinerx.com

              
	 
      	 	 
      
	
                Name:

              	 	
                Jonathan
      Leor, MD, Medical Advisor

              
	
                Address:

              	 	
                Head,
      Neufeld Cardiac Research Institute.

              
	 
      	 	
                Tel-Aviv
      University

              
	 
      	 	
                Sheba
      Medical Center

              
	 
      	 	
                Tel-Hashomer,
      Israel 52621

              
	
                Phone:

              	 	
                +972-3-534-8685,
      972-3-530-2614

              
	
                Fax:

              	 	
                +972-3-535-1139

              
	
                e-mail:

              	 	
                leorj@post.tau.ac.il

              
	 
      	 	 
      
	
                CRO:

              	 	
                Averion
      International

              
	
                Address:

              	 	
                Gewerbestrasse
      24, CH-4123 Allschwil, Switzerland

              
	
                Phone:

              	 	
                +41-61-487-1400

              
	
                Fax:

              	 	
                +41-61-487-1401

              


      

       

      
        	
                Authorized
      representative:

              	 	
                Voisin
      Consulting

              
	
                Address:

              	 	
                3,
      rue des Longs Prés, 92100 Boulogne, France

              
	
                Phone:

              	 	
                +33-1-41-31-8300

              
	
                Fax:

              	 	
                +33-1
      41-31-8309

              
	
                e-mail:

              	 	
                voisin@voisinconsulting.com

              


      

       

      
        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008

      

       

      
        
          
          

        

        
          Page 2 of
52

          
            

          

        

        
          
          

        

      

       

      
        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	e-mail: 	 	voisin@voisinconsulting.com 
	
                Medical
      Monitor, US (ISMB support only) 

              
	
                Name:

              	 	
                Kenneth
      Carlson, MD

              
	
                Address:

              	 	
                Averion
      International Corp.

              
	 
      	 	
                800
      Westchester Ave.

              
	 
      	 	
                Suite
      N341

              
	 
      	 	
                Rye
      Brook, NY, USA 10573

              
	
                Phone:

              	 	
                +914-733-3410

              
	
                Fax:

              	 	
                +914-6943293

              
	
                e-mail:

              	 	
                ken.carlson@averionintl.com

              
	 
      	 	 
      
	 
      	 	 
      
	
                Medical
      Monitor, Europe

              	 	 
      
	
                Name:

              	 	
                Christian
      Tuéni, MD

              
	
                Address:

              	 	
                Averion
      Clinical Research GmbH

              
	 
      	 	
                Pykergasse
      10/6

              
	 
      	 	
                1190
      Vienna, Austria

              
	
                Phone:

              	 	
                +43-1-367
      00-88-11

              
	
                Fax:

              	 	
                +43-1-367
      00-88-10

              
	
                e-mail:

              	 	
                christian.tueni@averionintl.com

              


      

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


      

      
        
          
          

        

        
          Page 3 of
52

          
            

          

        

        
          
          

        

      

      
         

        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      Investigator’s
Signature Page

      


      INVESTIGATOR:

      


      
        	
                Name:

                 

                Address:

              	 
      
	
                Phone:

                Fax:

                e-mail:

              	 
      


      

       

      I, the
undersigned, have reviewed this Protocol, including Appendices, and I will
conduct the clinical study as described and will adhere to GCP/ICH and all the
ethical and regulatory considerations stated. I have read and understood the
contents of the Investigator Brochure.

      


      
        
          	
                  Date/Place _______________________

                	 	 	
                  Signature _______________________

                  
                    (Name
      of Investigator)

                  

                	 


        

        
           

          Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

          01 December
2008


        

        
          
            
            

          

          
            Page 4 of
52

            
              

            

          

          
            
            

          

        

      

      
         

        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      Sponsor
Signature Page

      


      


      
        	
                Sponsor:

                Address:

              	
                BioLine
      Innovations Jerusalem

                19
      Hartum St., POB 45158

                Jerusalem,
      Israel 91450

              
	 	 
	
                Phone:

                Fax:

                e-mail:

              	
                +972-2-548-9100

                +972-2-548-9101

                info@biolineRx.com

              


      

      


      I have
read the protocol and confirm that the protocol follows the current GCP
guidelines.


      
        


        
          
            	
                    Date/Place _______________________

                  	 	 	
                    Signature _______________________

                    
                      (Prof
      Moshe Phillip, VP of Medical Affairs, Sr. Clinical
      Advisor)

                    

                  	 


          

           

          
            
              	
                      Date/Place _______________________

                    	 	 	
                      Signature _______________________

                      
                        (Shmuel
      Tuvia, PhD, Project Manager)

                      

                    	 


            

             

            
              
                	
                        Date/Place _______________________

                      	 	 	
                        Signature _______________________

                        
                          (Moti
      Gal, Clinical Operations Manager)

                        

                      	 


              

            

          

        

      

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


      

      
        
          
          

        

        
          Page 5 of
52

          
            

          

        

        
          
          

        

      

      
         

        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      Medical
Advisor Signature Page


      


      
        	
                Name:

                Address:

              	
                Prof
      Jonathan Leor, MD

                Head,
      Neufeld Cardiac Research Institute.

                Tel-Aviv
      University

                Sheba
      Medical Center

                Tel-Hashomer
      52621

                Israel

              
	 	 
	
                Phone:

                Fax:

              	
                +972-3-534-8685

                +972-3-5351139

              


      

      


      I have
read the protocol and confirm that the protocol follows the current GCP
guidelines.


      
        


        
          
            	
                    Date/Place _______________________

                  	 	 	
                    Signature _______________________

                    
                      (Jonathan
      Leor, MD, Medical Advisor)

                    

                  	 


          

           

          Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

          01 December
2008


           

          
            
              
              

            

            
              Page 6 of
52

              
                

              

            

            
              
              

            

          

        

      

      
         

        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      Synopsis

      


      
        	
                STUDY
      NUMBER

              	 	
                BL-1040.01

              
	 	 	 
	
                TITLE
      OF THE STUDY

              	 	
                A
      Phase I, multi-center, open label study designed to assess the safety and
      feasibility of the injectable BL-1040 implant to provide scaffolding to
      infarcted myocardial tissue

              
	 	 	 
	
                STUDY
      CENTER/ COUNTRY

              	 	
                Approximately
      10 centers in
      3 countries: Netherlands,
      Belgium, Germany, Israel

              
	 	 	 
	
                PLANNED
      STUDY 

                PERIOD
      +

                CLINICAL
      PHASE

              	 	
                Q1
      2008 to Q1 2010

                 

                Phase
      I

              
	 	 	 
	
                INDICATION
      AND RATIONALE

              	 	
                Heart
      failure after myocardial infarction (MI) is often precipitated by early
      and progressive extracellular matrix degradation and pathological
      remodeling of the left ventricle (LV). In response to MI, a series of
      molecular, cellular and physiological responses are triggered, which can
      lead to early infarct expansion (infarct thinning), which may result in
      early ventricular rupture or aneurysm formation and the transition to
      heart failure. Late remodeling involves the left ventricle globally and is
      associated with time-dependent dilatation, and the distortion of
      ventricular shape. The failure to normalize increased wall
      stresses results in progressive dilatation, recruitment of
      border zone myocardium into the infarct, and deterioration in contractile
      function. Current anti-remodeling therapies are clearly limited, as many
      ventricles continue to enlarge and mortality and morbidity remain
      significantly high.

                Based
      on the mechanism of LV remodeling, it has been hypothesized that injection
      of biomaterials into the infarct could thicken the infarct, arrest infarct
      expansion, prevent LV dilatation and reduce wall stress that initiates
      progressive adverse LV remodeling.

                BL-1040
      Myocardial Implant is a non-pharmacologic cross-linked alginate solution
      administered via intracoronary (IC) injection to infarcted tissue, forming
      a flexible, three-dimensional mechanical scaffold. BL-1040 Myocardial
      Implant presents a novel, safe and non-surgical therapy that directly
      addresses the stability and structural integrity of myocardial tissue
      while potentially preventing post infarction remodeling, primarily via
      limiting left ventricle dilation.

              
	 	 	 
	
                OBJECTIVES

              	 	
                · To evaluate
      the safety of the BL-1040 myocardial implant in patients after MI at high
      risk for LV remodeling and CHF.

              
	 
      	 	
                · To provide
      feasibility data in order to initiate and conduct a pivotal clinical study
      evaluating the safety and efficacy of the BL-1040 implant in patients
      following myocardial infarction.

              
	 	 	 
	
                ENDPOINTS

              	 	
                Primary
      safety endpoints

              
	 
      	 	
                Occurrence
      of all adverse events including but not limited to

              
	 
      	 	
                · All
      MIs

              
	 
      	 	
                ·
      Cardiovascular hospitalization

              
	 
      	 	
                · Serious
      ventricular arrhythmias sustained:

              
	 
      	 	
                · VT
      (symptomatic or sustained VT [duration longer than 30 seconds or 100
      beats, or associated with hemodynamic collapse])

              
	 
      	 	
                ·
      VF

              
	 
      	 	
                · symptomatic
      bradycardia, pauses of longer than 3.0 seconds, complete atrioventricular
      block, Mobitz II atrioventricular block

              
	 
      	 	
                · Symptomatic
      heart failure (NYHA criteria + physical examination OR hospitalization due
      to heart failure)

              
	 
      	 	
                · Renal
      failure

              
	 
      	 	
                ·
      Stroke

              
	 
      	 	
                ·
      Death

              


      

       

      Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

      01 December
2008


       

      
        
          
          

        

        
          Page 7 of
52

          
            

          

        

        
          
          

        

      

       

      
        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	 
      	 	
                Secondary
      safety endpoints

              
	 
      	 	
                · Change
      from baseline in LV dimensions (end-systolic volume index, end-diastolic
      volume index, left ventricular mass)

              
	 
      	 	
                · Change
      from baseline in regional (infarct related) and global wall motion
      score

              
	 
      	 	
                · Change
      from baseline in ejection fraction

              
	 
      	 	
                · Cardiac
      rupture

              
	 
      	 	
                · NT-proBNP

              
	 	 	 
	
                DESIGN

              	 	
                Multi-center,
      open label

              
	 	 	 	 	 
	
                PATIENTS

              	 	
                NUMBER

              	 	
                Maximum
      30

              
	 
      	 	
                MAIN
      INCLUSION CRITERIA

                 

              	 	
                · Signed
      informed consent

                · 18 to 75
      years of age, inclusive

                · Male or
      female

                · Negative
      pregnancy test for women of child-bearing potential, or surgically
      sterile, or post menopausal

                · Acute MI
      defined as:

                1.Typical
      rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of
      biochemical markers of myocardial necrosis with at least one of the
      following: a) ischemic symptoms; b) development of pathologic Qwaves on
      the ECG; c) ECG changes indicative of ischemia (ST segment elevation or
      depression)

                2.First
      anterior or inferolateral STEMI or Qwave MI (QMI Anterior: V1-V3 or V1-V4
      or V1-V5 or V1-V6.QMI Inferior: L2, L3, AVF, or L2, L3, AVF+ V5, V6 or L2,
      L3, AVF+ V6-V9 [posterior leads])

                3.Regional
      wall motion score index (at least 4 out of 16 akinetic
      segments)

                · One or more
      of the following:

                o LVEF >20%
      and <45% measured and calculated by 2-dimensional
      measurement

                o Biomarkers: peak CK
      > 2000 IU

                o Infarct size >
      25% as measured by MRI

                · Successful
      revascularization with PCI with 1 stent
      only, within 7 days of the index MI (only safe and MRI compatible
      stents)

                · At time of
      application of study device, patient must have patent infarct related
      artery (IRA) and TIMI flow grade = 3

              
	 
      	 	
                MAIN EXCLUSION
      CRITERIA

              	 	
                · History of
      CHF, Class I to Class IV, as per NYHA criteria

                · History of
      prior LV dysfunction

                · At time of
      application of study device - Killip III-IV (pulmonary edema, cardiogenic
      shock - hypotension [systolic < 90
      mmHg] and
      evidence of peripheral hypoperfusion [oliguria, cyanosis,
      sweating]) or HR
      > 100 bpm

                · Patient with
      pacemaker

                · Prior
      CABG

                · Prior
      MI

                · History of
      stroke

                · Significant
      valvular disease (moderate or severe)

                · Patient is a
      candidate for CABG or PCI on non-IRA

                · Patient is
      being considered for CRT within the next 30
days

              


      

       

      Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

      01 December
2008


       

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	 	 	 	 	
                · Renal
      insufficiency (eGFR < 60)

                · Chronic liver
      disease (> 3 times upper limit of normal)

                · Life
      expectancy < 12 months

                · Current
      participant in another clinical trial, or participation in another trial
      within the last 6 months

                · Any
      contraindication to coronary angiography, MRI or PCI
      procedures

                · Patient
      taking anti-coagulation medication prior to MI

                · Pregnant or
      lactating women; pregnancy confirmed by urine pregnancy
    test

              
	 	 	 	 	 
	
                STUDY
      DEVICE

              	 	
                ROUTE
      OF APPLICATION

              	 	
                Administered
      via intracoronary (IC) injection, using multiple commercially available
      devices

              
	 
      	 	
                DURATION
      AND FREQUENCY

              	 	
                2
      mL of BL-1040 administered for no longer than 30 seconds

              
	 
      	 	
                FORMULATION

              	 	
                Calcium
      D-Gluconate (Gluconic acid hemicalcium salt)

                PRONOVA
      UP VLVG (Generic name: Sodium Alginate)

                Water
      for Injection USP/EP

              
	 
	
                SAFETY
      EVALUATIONS

              
	
                TIMING
      AND ASSESSMENTS PERFORMED

              	 	
                Screening

                · 1st
      Coronary angiography, PCI and stent (as part of treatment of
      MI)

                · Physical
      examination

                · Vital
      signs

                · 12-lead
      ECG

                · Blood and
      urine sampling for laboratory safety parameters (biochemistry, hematology
      and urinalysis)

                · Total CK/CK
      MB

                ·
      NT-proBNP

                · Mandatory
      echocardiography; MRI as an additional measurement is
      encouraged

                 

                Telephone
      contact, 1 week post-procedure

                · Phone call to
      confirm status of patient discharged from the hospital

                 

                Day
      1 and during hospitalization

                · Physical
      examination daily during hospitalization

                · Vital signs
      daily during hospitalization

                · 12-lead ECG
      prior to and after administration of BL-1040; daily during
      hospitalization

                · 24 hour
      Holter monitor (after completion of 12-lead ECG)

                · Blood and
      urine sampling for laboratory safety parameters (biochemistry, hematology
      and urinalysis), on Day 1 (only if not done within
      the previous 48 hours) and on day of discharge (only if not done within
      the previous 48 hours)

                · Total CK/CK
      MB measured prior to, and 8, 16, 24 and 48 hours after administration of
      BL-1040

                · NT-proBNP on
      Day 1 (only if not done within the previous 48 hours) and on day of
      discharge (only if not done within the previous 48 hours)

                · continuous
      ECG during the procedure

                · 2nd cardiac
      catheterization (for implantation of BL-1040)

                · PTT or ACT
      measurements, during procedure only (prior to implantation of BL-1040 and
      prior to removal of sheath)

              


      

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


      

      
        
          
          

        

        
          Page 9 of
52

          
            

          

        

        
          
          

        

      

      
         

        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	 	 	
                Follow-up
      visits (Days 30, 90 180 [End of Study]; Months 12, 24, 36,
      48 and 60)

                · Physical
      examination

                · Vital
      signs

                · 12-lead
      ECG

                · 24 hour
      ambulatory Holter monitoring

                · Blood and
      urine sampling for laboratory safety parameters (biochemistry, hematology
      and urinalysis)

                · NT-proBNP
      (through Day 180 only)

                · Mandatory
      echocardiography; MRI as an additional measurement is encouraged (MRI
      through Day 180 only)

                · Minnesota
      Living with Heart FailureÒ
      questionnaire

                 

                AEs
      and SAEs will be collected throughout the study

              
	 	 	 
	
                PROCEDURE

                 

              	 	
                Patient
      is admitted to the hospital as a result of an AMI. As part of the
      inclusion criteria for this study, the patient will undergo
      revascularization with PCI stent implantation. Within 7 days of the index
      MI, the patient will undergo an echocardiogram to determine LVEF. Although
      not mandatory, the patient will be encouraged to undergo an MRI as an
      additional assessment. If the patient satisfies inclusion/exclusion
      criteria, a 2nd
      cardiac catheterization will be performed to administer BL-1040 after
      revascularization but within 7 days of the index AMI. BL-1040 is applied
      via intracoronary injection through the infarct related artery. Patients
      discharged from the hospital will be contacted by phone on Day 8 for a
      safety follow-up. Follow-up examinations are scheduled for Day 30, Day 90
      and Day 180 (End of Study) post-procedure. In addition, the patient will
      return to the hospital at Months 12, 24, 36, 48 and 60 for yearly
      follow-up assessments, as part of a long-term safety
      follow-up.

              
	 	 	 
	
                STATISTICAL
      METHODS

                 

              	 	
                All
      data recorded will be presented in data listings and summary tables, as
      appropriate. Missing values will not be replaced. No formal hypothesis
      testing will be performed.

                All
      participants who received BL-1040 will be included in the safety analysis.
      Any excluded cases will be documented together with the reason for
      exclusion. All decisions on exclusions from the analysis will be finalized
      prior to database lock.

                Continuous
      variables (age, height, weight) will be summarized using mean, median,
      standard deviation, minimum, maximum, and number of available
      observations. Qualitative variables will be summarized by counts and
      percentages.

                An
      interim safety analysis will be performed after 5 patients have completed
      the Day 30 visit, on all data collected up to this
    timepoint.

              


      

       

      Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

      01 December
2008


      


      
        
          
          

        

        
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of 52

          
            

          

        

        
          
          

        

      

      
         

        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      Schedule
of Events

       

      
        
          	
                  Visits/Week

                	 	
                  Hospitalization

                	 	
                  Post
      discharge follow-up

                
	
                  Study
      days

                	 	
                  Screening
      

                  Day
      (-7) 

                  to  

                  Day
      (-1)

                	 	
                  Day
      1 

                  Day
      of 

                  application1

                	 	
                  Daily
      

                  during
      

                  hospitalization2

                	 	
                  Day
      of 

                  discharge

                	 	
                  Telephone

                   Contact
      

                  Day
      8 

                  (± 1
    day)

                	 	
                  Day
      30 

                  (± 5
    days)

                	 	
                  Day
      90

                   (± 5
    days)

                	 	
                  Day
      180

                   (± 7 days)


                  End
      of 

                  Study
      Visit

                	 	
                  Follow-up

                   Safety
      Visits
      

                  (Months
      12, 

                  24,
      36, 48 60,
      

                  ± 30
    days)

                
	
                  AMI

                	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  Hospitalization

                	 	 
      <------------------------X---------------------------------->	 	 
      	 	 
      	 	 
      	 	 
      
	
                  Coronary
      angiography, PCI, stent3

                	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  Informed
      consent

                	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  Inclusion/exclusion
      criteria

                	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  Pregnancy
      test

                	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  Demography;
      medical history; concurrent illnesses

                	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  Physical
      examination

                	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	 
      	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                
	
                  Vital
      signs (temperature, arterial BP, weight)

                	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	 
      	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                
	
                  12-lead
      ECG

                	 	
                  X

                	 	
                  X4

                	 	
                  X

                	 	
                  X

                	 	 
      	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                
	
                  Laboratory
      safety parameters

                	 	
                  X5

                	 	
                  X6

                	 	 
      	 	
                  X6

                	 	 
      	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                
	
                  Total
      CK/CK MB

                	 	
                  X

                	 	
                  X7

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  NT-proBNP

                	 	
                  X

                	 	
                  X6

                	 	 
      	 	
                  X6

                	 	 
      	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	 
      
	
                  Echocardiography/MRI8

                	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	 
      	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                
	
                  Continuous
      ECG monitoring

                	 	 
      	 	
                  X9

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  Cardiac
      catheterization; application of BL-1040; coronary
    angiography

                	 	 
      	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  PTT
      or ACT measurements

                	 	 
      	 	
                  X10

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                  24-hour
      ambulatory Holter monitoring

                	 	 
      	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                
	
                  Safety
      contact for discharged patients

                	 	 
      	 	 
      	 	 
      	 	 
      	 	
                  X

                	 	 
      	 	 
      	 	 
      	 	 
      
	
                  Minnesota
      Living with Heart FailureÒ

                	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                
	
                  Serious/Adverse
      events and concomitant medication

                	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	 
      	 	
                  X

                	 	
                  X

                	 	
                  X

                	 	
                  X

                


        

      

      
         

        
          

        

      

      
        	
                1.

              	
                Device
      to be administered within 7 days of AMI

              
	 	 


      

      
        	
                2.

              	
                Patient
      must remain hospitalized for at least 48 hours after
      procedure.

              
	 	 


      

      
        	
                3.

              	
                Done
      as treatment of AMI

              
	 	 


      

      
        	
                4.

              	
                Prior
      to and after administration of BL-1040

              
	 	 


      

      
        	
                5.

              	
                Troponin
      I or T to be measured at Screening only

              
	 	 


      

      
        	
                6.

              	
                If
      not done within previous 48 hours

              
	 	 


      

      
        	
                7.

              	
                Parameters
      to be assessed prior to, and 8, 16, 24 and 48 hours after administration
      of BL-1040

              
	 	 


      

      
        	
                8.

              	
                Echocardiography
      to be done at each visit. MRIs are to be encouraged as an additional
      assessment through Day 180, but are contingent upon patient agreement.
      MRIs are not to be requested as part of the Follow-up Safety
      visits.

              
	 	 


      

      
        	
                9.

              	
                Patient
      to be connected prior to implantation of BL-1040, and for the duration of
      the procedure

              
	 	 


      

      
        	
                10.

              	
                Measured
      prior to implantation of BL-1040, and prior to removal of
      sheath

              


      

       

      Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

      01 December
2008


       

      
        
          
          

        

        
          Page 11
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      Table
of Contents

       

      
        
          	
                  List
      of Abbreviations

                	 	
                  14

                
	
                  1

                	 	
                  Introduction

                	 	
                  
                    15

                  

                
	
                  1.1

                	 	
                  Background

                	 	
                  
                    15

                  

                
	
                  1.1.1

                	 	
                  Acute
      Myocardial Infarction- Definition

                	 	
                  
                    15

                  

                
	
                  1.1.2

                	 	
                  Infarction
      types and pathogenesis

                	 	
                  
                    15

                  

                
	
                  1.1.3

                	 	
                  Mechanisms
      of myocardial damage

                	 	
                  
                    15

                  

                
	
                  1.1.4

                	 	
                  Treatment
      of AMI

                	 	
                  
                    15

                  

                
	
                  1.2

                	 	
                  Rationale
      and justification

                	 	
                  
                    16

                  

                
	
                  2

                	 	
                  Study
      Objectives

                	 	
                  
                    17

                  

                
	
                  3

                	 	
                  Safety
      Endpoints

                	 	
                  
                    18

                  

                
	
                  3.1

                	 	
                  Primary
      endpoints

                	 	
                  
                    18

                  

                
	
                  3.2

                	 	
                  Secondary
      endpoints

                	 	
                  
                    18

                  

                
	
                  4

                	 	
                  Investigational
      Plan

                	 	
                  
                    19

                  

                
	
                  4.1

                	 	
                  Summary
      of study design

                	 	
                  
                    19

                  

                
	
                  4.1.1

                	 	
                  Estimated
      study duration

                	 	
                  
                    19

                  

                
	
                  4.1.2

                	 	
                  Number
      of Patients

                	 	
                  
                    19

                  

                
	
                  4.2

                	 	
                  Sequential
      enrollment

                	 	
                  
                    19

                  

                
	
                  4.3

                	 	
                  Responsibilities
      of the Independent Safety Monitoring Board

                	 	
                  
                    19

                  

                
	
                  4.3.1

                	 	
                  Stopping
      Criteria

                	 	
                  
                    20

                  

                
	
                  4.4

                	 	
                  Inclusion
      criteria

                	 	
                  
                    20

                  

                
	
                  4.5

                	 	
                  Exclusion
      criteria

                	 	
                  
                    21

                  

                
	
                  4.6

                	 	
                  Withdrawal
      criteria during the study

                	 	
                  
                    22

                  

                
	
                  4.7

                	 	
                  Treatment
      allocation

                	 	
                  
                    22

                  

                
	
                  4.8

                	 	
                  Method
      of blinding and unblinding

                	 	
                  
                    22

                  

                
	
                  5

                	 	
                  Product
      Overview

                	 	
                  
                    23

                  

                
	
                  5.1

                	 	
                  BL-1040

                	 	
                  
                    23

                  

                
	
                  5.2

                	 	
                  Formulation

                	 	
                  
                    23

                  

                
	
                  5.3

                	 	
                  Dosage
      and application

                	 	
                  
                    23

                  

                
	
                  5.4

                	 	
                  Labelling/Packaging

                	 	
                  
                    24

                  

                
	
                  5.5

                	 	
                  Storage

                	 	
                  
                    24

                  

                
	
                  5.6

                	 	
                  Compliance

                	 	
                  
                    24

                  

                
	
                  5.7

                	 	
                  BL-1040
      accountability

                	 	
                  
                    24

                  

                
	
                  5.8

                	 	
                  Concomitant
      medication

                	 	
                  
                    24

                  

                
	
                  6

                	 	
                  Study
      Procedures

                	 	
                  
                    26

                  

                
	
                  6.1

                	 	
                  General
      study aspects

                	 	
                  
                    26

                  

                
	
                  6.2

                	 	
                  Outline
      of study procedures

                	 	
                  
                    26

                  

                
	
                  6.2.1

                	 	
                  Detailed
      description of study stages/visits

                	 	
                  
                    28

                  

                
	
                  6.2.1.1

                	 	
                  Screening,
      Day -7 to Day -1

                	 	
                  
                    28

                  

                
	
                  6.2.1.2

                	 	
                  Day
      1

                	 	
                  
                    28

                  

                
	
                  6.2.1.3

                	 	
                  Daily
      during hospitalization

                	 	
                  
                    29

                  

                
	
                  6.2.1.4

                	 	
                  Telephone
      Contact, Day 8, ±1

                	 	
                  
                    29

                  

                
	
                  6.2.1.5

                	 	
                  Day
      30, Day 90 and Day 180 (End of Study)

                	 	
                  
                    29

                  

                
	
                  6.2.1.6

                	 	
                  Extended
      safety follow-up (Months 12, 24, 36, 48, 60 ± 30
      days)

                	 	
                  
                    30

                  

                
	
                  6.3

                	 	
                  Study
      evaluations and procedures

                	 	
                  
                    30

                  

                
	
                  6.3.1

                	 	
                  Safety

                	 	
                  
                    30

                  

                
	
                  6.3.1.1

                	 	
                  Physical
      examinations

                	 	
                  
                    30

                  

                
	
                  6.3.1.2

                	 	
                  Vital
      signs

                	 	
                  
                    30

                  

                
	
                  6.3.1.3

                	 	
                  ECGs

                	 	
                  31

                
	
                  6.3.1.4

                	 	
                  Echocardiograms

                	 	
                  
                    31

                  

                
	
                  6.3.1.5

                	 	
                  MRIs

                	 	
                  
                    31

                  

                


        

         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

        
          
            
            

          

          
            Page 12
of 52

            
              

            

          

          
            
            

          

        

        
           

          
            	
                     

                  	 	
                    Protocol
      BL-1040.01, Version 5.00

                    Safety
      and Feasibility study of BL-1040

                    Final

                  	 	
                    CONFIDENTIAL

                  


          

           

        

        
          	
                  6.3.1.6

                	 	
                  Clinical
      safety evaluations

                	 	
                  32

                
	
                  6.3.2

                	 	
                  Core
      laboratories

                	 	
                  33

                
	
                  6.4

                	 	
                  Minnesota
      Living with Heart Failure®
      questionnaire

                	 	
                  
                    33

                  

                
	
                  7

                	 	
                  Adverse
      and Serious Adverse Events

                	 	
                  
                    
                      34

                    

                  

                
	
                  7.1

                	 	
                  Adverse
      event definition

                	 	
                  
                    34

                  

                
	
                  7.2

                	 	
                  Recording
      adverse events

                	 	
                  
                    34

                  

                
	
                  7.3

                	 	
                  Pre-device
      events

                	 	
                  
                    34

                  

                
	
                  7.4

                	 	
                  General
      adverse events

                	 	
                  
                    35

                  

                
	
                  7.4.1

                	 	
                  Assessment
      of severity of general adverse events

                	 	
                  
                    35

                  

                
	
                  7.4.2

                	 	
                  Assessment
      of causality of adverse events

                	 	
                  
                    35

                  

                
	
                  7.4.3

                	 	
                  Follow-up
      of adverse events and assessment of outcome

                	 	
                  
                    35

                  

                
	
                  7.5

                	 	
                  Serious
      Adverse Events

                	 	
                  36

                
	
                  7.5.1

                	 	
                  Definition
      of Serious Adverse Event (SAE)

                	 	
                  
                    36

                  

                
	
                  7.5.2

                	 	
                  Pre-defined
      SAEs

                	 	
                  37

                
	
                  7.5.3

                	 	
                  Reporting
      serious adverse events

                	 	
                  
                    37

                  

                
	
                  7.5.4

                	 	
                  Follow-up
      of serious adverse events

                	 	
                  38

                
	
                  7.6

                	 	
                  Treatment
      of adverse events

                	 	
                  
                    38

                  

                
	
                  7.7

                	 	
                  Pregnancy

                	 	
                  
                    38

                  

                
	
                  8

                	 	
                  Data
      Evaluation and Statistics

                	 	
                  
                    39

                  

                
	
                  8.1

                	 	
                  Endpoints

                	 	
                  
                    39

                  

                
	
                  8.2

                	 	
                  Estimated
      sample size

                	 	
                  
                    39

                  

                
	
                  8.3

                	 	
                  Planned
      methods of analysis

                	 	
                  
                    39

                  

                
	
                  8.3.1

                	 	
                  Analysis
      population

                	 	
                  
                    39

                  

                
	
                  8.3.2

                	 	
                  Analysis
      of demographics

                	 	
                  
                    39

                  

                
	
                  8.3.3

                	 	
                  Analysis
      of safety

                	 	
                  40

                
	
                  8.4

                	 	
                  Interim
      analysis

                	 	
                  
                    40

                  

                
	
                  8.5

                	 	
                  Final
      and follow-up reporting

                	 	
                  
                    40

                  

                
	
                  8.6

                	 	
                  Quality
      assurance

                	 	
                  
                    40

                  

                
	
                  9

                	 	
                  Ethics
      and regulatory considerations

                	 	
                  
                    41

                  

                
	
                  9.1

                	 	
                  Informed
      Consent

                	 	
                  
                    41

                  

                
	
                  9.2

                	 	
                  Authorities

                	 	
                  
                    41

                  

                
	
                  9.3

                	 	
                  Protocol
      Amendments

                	 	
                  
                    41

                  

                
	
                  9.4

                	 	
                  Patient
      confidentiality

                	 	
                  
                    41

                  

                
	
                  9.5

                	 	
                  Insurance

                	 	
                  
                    42

                  

                
	
                  9.6

                	 	
                  Duration
      of the study

                	 	
                  
                    42

                  

                
	
                  10

                	 	
                  Data
      Handling and Record Keeping

                	 	
                  
                    43

                  

                
	
                  10.1

                	 	
                  Documentation

                	 	
                  
                    43

                  

                
	
                  10.2

                	 	
                  Case
      Report Forms

                	 	
                  
                    43

                  

                
	
                  10.3

                	 	
                  Monitoring
      and quality control

                	 	
                  
                    43

                  

                
	
                  10.4

                	 	
                  Publication
      policy

                	 	
                  
                    43

                  

                
	
                  11

                	 	
                  References

                	 	
                  
                    44

                  

                


        

         

        
          Appendix
A: Declaration of Helsinki

        

         

        
          Appendix
B: Minnesota Living with Heart FailureÒ questionnaire

           

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                        CONFIDENTIAL

                      


              

               

            

          

        

      

      List
of Abbreviations


      
        	
                AE(s)

              	 	
                Adverse
      event(s)

              
	
                ALT

              	 	
                Alanine
      transminase

              
	
                AMI

              	 	
                Acute
      myocardial infarction

              
	
                AST

              	 	
                Aspartate
      transaminase

              
	
                BP

              	 	
                Blood
      pressure

              
	
                bpm

              	 	
                Beats
      per minutes

              
	
                BUN

              	 	
                Blood
      urea nitrogen

              
	
                CABG

              	 	
                Coronary
      artery bypass graft

              
	
                CHF

              	 	
                Chronic
      heart failure

              
	
                CRF

              	 	
                Case
      Report Form

              
	
                CRT

              	 	
                Cardiac
      Resynchronization Therapy

              
	
                CV

              	 	
                Cardiovascular

              
	
                ECG

              	 	
                Electrocardiogram

              
	
                EF

              	 	
                Ejection
      fraction

              
	
                eGFR

              	 	
                Estimated
      glomerular filtration rate

              
	
                EOS

              	 	
                End
      of study

              
	
                GCP

              	 	
                Good
      Clinical Practice

              
	
                GGT

              	 	
                Gamma
      glutamyl transferase

              
	
                GLP

              	 	
                Good
      Laboratory Practice

              
	
                GMP

              	 	
                Good
      Manufacturing Practices

              
	
                HPF

              	 	
                High
      power field

              
	
                HR

              	 	
                Heart
      rate

              
	
                IC

              	 	
                Intracoronary

              
	
                ICH

              	 	
                International
      Conference on Harmonization

              
	
                IRA

              	 	
                Infarct
      related artery

              
	
                ISMB

              	 	
                Independent
      Safety Monitoring Board

              
	
                LDH

              	 	
                Lactate
      dehydrogenase

              
	
                LV

              	 	
                Left
      ventricle

              
	
                LVEF

              	 	
                Left
      ventricular ejection fraction

              
	
                MedDRA

              	 	
                Medical
      Dictionary for Regulatory Activities

              
	
                mg

              	 	
                Milligram

              
	
                MI

              	 	
                Myocardial
      infarction

              
	
                min

              	 	
                Minute

              
	
                mL

              	 	
                Milliliter

              
	
                MRI

              	 	
                Magnetic
      resonance imaging

              
	
                NCE

              	 	
                New
      chemical entity

              
	
                NT-proBNP

              	 	
                N-terminal
      prohormone brain natriuretic peptide

              
	
                NYHA

              	 	
                New
      York Heart Association

              
	
                oC

              	 	
                Degrees
      centigrade

              
	
                OTC

              	 	
                Over
      the Counter

              
	
                PCI

              	 	
                Primary
      coronary intervention

              
	
                QMI

              	 	
                Qwave
      myocardial infarction

              
	
                SAE(s)

              	 	
                Serious
      Adverse Event(s)

              
	
                SAS

              	 	
                Statistical
      Analysis System

              
	
                STEMI

              	 	
                ST-segment
      elevation myocardial infarction

              
	
                TIMI

              	 	
                Thrombolysis
      in Myocardial Infarction

              
	
                VF

              	 	
                Ventricular
      fibrillation

              
	
                VT

              	 	
                Ventricular
      tachycardia

              


      

      
         

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        	1	
                Introduction

              
	 	 
	
                1.1

              	
                Background

              


      

       

      
        	
                1.1.1

              	
                Acute
      Myocardial Infarction- Definition

              


      

       

      Acute
myocardial infarction (AMI) is defined as death or necrosis of myocardial cells.
It is a diagnosis at the end of the spectrum of myocardial ischemia or acute
coronary syndromes. AMI occurs when myocardial ischemia exceeds a critical
threshold and overwhelms myocardial cellular repair mechanisms that are designed
to maintain normal cardiac function. Ischemia at this critical threshold level,
when present for an extended time period, results in irreversible myocardial
cell damage and cell death.


       

      
        	
                1.1.2

              	
                Infarction
      types and pathogenesis

              


      

       

      Critical
myocardial ischemia may arise as a result of increased myocardial metabolic
requirement and/or reduction in the delivery of oxygen and nutrients to the
myocardium through the coronary circulation, or both. An interruption in the
supply of myocardial oxygen and nutrients occurs when blood flow to the
myocardium is interrupted by occlusion of a coronary artery. Often, this event
is caused by a thrombus superimposed on an ulcerated or unstable atherosclerotic
plaque that left untreated for as little as a 20-40 minutes, can lead to
irreversible cell damage and cell death. A high-grade (> 75%) permanent
coronary artery stenosis due to atherosclerosis or a dynamic stenosis coupled
with coronary vasospasm can also reduce the supply of oxygen and nutrients and
be a factor involved in AMI. Additional cardiac valvular pathologies and low
cardiac output states associated with a decreased aortic diastolic pressure,
which is the prime component of coronary perfusion pressure, can also
precipitate AMI.


       

      
        	
                1.1.3

              	
                Mechanisms
      of myocardial damage

              


      

       

      The
severity of an AMI is dependent on three factors: the level of the occlusion in
the coronary artery, the length of time of the occlusion, and the presence or
absence of collateral circulation. In general, the more proximal the coronary
occlusion, there is a greater risk of an increased area of necrosis. The larger
the AMI, the chance of death due to a mechanical complication or pump failure
increases. In addition, the longer the time period of vessel occlusion, there is
a greater chance of irreversible myocardial damage distal to the
occlusion.

      


      The death
of myocardial cells first occurs in the area of myocardium that is most distal
to the arterial blood supply, the endocardium. As the duration of the occlusion
increases, the area of myocardial cell death enlarges, extending from the
endocardium to the myocardium and ultimately to the epicardium. The area of
myocardial cell death then spreads laterally to areas of watershed or collateral
perfusion. The extent of myocardial cell death defines the magnitude of the AMI.
If blood flow can be restored to at-risk myocardium, more heart muscle can be
saved from irreversible damage or death. The ischemic zone will undergo
inflammatory necrotic changes, and the myocardial tissue will eventually be
completely replaced by fibrous infarct tissue. In the early stages after an AMI,
the damage causes deterioration of cardiac muscle contractility and structural
integrity. This results in thinning of the walls of the heart, which can have
severe consequences including rupture at the site, expansion of the area of
damage, and the formation of blood clots. After some weeks or months, this can
evolve to dilatation of the heart, which further reduces its ability to pump
blood efficiently, resulting in heart failure.


       

      
        	
                1.1.4

              	
                Treatment
      of AMI

              


      

       

      The goal
of treatment for AMI is early reperfusion by rapid revascularization of the
occluded culprit coronary artery both by medical means to dissolve the clot with
thrombolytics or by cardiac catheterization with primary coronary intervention
(PCI) and deployment of stents to maintain patency of the culprit coronary
artery. However, while re-opening of the culprit coronary vessel can prevent the
development of a large AMI and prevent further loss of viable myocardium, it
does not affect myocardial tissue that has already undergone irreversible
damage.  An undeniable adverse outcome of AMI is progressive worsening
of ventricular function that, if left unattended, culminates in the syndrome of
congestive heart failure. To date, no treatment has been developed to reliably
prevent the deterioration of ventricular function that follows a large AMI.
Treatment options for AMI and for the resulting heart failure include medical
management, heart transplantation, mechanical circulatory assist devices (left
ventricular assist device, etc.), and surgical ventricular restoration, all of
which have specific limitations.

         

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                1.2

              	
                Rationale
      and justification

              


      

       

      BL-1040
Myocardial Implant presents a novel, safe and non-surgical therapy that directly
addresses the stability and structural integrity of myocardial tissue in this
patient population. BL-1040 potentially prevents post infarction remodeling
primarily via limiting left ventricle (LV) dilation, while the untreated patient
LV will continue to dilate or enlarge. BL-1040, by creating a scaffold, may
stabilize the AMI and limit post AMI expansion manifested as LV
dilation.

      


      There are
currently no other available medical and/or surgical interventions that directly
address the stability and structural integrity of myocardial tissue damaged as a
result of AMI.  In the setting of an AMI, an inflammatory response
triggers the degradation of the extracellular matrix, thus weakening of the
collagen cross-link structure or structural “backbone” of the myocardium.
Degradation of the extracellular matrix leads to infarct expansion manifested by
myocardial wall thinning and often, aneurysmal dilation with subsequent
ventricular enlargement. This process results in progressive LV remodeling and
increased LV wall stress. The latter can increase myocardial oxygen consumption,
a condition that the infarcted and/or failing LV can ill afford and one that can
contribute to increased long-term mortality and morbidity.

      


      LV
dilation is the predominant cause for morbidity and mortality in congestive
heart failure [2]. demonstrated that patients with LV end systolic volume
smaller than 95 mL showed a 94 % survival after 5 years while LV patients with
LV end systolic volume greater than 130 mL showed a 52 % survival after 5 years.
Both diastolic and systolic were the main predictors for mortality. Patients
with end-stage ischemic heart failure presenting dilated LV with an
akinetic/dyskinetic region over 35% and with left ventricular end systolic index
>60 mL/m2 are offered LV reconstruction or surgical ventricular restoration
(SVR) in order to reduce LV volume and to restore normal LV shape. Overall, in a
large number of studies performed using SVR, there is strong evidence that SVR
is safe and effective, showing significant reduction in mortality and
readmission levels together with significant improvement in ejection fraction as
well as in LV end systolic/diastolic index.

       

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          	2	
                  Study
      Objectives

                


        

         

      

      The
objectives of this study are:

       

      
        	
                 
      

              	
                ·

              	
                to
      evaluate the safety of the BL-1040 myocardial implant in patients after MI
      at high risk for LV remodeling and CHF,
and

              


      

       

      
        	
                 
      

              	
                ·

              	
                to
      provide feasibility data in order to initiate and conduct a pivotal
      clinical study evaluating the safety and efficacy of the BL-1040 implant
      in patients following myocardial
infarction.

              


      

       

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                  CONFIDENTIAL

                


        

         

      

      
        	
                3

              	
                Safety
      Endpoints

              


      

       

      
        	
                3.1

              	
                Primary
      endpoints

              


      

       

      Primary
safety endpoints include:

      


      
        	
                 
      

              	
                ·

              	
                occurrence
      of all adverse events including but not limited to

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                all
      MIs

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                cardiovascular
      hospitalization

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                serious
      ventricular arrhythmias sustained

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                VT
      (symptomatic or sustained VT [duration longer than 30 seconds or 100
      beats, or associated with hemodynamic collapse])

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                VF

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                symptomatic
      bradycardia, pauses of longer than 3.0 seconds, complete atrioventricular
      block, Mobitz II atrioventricular block

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                symptomatic
      heart failure (NYHA criteria + physical examination OR hospitalization
      because of heart failure)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                renal
      failure

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                stroke

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                death

              


      

       

      
        	
                3.2

              	
                Secondary
      endpoints

              


      

       

      Secondary
safety endpoints include:

      


      
        	
                 
      

              	
                ·

              	
                change
      from baseline in LV dimensions (end-systolic volume index, end-diastolic
      volume index, left ventricular mass)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                change
      from baseline in regional (infarct related) and global wall motion
      score

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                change
      from baseline in ejection fraction

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                cardiac
      rupture

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                NT-proBNP

              


      

       

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                  4

                	
                  Investigational
      Plan

                


        

      

       

      
        	
                4.1

              	
                Summary
      of study design

              


      

       

      This is
an open label, multi-center, sequentially enrolled, Phase I study to assess the
safety and feasibility of the injectable BL-1040 myocardial implant to provide
scaffolding to infarcted myocardial tissue.

      


      Patients
who experience an MI will be admitted to the hospital. As part of the treatment
for the MI, patients will undergo PCI and stent implantation. Patients will also
undergo an echocardiography (and if they agree, an MRI) to determine the extent
of damage to the infarct related artery (IRA). Patients who satisfy
inclusion/exclusion criteria will be enrolled into the study. The BL-1040
myocardial implant will be injected into the IRA, distally to the implanted
stent.

      


      The first
2 patients will be sequentially enrolled. After both patients have completed Day
30 assessments, and after approval by the Independent Safety Monitoring Board
(ISMB), the decision will be made to enroll 3 additional patients. After the
ISMB reviews the Day 30 assessments of these patients, the decision will be made
to enroll a maximum of 25 additional patients. Details are provided in Sec.
4.2.

      


      Both
female and male patients must agree to use effective contraception (as agreed
with the Investigator) for 6 months (180 days) after the
procedure.


       

      
        	
                4.1.1

              	
                Estimated
      study duration

              


      

       

      The study
is planned to last from Q1 2008 to Q1 2010. The clinical
study phase is 180 days for each patient. A long term safety follow-up will
include visits at Months 12, 24, 36, 48, and 60. Patients will be consented for
the entire 5 year period.


       

      
        	
                4.1.2

              	
                Number
      of Patients

              


      

       

      The
maximum number of patients enrolled in this study will be 30.


       

      
        	
                4.2

              	
                Sequential
      enrollment

              


      

       

      The first
2 patients will be sequentially enrolled into the study. After the 1st patient
has completed Day 30 assessments, the Independent Safety Monitoring Board (ISMB,
Sec. 4.3) will review the patient’s data through Day 30. The ISMB will then
decide whether to give approval to enroll the 2nd
patient. After the 2nd patient
has completed Day 30 assessments, the ISMB will again review the data and
provide approval for enrollment of the next 3 patients. After all 3 patients
have completed Day 30 assessments, the ISMB will review the data from these
patients and provide approval for opening enrollment to the balance of the
patients (maximum of 25).


       

      
        	
                4.3

              	
                Responsibilities
      of the Independent Safety Monitoring
Board

              


      

       

      An
Independent Safety Monitoring Board (ISMB) will be established prior to the
start of the study to monitor the safety of BL-1040 during the conduct of the
protocol. This ISMB will consist of physicians with expertise in cardiovascular
disease, particularly in the area of coronary artery disease and with experience
monitoring safety of drugs and/or devices for cardiovascular applications, and
will have no participation in the trial in any other capacity.

       

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      The ISMB
will ensure that this study meets the highest standards of patient safety.
During the study the ISMB will have the following main
responsibilities:

      


      
        	
                 
      

              	
                ·

              	
                review
      30 day safety data patients from the first 2 sequentially enrolled
      patients to determine whether 3 additional patients may be enrolled; after
      reviewing the 30 day safety data from these 3 patients, will determine
      whether the balance of patients may be enrolled

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                within
      30 days of enrolment of each successive group of 5 patients receiving the
      device, will review all SAEs occurring to date and will recommend
      continuation, discontinuation, or modification of the procedure or
      protocol, based on a determination of whether the occurrence of serious,
      unexpected, or device-related adverse events (Sec. 7) might outweigh the
      potential benefit achievable with the device

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                review
      emerging findings in patients and identify potential safety concerns with
      BL-1040

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                will
      receive information, on an expedited basis, on all Serious Adverse Events
      (SAEs), clinically significant laboratory values/vital signs, ECG
      abnormalities and data from patients who decided to prematurely
      discontinue the study. All SAES that occur in the cath lab during or after
      the procedure to administer BL-1040 should be reviewed promptly by the
      ISMB. The ISMB will review this information and may decide to interrupt,
      alter, or terminate the trial

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                will
      adjudicate whether or not an event is unexpected, based on a pre-specified
      list of expected SAEs within the study
  population.

              


      

       

      
        	
                4.3.1

              	
                Stopping
      Criteria

              


      

       

      Given the
uncontrolled nature of the study, and the small sample size, it is not practical
to provide a quantitative stopping rule.

      Moreover,
given the severely ill nature of the patients who will be enrolled in the study
(those with large myocardial infarction and substantial LV dysfunction), adverse
cardiac outcomes, including fatal ones, are to be expected in this population,
regardless of participation in the study.

      


      The study
will be stopped when any of the following occur:

      


      
        	
                 
      

              	
                1.

              	
                Completion
      of the study

              
	 	 	 


      

      
        	
                 
      

              	
                2.

              	
                ISMB
      and sponsor judge that the study treatment appears to be unsafe for
      patients. The ISMB will make this assessment based not only upon the
      frequency of observed complications, but also upon the character and
      qualitative nature of the events.  This determination will be
      made in the context of clinical judgement of experienced cardiologists
      regarding the expected outcome in this population of patients and whether
      observed outcomes differ substantively from the
    expectation.

              
	 	 	 
	 	 	The
      committee reserves the right to stop the study after analysis of outcomes
      of sequential procedures. A decision to stop will be considered by the
      ISMB in the event of occurrence of severe, unusual or unexpected
      events.


      

       

      
        	
                 
      

              	
                3.

              	
                The
      ISMB may consider putting the trial on hold or terminating it and will
      base it decision on weighing the balance between potential but
      hypothetical benefits and possible risks to the participants in the
      study.

              


      

       

      
        	
                4.4

              	
                Inclusion
      criteria

              


      

       

      
        	
                ·

              	
                The
      inclusion criteria for this study are:

              
	 	 


      

      
        	
                ·

              
	 


      

      
        	
                 
      

              	
                ·

              	
                voluntarily
      signed the informed consent form prior to the conduct of any study
      specific procedures

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                male
      or female inpatients aged 18 to 75,
inclusive

              


      

       

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                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                 
      

              	
                ·

              	
                negative
      pregnancy test for all women of child-bearing potential, or surgically
      sterilized (i.e. tubal ligation, hysterectomy) prior to Screening, or
      post-menopausal for at least 1 year

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                acute
      MI defined as:

              
	 	 	 


      

      
      

      
        	 	
                o

              	
                typical
      rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of
      biochemical markers of myocardial necrosis with at least one of the
      following: a) ischemic symptoms; b) development of pathologic Qwaves on
      the ECG; c) ECG changes indicative of ischemia (ST segment elevation or
      depression)

              
	 	 	 
	
                 
      

              	
                o

              	
                first
      anterior or inferolateral STEMI or Qwave MI (QMI Anterior: V1-V3 or V1-V4
      or V1-V5 or V1-V6.QMI Inferior: L2, L3, AVF, or L2, L3, AVF+ V5, V6 or L2,
      L3, AVF+ V6-V9 [posterior leads])

              
	 	 	 


      

      
        	
                 
      

              	
                o

              	
                regional
      wall motion score index (at least 4 out of 16 akinetic
      segments)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                one
      or more of the following:

              
	 	 	 


      

      
        	
                 
      

              	
                o

              	
                LVEF
      >20% and <45% measured and calculated by 2-dimensional
      measurement

              
	 	 	 


      

      
        	
                 
      

              	
                o

              	
                Biomarkers:
      peak CK > 2000 IU

              
	 	 	 


      

      
        	
                 
      

              	
                o

              	
                infarct
      size > 25% as measured by MRI

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                successful
      revascularization with PCI with 1 stent
      only, within 7 days of the index MI (only safe and MRI compatible
      stents)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                at time of application of device
      patient must have patent infarct related artery (IRA) and TIMI
      flow  grade = 3

              


      

       

      
        	
                4.5

              	
                Exclusion
      criteria

              


      

       

      Exclusion
criteria for this study are:

      


      
        	
                 
      

              	
                ·

              	
                history
      of CHF, Class I to Class IV, as per NYHA criteria

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                history
      of prior LV dysfunction

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                at
      time of application of study device - Killip III-IV (pulmonary edema,
      cardiogenic shock - hypotension (systolic < 90 mmHg) and evidence of
      peripheral hypoperfusion (oliguria, cyanosis, sweating) or HR > 100
      bpm

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                patient
      with pacemaker

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                prior
      CABG

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                prior
      MI

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                history
      of stroke

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                significant
      valvular disease (moderate or severe)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                patient
      is a candidate for CABG or PCI on non-IRA

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                patient
      is being considered for CRT within the next 30 days

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                renal
      insufficiency (eGFR < 60)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                chronic
      liver disease (> 3 times upper limit of normal)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                life
      expectancy < 12 months

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                current
      participant in another clinical trial, or participation in another trial
      within the last 6 months

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                any
      contraindication to coronary angiography, MRI or PCI
      procedures

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                patient
      taking anti-coagulation medication prior to MI

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                pregnant
      or lactating women; pregnancy confirmed by urine pregnancy
      test

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                patients
      with a reasonable likelihood for non-compliance with the
      protocol

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                any
      other reason that, in the Investigator’s opinion, prohibits the inclusion
      of the patient into the study

              


      

       

      Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

      01 December
2008


       

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                4.6

              	
                Withdrawal
      criteria during the study

              


      

       

      Each
patient has the right to withdraw from the trial at any time for any
reason.

      


      The
Investigator must make at least 3 documented attempts to contact those patients
who do not return for the scheduled follow-up visits. Attempts must be recorded
in the patient's file.

      


      The
Sponsor reserves the right to terminate the study at any time.

      


      Upon
withdrawal from the study any time after administration of study device, the
patient will undergo the End of Study assessments (Section 6.2.1.5; Table
6.1).

      


      Dropouts
that occur after implantation of BL-1040 will not be replaced.


       

      
        	
                4.7

              	
                Treatment
      allocation 

              


      

       

      This is
an open label study. All patients will be treated with BL-1040. Patient
eligibility will be established prior to treatment with BL-1040.

      


      If a
patient discontinues from the study, the patient number will not be
reused.


       

      
        	
                4.8

              	
                Method
      of blinding and unblinding

              


      

       

      As this
is an open label study, there will be no blinding or unblinding
procedure.

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                5

              	
                Product
      Overview

              


      

       

      
        	
                5.1

              	
                BL-1040

              


      

       

      BL-1040
myocardial implant is a non-pharmacologic, non-surgical, cross-linked alginate
solution administered via intracoronary (IC) injection to infarcted tissue.
BL-1040 completely disintegrates into its constituent polymers within
approximately 90 days after deposition, and is excreted in the
urine.


       

      
        	
                5.2

              	
                Formulation

              


      

       

      The
formulation of BL-1040 is shown in Table 5.1.

      


      Table
5.1 Formulation of BL-1040

       

      
        	
                0.3%
      Calcium D-Gluconate (Gluconic acid hemicalcium salt)

              	 	
                Sigma,
      Dr. Paul Lohmann GmbH KG

              
	
                1%
      PRONOVA UP VLVG

                Generic
      name: Sodium Alginate

              	 	
                FMC
      BioPolymer/ NovaMatrix

              
	
                Water
      for Injection USP/EP

              	 	 
      


      

       

      
        	
                 
      

              	
                5.3

              	
                Dosage
      and application

              


      

       

      BL-1040
will be administered to the coronary vasculature using multiple commercially
available devices. Table 5.2 provides a list of the commercially available
components that will be required in order to delivery the Bl-1040
implant.

      


      Table
5.2 List of Commercially Available BL-1040 Delivery Devices

       

      BL-1040
Implant Delivery Devices

      


      
        	
                1

              	
                Standard
      endovascular sheath (femoral or radial or brachial)

              
	 	 
	
                2

              	
                Standard
      coronary guiding catheter (example – Launcher, ref
    LA6AR10SH)

              
	 	 
	
                3

              	
                Guidewire
      0.014 inch (example - Boston Scientific, ref.
  383931-035J)

              
	 	 
	
                4

              	
                Torque
      device (example - Boston Scientific, ref. K903606))

              
	 	 
	
                5

              	
                Guidewire
      introducer (example Input Ref. 87311)

              
	 	 
	
                6

              	
                Microcatheter
      designed for coronary intravascular use such as multipurpose probing
      endovascular microcatheter.

                Example:(Boston
      Scientific Catalog number SCH 50058) or Transit microcatheter, (Cordis
      Endovascular Systems, MiMI Lakes, Fla.) or Renegase Hi-Flo microcatheter
      (Boston Scientific)

              
	 	 
	
                7.

              	
                Disposable
      syringe, Intmed 5 mL sterile CE, ISO9001,
  ISO13488

              


      

      


      Cardiac
catheterization should be done according to the guidelines of the American
College of Cardiology/Society for Cardiac Angiography and Interventions Clinical
Expert Consensus Document on Cardiac Catheterization Laboratory Standards. All
angiographies will be evaluated by a core laboratory. BL-1040 is delivered
intra-coronary (IC) via a microcatheter that is intended for coronary
intravascular use.

      


      The
timing of BL-1040 administration is within 7 days after the index MI. Two (2) mL
of BL-1040 will be injected IC through the infarct related artery supplying the
infarcted area. BL-1040 may not be mixed with any contrast medium.

      


      All
patients will be treated in the same manner.

       

      Detailed
instructions for the application of BL-1040 are provided in a separate
Instruction Manual.

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                5.4

              	
                Labelling/Packaging

              


      

       

      BL-1040
will be packed in a sterile cylindrical injection vial, type A glass. Vials are
filled with sterile BL-1040 and sealed with a 20 mm rubber stopper, spun-on
aluminum seal and a flip-off top.

      


      All
packages will be labeled according to the GMP guideline Volume 4, Annex 13
Manufacture of Investigational Medicinal Products (July 2003 Revision 1) [1] and
local laws.

      


      BL-1040
will be packed in labeled boxes, with at least the following information: study
number, patient number, route of administration, storage guidelines, batch
number, expiry date, instructions for administration, manufacturer name/code,
and "Investigational use only".

      


      The
Sponsor must notify the Site Investigator, who has the overall responsibility
for the study device, of the anticipated date of arrival.


       

      
        	
                5.5

              	
                Storage

              


      

       

      The Site
Investigator is responsible for ensuring that BL-1040 is stored in a safe
refrigerated location (2-8° C) with controlled access.
At this temperature, BL-1040 has a shelf life of 3 months. The temperature must
be monitored once daily, and recorded on a temperature log.

      


      BL-104
must be removed from the refrigerator and kept at room temperature 30 minutes
prior to administration.


       

      
        	
                5.6

              	
                Compliance

              


      

       

      BL-1040
will be administered by the Investigator only, and will not be dispensed to the
patient or any other personnel.


       

      
        	
                5.7

              	
                BL-1040
      accountability

              


      

       

      Under no
circumstances is it permitted to use study supplies for any purposes other than
those specified in the protocol.

      


      The
Investigator will be provided with forms to enable accurate recording of all
investigational product at all times. The Investigator must sign a statement
that he/she has received BL-1040 for the study. At any time the figures of
supplied, used and remaining BL-1040 must match. At the end of the study, it
must be possible to reconcile delivery records with those of used and unused
stocks. Account must be given of any discrepancies.

      


      At the
end of the study, all unused BL-1040 supplies and empty containers must be
returned to the Sponsor.


       

      
        	
                5.8

              	
                Concomitant
      medication

              


      

       

      The
following medications may only be administered as indicated:

       

      
        	
                 
      

              	
                ·

              	
                ceftriaxone
      may not be administered during the 48 hours immediately prior to the
      administration of BL-1040, and for the 48 hours immediately following
      administration of BL-1040

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                calcium
      solutions may not be administered during the first week of the
      study

              


      

      


      The
introduction of any medication not allowed by the protocol at any point in the
study will require a discussion between the Investigator and the Sponsor. If, in
the opinion of the Investigator, it becomes necessary to administer any
medication during the study, the Investigator will determine the dose and time
of intake, and document the medication(s) in the patient's CRF.

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      Patients
must be instructed not to begin any new medication before consulting with the
Investigator (unless required for emergency medical use). The patient must be
instructed that this prohibition applies to over-the-counter products as well as
prescription drugs.

      


      All
patients will receive optimal medical therapy according to the relevant, updated
guidelines from the European Society of Cardiology [3,4,5]. Optimal therapy
including aspirin, anticoagulation
if indicated, angiotensin-converting-enzyme inhibition,
beta-blockade, aldosterone antagonists, when appropriate, and lipid-lowering
therapy, unless contraindicated.
Clopidogrel therapy will be initiated before PCI
and continued for 1 year after myocardial infarction [3].

       

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                6

              	
                Study
      Procedures

              


      

       

      
        	
                6.1

              	
                General
      study aspects

              


      

       

      This is
an open label, multi-center study to assess the safety and feasibility of the
injectable BL-1040 myocardial implant to provide scaffolding to infarcted
myocardium.

      


      Patients
will be admitted to the hospital for treatment of an acute myocardial infarction
(AMI), to include angioplasty and implantation of a stent/s. Within 7 days of
successful revascularization, patients will undergo an echocardiogram for
assessment of the extent of the changes to the heart, and to verify cardiac
inclusion/exclusion criteria. MRIs are to be encouraged as an additional
assessment, but are contingent upon the agreement of the patient. After the
echocardiogram/MRI, but still within 7 days of the index AMI, patients will
undergo a 2nd cardiac
catheterization to administer BL-1040. Patients will remain hospitalized for at
least 48 hours after the procedure.

      


      The
BL-1040 scaffold will be injected into one infarct related artery (IRA),
distally to the implanted stent/s. Patients will undergo
cardiac monitoring before, during and after the procedure: a 12-lead ECG will be
done prior to and after administration of BL-1040; patients will be connected to
a continuous ECG monitor and will have continuous hemodynamic measurements
during the procedure; immediately after the completion of the 12-lead ECG, a
Holter monitor will be placed and will remain connected for the following
24 hours.

      


      Patients
will undergo physical examinations, assessment of vital signs and an ECG daily
during hospitalization; safety blood sampling will be done on the day of
discharge.

      


      Patients
who have been discharged from the hospital will be contacted by phone on Day 8
to confirm the administration of any concomitant medications, general status of
the patient, and any doctor visits since hospital discharge.

      


      Patients
will return for follow-up visits on Day 30, Day 90 and Day 180 (End of Study).
Additional follow-up safety visits are planned for Months 12, 24, 36, 48 and 60.
At each visit, patients will again undergo a physical examination with
measurement of vital signs, ECG, blood sampling, echocardiography and completion
of the Minnesota Living with Heart Failure questionnaireÒ. At each follow-up visit,
the patients will be hooked up to a 24-hour ambulatory Holter monitor, which
will be returned the following day. MRIs are to be encouraged through Day 180 as
an additional assessment, but are contingent upon the agreement of the patient.
MRIs are not to be requested as part of the long term safety
visits.

      


      Echocardiograms,
ECGs, Holters, angiographies and MRIs, will be evaluated in a core
laboratory.

      


      The first
2 patients will be sequentially enrolled; if approved by the ISMB; 3 additional
patients will be enrolled. After review and approval of the 30 day safety data
from these 3 patients, the balance of patients may be enrolled. Details are
provided in Sec. 4.2.

      


      Both
female and male patients must agree to use effective contraception (as agreed
with the Investigator) for 6 months (180 days) after the
procedure.


       

      
        	
                6.2

              	
                Outline
      of study procedures

              


      

       

      All study
procedures are outlined in the Schedule of Assessments below (Table 6.1). A more
detailed description of the study procedures performed at each study stage/visit
is given in the following sections.

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      Table
6.1                          Schedule
of Events

       

      
        	
                Visits/Week

              	 	
                Hospitalization

              	 	
                Post
      discharge follow-up

              
	
                Study
      days

              	 	
                Screening

                Day
      (-7) 

                to

                Day
      (-1)

              	 	
                Day
      1

                Day
      of 

                application1

              	 	
                Daily
      

                during
      

                hospitalization2

              	 	
                Day
      of 

                discharge

              	 	
                Telephone

                 Contact

                Day
      8

                (± 1
    day)

              	 	
                Day
      30

                (± 5
    days)

              	 	
                Day
      90

                (± 5
    days)

              	 	
                Day
      180

                (± 7 days)

                End
      of 

                Study
      Visit

              	 	
                Follow-up
      

                Safety
      Visits

                (Months
      12, 

                24,
      36, 48 60,

                ± 30
    days)

              
	
                AMI

              	 	
                X

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                Hospitalization

              	 	 
      <-----------------------X---------------------------------->	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                Coronary
      angiography, PCI, stent3

              	 	
                X

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                Informed
      consent

              	 	
                X

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                Inclusion/exclusion
      criteria

              	 	
                X

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                Pregnancy
      test

              	 	
                X

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                Demography;
      medical history; concurrent illnesses

              	 	
                X

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                Physical
      examination

              	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              	 	 
      	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              
	
                Vital
      signs (temperature, arterial BP, weight)

              	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              	 	 
      	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              
	
                12-lead
      ECG

              	 	
                X

              	 	
                X4

              	 	
                X

              	 	
                X

              	 	 
      	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              
	
                Laboratory
      safety parameters

              	 	
                X5

              	 	
                X6

              	 	 
      	 	
                X6

              	 	 
      	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              
	
                Total
      CK/CK MB

              	 	
                X

              	 	
                X7

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                NT-proBNP

              	 	
                X

              	 	
                X6

              	 	 
      	 	
                X6

              	 	 
      	 	
                X

              	 	
                X

              	 	
                X

              	 	 
      
	
                Echocardiography/MRI8

              	 	
                X

              	 	 
      	 	 
      	 	 
      	 	 
      	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              
	
                Continuous
      ECG monitoring

              	 	 
      	 	
                X9

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                Cardiac
      catheterization; application of BL-1040; coronary
    angiography

              	 	 
      	 	
                X

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                PTT
      or ACT measurements

              	 	 
      	 	
                X10

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      
	
                24-hour
      ambulatory Holter monitoring

              	 	 
      	 	
                X

              	 	 
      	 	 
      	 	 
      	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              
	
                Safety
      contact for discharged patients

              	 	 
      	 	 
      	 	 
      	 	 
      	 	
                X

              	 	 
      	 	 
      	 	 
      	 	 
      
	
                Minnesota
      Living with Heart FailureÒ

              	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              
	
                Serious/Adverse
      events and concomitant medication

              	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              	 	 
      	 	
                X

              	 	
                X

              	 	
                X

              	 	
                X

              


      

       

      
        

      

      
        	
                1.

              	
                Device
      to be administered within 7 days of AMI

              
	 	 


      

      
        	
                2.

              	
                Patient
      must remain hospitalized for at least 48 hours after
      procedure.

              
	 	 


      

      
        	
                3.

              	
                Done
      as treatment of AMI

              
	 	 


      

      
        	
                4.

              	
                Prior
      to and after administration of BL-1040

              
	 	 


      

      
        	
                5.

              	
                Troponin
      I or T to be measured at Screening only

              
	 	 


      

      
        	
                6.

              	
                If
      not done within previous 48 hours

              
	 	 


      

      
        	
                7.

              	
                Parameters
      to be assessed prior to, and 8, 16, 24 and 48 hours after administration
      of BL-1040

              
	 	 


      

      
        	
                8.

              	
                Echocardiography
      to be done at each visit. MRIs are to be encouraged as an additional
      assessment through Day 180, but are contingent upon patient agreement.
      MRIs are not to be requested as part of the Follow-up Safety
      visits.

              
	 	 


      

      
        	
                9.

              	
                Patient
      to be connected prior to implantation of BL-1040, and for the duration of
      the procedure

              
	 	 


      

      
        	
                10.

              	
                Measured
      prior to implantation of BL-1040, and prior to removal of
      sheath

              


      

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008



      
        
          
          

        

        
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      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                6.2.1

              	
                Detailed
      description of study stages/visits

              


      

       

      
        	
                6.2.1.1

              	
                Screening,
      Day -7 to Day -1

              


      

       

      Patients
are admitted to the hospital for treatment of an AMI, prior to enrollment into
the study. The treatment will include PCI with placement of a stent. After
signing of Informed Consent, and prior to initiation of any study-related
procedures, the following activities will be carried out:

      


      
        	
                 
      

              	
                ·

              	
                confirmation
      of inclusion/exclusion criteria

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                negative
      pregnancy test for all women of child-bearing potential (as defined in
      Inclusion Criteria)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                demographics

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                medical
      history

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                physical
      examination

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                vitals
      signs

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                12-lead
      ECG, in supine position

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                blood
      and urine sampling for laboratory safety parameters (biochemistry,
      hematology and urinalysis)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                blood
      sampling for Total CK/CK MB

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                blood
      sampling for NT-proBNP

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                echocardiography

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                MRI,
      if patient agrees

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                concomitant
      medication record (all currently prescribed and over the counter
      medications must be recorded in the Case Report Form [CRF], with dose and
      reason for use)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                pre-device
      serious/adverse events

              


      

       

      
        	
                6.2.1.2

              	
                Day
      1

              


      

       

      BL-1040
must be implanted within 7 days of the index AMI; the day of implant will be
considered Day 1 of the study. Prior to implantation, the following assessments
will be carried out:

      


      
        	
                 
      

              	
                ·

              	
                physical
      examination

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                vital
      signs

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                12-lead
      ECG

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                blood
      and urine sampling for laboratory safety parameters (biochemistry
      [excluding troponin I or T], hematology, and urinalysis), if not done
      within the previous 48 hours

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                Total
      CK/CK MB

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                NT-proBNP,
      if not done within the previous 48 hours

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                connection
      to continuous ECG monitoring

              


      

      


      BL-1040
will be implanted in the infarcted tissue via the IRA, distally to the stent as
outlined in the separate BL-1040 Instruction Manual. During the procedure the
following assessments will be done:

      


      
        	
                 
      

              	
                ·

              	
                continuous
      ECG monitoring

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                continuous
      hemodynamic measurements (arterial blood pressure)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                blood
      sampling for PTT or ACT, prior to implantation of BL-1040 and prior to
      removal of sheath

              


      

      


      An
additional coronary angiography will be done 3 minutes after implantation of the
BL-1040, and will include an assessment of TIMI flow and myocardial
blush.

      
         

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4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      The
following assessments will be done after the procedure:

      


      
        	
                 
      

              	
                ·

              	
                urinalysis

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                blood
      sampling at 8 hours, 16 hours and 24 hours after the procedure, for
      assessment of Total CK/CK MB

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                12-lead
      ECG

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                connection
      to 24 hour Holter monitor

              


      

      


      Adverse
events and concomitant medications will be monitored continuously during the
procedure and recorded on the patient’s CRF.


       

      
        	
                6.2.1.3

              	
                Daily
      during hospitalization

              


      

       

      The
patient must remain hospitalized for at least 48 hours after the procedure. The
following assessments and procedures will be carried out during each day of
hospitalization, including day of discharge:

      


      
        	
                 
      

              	
                ·

              	
                physical
      examination

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                vital
      signs

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                12-lead
      ECG

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                blood
      and urine sampling for laboratory safety parameters (biochemistry
      [excluding troponin I or T], hematology and urinalysis) on day of
      discharge and only if not done within the previous 48
  hours

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                NT-proBNP
      on day of discharge and only if not done within the previous 48
      hours

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                serious/adverse
      events

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                concomitant
      medication

              


      

       

      
        	
                6.2.1.4

              	
                Telephone
      Contact, Day 8, ±1

              


      

       

      Patients
who have been discharged from the hospital will be contacted by phone 7 days
after application of BL-1040. The patient should be asked the following
questions:

      


      
        	
                 
      

              	
                1.

              	
                How
      have you been feeling since your discharge? Have you had any chest pain or
      experienced any shortness of breath?

              
	 	 	 


      

      
        	
                 
      

              	
                2.

              	
                Did
      you call your doctor for any reason? If so, when, and for what
      reason?

              
	 	 	 


      

      
        	
                 
      

              	
                Did
      you go to the emergency room for any reason? If so, when and for what
      reason?

              
	 	 


      

      
        	
                 
      

              	
                3.

              	
                Are
      you taking any medications? If so, which
ones?

              


      

      


      The
information collected from this phone call is to be recorded in the patient’s
CRF.


       

      
        	
                6.2.1.5

              	
                Day
      30, Day 90 and Day 180 (End of
Study)

              


      

       

      The
patient will return to the hospital for the following assessments and procedures
on Day 30, Day 90 and Day 180. The visit on Day 180 will be considered the End
of Study visit. If a patient is discontinued prior to Day 180 for any reason,
the following assessments should be done at the time of
discontinuation.

      


      Assessments
to be carried out include:

      


      
        	
                 
      

              	
                ·

              	
                physical
      examination:

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                vital
      signs

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                12-lead
      ECG

              


      

      
         

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Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                 
      

              	
                ·

              	
                connection
      to 24-hour Holter monitor; to be returned on Day 31/Day 91/Day
  181

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                blood
      and urine sampling for laboratory safety parameters (biochemistry
      [excluding troponin I or T], hematology and urinalysis)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                NT-proBNP

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                echocardiography

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                MRI,
      if patient agrees

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                completion
      of the Minnesota Living with Heart FailureÒ
      questionnaire

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                serious/adverse
      events

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                concomitant
      medication

              


      

       

      
        	
                6.2.1.6

              	
                Extended
      safety follow-up (Months 12, 24, 36, 48, 60 ± 30
    days)

              


      

       

      Patients
will return to the hospital yearly for completion of follow-up
assessments.

      


      Assessments
are to include::

      


      
        	
                 
      

              	
                ·

              	
                physical
      examination

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                vital
      signs

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                12-lead
      ECG

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                connection
      to 24-hour Holter monitor; the patient is to be connected at the time of
      the follow-up visit, and the monitor is to be returned the following
      day

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                blood
      and urine sampling for laboratory safety parameters (biochemistry
      [excluding troponin I or T], hematology and urinalysis)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                echocardiography

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                completion
      of the Minnesota Living with Heart FailureÒ
      questionnaire

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                completion
      of the following questions:

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                How
      have you been feeling since your last check up?

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                Have
      you been hospitalized for any reason? If so, when, and for what
      reason?

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                serious/adverse
      events

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                concomitant
      medication

              


      

       

      
        	
                6.3

              	
                Study
      evaluations and procedures

              


      

       

      Safety
will be evaluated by analyzing the results of physical examinations, laboratory
examinations and cardiac assessments, as well as AEs (Section 7) and vital
signs. Assessments will be carried out at the time points specified in Section
6.2, and as shown in Table 6.1.

      


      All
safety related investigations are to be performed by the Principal Investigator
or a medically qualified designee, who is responsible for the overall treatment
of the patient.


       

      
        	
                6.3.1

              	
                Safety

              


      

       

      
        	
                6.3.1.1

              	
                Physical
      examinations

              


      

       

      Physical
examinations will include height (Screening only), weight, and a general
assessment of overall body systems (cardiovascular,
respiratory).


       

      
        	
                6.3.1.2

              	
                Vital
      signs

              


      

       

      The
following vital signs will be assessed:

      


      
        	
                 
      

              	
                ·

              	
                pulse
      rate

              


      

      
         

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Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                 
      

              	
                ·

              	
                blood
      pressure (supine, systolic and
diastolic)

              


      

       

      
        	
                 
      

              	
                ·

              	
                body
      temperature

              


      

      


      The
actual blood pressure and pulse rate should be recorded in the patient’s CRF.
Rounding of values is not allowed.

      


      The
following ranges will be used to define acceptable blood pressure:

       

      
        	
                 
      

              	
                ·

              	
                supine
      systolic blood pressure: 100 - 160
mmHg

              


      

       

      
        	
                 
      

              	
                ·

              	
                supine
      diastolic blood pressure: 60 - 95
mmHg

              


      

       

      
        	
                 
      

              	
                ·

              	
                supine
      pulse <100 bpm

              


      

      


      Body
temperature should be measured using the same methodology at each assessment,
and should be measured in decimals.


       

      
        	
                6.3.1.3

              	
                ECGs

              


      

       

      A
standard supine 12-lead ECG shall be recorded. ECG morphology and ECG intervals
(PR, RR, QRS, QT, and QTc) will be determined; QTc will be calculated using
Bazett’s formula.

      


      Patients
will be connected to a 24-hour ambulatory Holter monitor at each follow-up visit
(Day 30, Day 90, Day 180).

      


      Printouts/copies
must be placed in the patient’s chart, clearly labeled with the patient number,
time, date, visit, and study number, and signed by the Investigator. A core
laboratory will evaluate the results of both the ECG and Holter.

      


       

      
        	
                6.3.1.4

              	
                Echocardiograms

              


      

       

      Echocardiograms
will be performed and recorded according to specific criteria established for
this study, and provided in a separate Echocardiogram Reference Manual. The same
parameters will be measured at each assessment, throughout the
study.

      


      A core
laboratory will evaluate echocardiograms.

      


      The
Principal Investigator, the Sponsor or the ISMB may review echocardiograms at
any time if any safety concerns arise. Echocardiograms will be performed at the
times indicated on the Schedule of Events and in Sec. 6.2 of the
protocol.


       

      
        	
                6.3.1.5

              	
                MRIs

              


      

       

      While the
MRI is an optional procedure for cardiac assessment at Screening and all
follow-up visits (Day 30, Day 90, Day 180/End of Study), patients should be
encouraged to undergo the procedure at each relevant visit. Performance of the
procedure is always contingent upon patient agreement.

      


      MRIs will
be performed according to specific criteria established for this study, and
provided in a separate MRI Reference Manual. A core laboratory will evaluate
MRIs.

      


      The
Principal Investigator, the Sponsor or the ISMB may review MRIs at any time if
any safety concerns arise.

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                6.3.1.6

              	
                Clinical
      safety evaluations

              


      

       

      Safety
blood sampling

       

      All
laboratory samples will be processed at the local laboratory, except for
NT-proBNP, which will be assessed at a core lab.

      


      The
Investigator must review the laboratory assessments (initialed and dated) within
24 hours after the receipt of those results. Out of range values will be
interpreted by the Investigator with a comment of “not clinically significant”
(NCS) or “clinically significant” (CS). Clinically significant abnormal
laboratory values must be repeated on the appropriate clinical follow-up
arranged by the Investigator and documented on the lab report until the lab
value has stabilized or has returned to a clinically acceptable range
(regardless of relationship to BL-1040). Any laboratory value that remains
abnormal at the End of Study visit and is judged to be clinically significant
will be followed according to accepted medical standards for up to 30 days or
until resolution of the abnormality.

      


      Approximately
15 mL safety blood samples will be collected at the time points indicated in Sec
6.2 and shown in Table 6.1. Analyses will include:

      


      
        	
                 
      

              	
                ·

              	
                biochemistry

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                total
      protein

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                albumin

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                total
      bilirubin

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                ALT

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                AST

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                GGT

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                LDH

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                alk
      phosphate

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                glucose

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                sodium

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                potassium

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                calcium

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                phosphate

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                urea/BUN

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                creatinine

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                PTT
      or ACT

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                troponin
      I or T (Screening only)

              


      

      


      
        	
                 
      

              	
                ·

              	
                hematology

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                red
      blood cell count

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                hemoglobin

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                hematocrit

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                mean
      cell hemoglobin

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                mean
      cell hemoglobin concentration

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                mean
      cell volume

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                white
      blood cell count and differential

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                platelet
      count

              


      

      


      
        	
                 
      

              	
                ·

              	
                cardiac
      biomarkers

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                Total
      CK/CK MB

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                NT-proBNP

              


      

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

      

      
        
          
          

        

        
          Page 32
of 52

          
            

          

        

        
          
          

        

      

      
         

        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                 
      

              	
                ·

              	
                urinalysis

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                urine
      protein

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                urine
      glucose

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                urine
      blood

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                leukocytes

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                nitrites

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                urobilinogen

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                bilirubin

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                pH

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                specific
      gravity

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                ketones

              


      

      


      If
dipstick analysis reveals any pathological results, a full urine analysis will
be conducted and the following should be checked:

       

      
        	
                 
      

              	
                1.

              	
                Color

              
	 	 	 


      

      
        	
                 
      

              	
                2.

              	
                Appearance

              
	 	 	 


      

      
        	
                 
      

              	
                3.

              	
                Leukocytes
      + erythrocytes per HPF (High Power Field)

              
	 	 	 


      

      
        	
                 
      

              	
                4.

              	
                Squamos
      epithelial cells

              
	 	 	 


      

      
        	
                 
      

              	
                5.

              	
                Non
      squamos epithelial cells

              
	 	 	 


      

      
        	
                 
      

              	
                6.

              	
                Yeast
      in urine

              
	 	 	 


      

      
        	
                 
      

              	
                7.

              	
                Amorphous
      cells

              
	 	 	 


      

      
        	
                 
      

              	
                8.

              	
                Mucous
      in urine

              
	 	 	 


      

      
        	
                 
      

              	
                9.

              	
                Casts

              
	 	 	 
	 	
                10.

              	
                Crystals

              


      

      
      

       

      
        	
                6.3.2

              	
                Core
      laboratories

              


      

       

      Results
of echocardiograms, ECGs, Holters, angiographies, and MRIs will be evaluated at
Biomedical Systems:

      


      Biomedical Systems

      1945 Ch. de Wavre

      B-1160 Brussels-Belgium

      phone: +32 2 661 20 70

      fax: +32 2 661 20 71

      email: sjacobs@biomedsys.com

      


      NT-proBNP
samples will be assessed at the central laboratory at the University of
Heidelberg:

      


      Universitätsklinikum
Heidelberg

      Zentrallabor

      Im Neuenheimer Feld 671

      69120 Heidelberg,
Germany

      Tel.: 06221-56-8803

      Fax: 06221-56-5205

      


       

      
        	
                6.4

              	
                Minnesota
      Living with Heart FailureÒ
      questionnaire

              


      

       

      The
Minnesota Living with Heart FailureÒ questionnaire (MLHQ) is a
standardized and validated questionnaire designed to measure the effects of
heart failure and treatments for heart failure on an individual’s quality of
life (ref. 6-8). The questionnaire measures the effects of symptoms, functional
limitations, and psychological distress on the individual’s life. These items
are measured using a 6 point Likert scale (0-5) to indicate how much each of 21
items has affected their quality of life.

       

      
        
          
          

        

        
          Page 33
of 52

          
            

          

        

        
          
          

        

      

       

      The
scales will be administered by the Investigator or trained/designated personnel,
in the local language.

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


         

      

      
        
          
          

        

        
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of 52

          
            

          

        

        
          
          

        

      

      
         

        
          	
                   

                	 	
                  Protocol
      BL-1040.01, Version 5.00

                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                7

              	
                Adverse
      and Serious Adverse Events

              


      

       

      
        	
                7.1

              	
                Adverse
      event definition

              


      

       

      An
adverse event (AE) is any untoward medical occurrence in a clinical trial
patient who was administered a medicinal product and/or medical device and which
does not necessarily have a causal relationship with this treatment. This
includes any noxious, pathological or unintended change in anatomical,
physiological or metabolic functions as indicated by physical signs, symptoms
and/or laboratory detected changes occurring in any phase of the clinical study
whether associated with the study drug/device and whether or not considered
related to study intervention. This includes an exacerbation of pre-existing
conditions or events, intercurrent illnesses, or drug/device interaction.
Anticipated day-to-day fluctuations of pre-existing conditions that do not
represent a clinically significant exacerbation need not be considered AEs.
Discrete episodes of chronic conditions occurring during a study period should
be reported as AEs in order to assess changes in frequency or
severity.

      


      AEs
should be documented in terms of signs and symptoms observed by the Investigator
or reported by the patient at each study visit. A medical diagnosis should be
added.

      


      Pre-existing
conditions or signs and/or symptoms (including any which are not recognized at
study entry but are recognized during the study period) present in a patient
prior to the start of the study should be recorded in the Medical History form
within the patient's CRF.


       

      
        	
                7.2

              	
                Recording
      adverse events

              


      

       

      All
non-serious AEs (serious or non-serious)
will be recorded from the time of implantation of BL-1040 on Day 1 until the end
of the active study period (Day 180); all serious AEs will be recorded from the
time of implantation of BL-1040 until the end of the long term follow-up (Month
60). AEs are to be recorded on the appropriate AE pages in the patient's CRF; if
the AE is serious, the appropriate box on the AE page of the CRF should also be
ticked. Where possible, a diagnosis rather than a list of symptoms should be
recorded. If a diagnosis has not been made then each symptom should be listed
individually. The nature, time of onset and cessation, and any treatment
provided shall be recorded.

      


      According
to “Medical Devices: Post Market Surveillance: Global Guidance for Adverse Event
Reporting for Medical Devices – GHTF/SG2/N54R8:2006, Study Group 2 Final
Document”, typical adverse events for medical devices include but are not
limited to:

      


      
        	
                 
      

              	
                ·

              	
                a
      malfunction or deterioration in the characteristics or
      performance

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                an
      incorrect or out of specification test result

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                an
      inaccuracy in the labeling, instructions for use and/or promotional
      materials.  Inaccuracies include omissions and deficiencies.
      Omissions do not include the absence of information that should generally
      be known by the intended users.

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                use
      error

              


      

      


      All AEs
(serious and non-serious) shall be reported as specified in this section of the
Protocol, and the expanded Medical Device Reporting Guidelines, which will be
provided to all investigators prior to the start of the study.

       

      
        	
                7.3

              	
                Pre-device
      events

              


      

       

      The
Investigator will report any pre-device event directly observed or mentioned by
the patient from the time of signing Informed Consent until the implantation of
BL-1040 on Day 1. Pre-device events are reported in the CRF with at least the
nature, the start date and the treatment (if applicable).

       

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4 

      01 December
2008


       

      
        
          
          

        

        
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                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                7.4

              	
                General
      adverse events

              


      

       

      Information
on any AE must be recorded when volunteered by the patient, observed by study
personnel, or elicited by a non-leading question, such as "How are you
feeling?".


       

      
        	
                7.4.1

              	
                Assessment
      of severity of general adverse
events

              


      

       

      General
events should be assessed according to the following scale:

      


      
        	
                ·   
      mild

              	 	
                the
      event is easily tolerated and does not interfere with usual activity;
      disappears without residual effects

              
	 	 	 
	
                ·  
       moderate

              	 	
                the
      event interferes with daily activity, but the patient is still able to
      function

              
	 	 	 
	
                ·   
      severe

              	 	
                the
      event is incapacitating and the patient is unable to work or complete
      usual activity; considered as unacceptable by the
    Investigator

              


      

       

      
        	
                7.4.2

              	
                Assessment
      of causality of adverse events

              


      

       

      Every
effort should be made by the Investigator to explain each AE, both serious and
non-serious, and assess its causal relationship, if any, to implantation of
BL-1040.

      


      The
relationship of BL-1040 to the event will be determined by how well the event
can be understood in terms of one or more of the following


      


      
        	
                related

              	 	
                there
      is suspicion of a relationship between BL-1040 and AE (without determining
      the extent of probability); there are no other more likely causes and
      administration of BL-1040 is suspected to have contributed to the
      AE

              
	 
      	 	 
      
	 
      	 	 
      
	
                possible

              	 	
                AE
      occurs within a reasonable time after the implantation of BL-1040 but can
      also be reasonably explained by other factors (as mentioned
      below)

              
	 
      	 	 
      
	 
      	 	 
      
	
                unrelated

              	 	
                there
      is no suspicion that there is a relationship between BL-1040 and AE, there
      are other more likely causes and implantation of BL-1040 is not suspected
      to have contributed to the AE

              


      

      


      Non-serious
and serious AEs will be evaluated as two distinct types of events given their
different medical nature. The Investigator will examine all events assessed as
“serious” (Sec. 7.5.1) in order to determine, as far as possible, ALL
contributing factors applicable to each serious AE.

      


      Other
possible contributors include:

       

      
        	
                 
      

              	
                ·

              	
                underlying
      disease

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                other
      medication

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                protocol
      required procedure

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                other
      (specify)

              


      

      


       

      
        	
                7.4.3

              	
                Follow-up
      of adverse events and assessment of
outcome

              


      

       

      All AEs
will be followed to resolution (patient's health has returned to baseline status
or all variables have returned to normal); until an outcome has been reached;
stabilization (Investigator does not expect any further improvement of worsening
of the event); or the event is otherwise explained, regardless of whether the
patient is still participating in the study. Where appropriate, medical tests
and examinations will be performed to document resolution of the event. All
follow-up information will be recorded in the patient's CRF until Day
180. 

      
         

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4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                7.5

              	
                Serious
      Adverse Events

              


      

       

      
        	
                7.5.1

              	
                Definition
      of Serious Adverse Event (SAE)

              


      

       

      A serious
adverse event (SAE) is any untoward medical occurrence or effect that led
to one of the following outcomes:

      


      
        	
                 
      

              	
                ·

              	
                death
      of a patient, user or other person

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                serious
      injury of a patient, user or other person

                 

                
                  Serious
      injury (also known as serious deterioration in state of health) is
      either:

                   

                

              


      

      
        	
                 
      

              	
                -

              	
                a
      life threatening illness or injury *

              
	 	 	 


      

      
        	
                 
      

              	
                -

              	
                permanent
      impairment of a body function or permanent damage to a body structure†

              
	 	 	 
	 	
                -

              	
                a
      condition necessitating medical or surgical intervention to prevent
      permanent impairment of a body function or permanent damage to a body
      structure

                 

                The term “permanent” means irreversible
      impairment or damage to a body structure or function, excluding minor
      impairment or damage Medical
      intervention is not in itself a serious injury. It is the reason that
      motivated the medical intervention that should be used to assess the
      reportability of an event.

              


      

       

      
        	
                 
      

              	
                -

              	
                in-patient
      hospitalization‡ or
      prolongation of existing hospitalization

              
	 	 	 


      

      
        	
                 
      

              	
                -

              	
                an
      event that might lead to death or serious injury of a patient, user or
      other person if the event recurs (sometimes called a “near
      incident”)

              


      

      


      *Life
threatening: An AE is life threatening if the patient was at risk of death at
the time of the event; it does not refer to an event which hypothetically might
have caused death if it were more severe.

      


      †Disabling/incapacitating:
An AE is incapacitating or disabling if the event results in a substantial
disruption of the patient's ability to carry out normal life functions. This
definition is not intended to include experiences of relatively minor medical
significance such as headache, nausea, vomiting, diarrhea, influenza, or
accidental trauma (e.g. sprained ankle).

      


      ‡Hospitalization:
In general, hospitalization signifies that the patient has been detained
(usually involving at least an overnight stay) at the hospital or emergency ward
for treatment that would not have been appropriate in the physician's office or
out-patient setting.

      


      Hospitalization
for either elective surgery related to a pre-existing condition which did not
increase in severity or frequency following initiation of the study or for
routine clinical procedures¶
(including hospitalization for "social" reasons) that are not the result of an
AE need not be considered as AEs and are therefore not SAEs. When in doubt as to
whether ‘hospitalization’ occurred or was necessary, the AE should be considered
serious.

      


      ¶Routine
Clinical Procedure: procedure which may take place during the study period and
should not interfere with the implantation of BL-1040 or any of the ongoing
protocol specific procedures. If anything untoward is reported during an
elective procedure, that occurrence must be reported as an AE, either `serious'
or non-serious according to the usual criteria.

      


      For
medical devices, typical serious adverse events include but are not limited
to:

      


      
        	
                 
      

              	
                ·

              	
                use
      error (e.g. untrained user, incorrect route of administration) related to medical
      devices, which did result in
      death or serious injury

              


      

       

      
        	
                 
      

              	
                ·

              	
                damage
      to tissue or tissue function following administration of study
      device

              


      

      
         

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        01 December
2008


         

      

      
        
          
          

        

        
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      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                 
      

              	
                ·

              	
                impairment
      of an organ or organ function following administration of study
      device

              


      

       

      
        	
                 
      

              	
                ·

              	
                interaction
      with concomitant treatment (other devices or drugs) that might lead to
      death or serious injury

              


      

       

      
        	
                 
      

              	
                ·

              	
                interaction
      with materials (e.g. catheters, stent), substances or gases entering into
      contact with the device during normal use that might lead to death or
      serious injury

              


      

       

      
        	
                 
      

              	
                ·

              	
                non-biocompatibility
      leading to serious irritation/allergy that results in in-patient
      hospitalization or
      prolongation of existing
hospitalization

              


      

       

      
        	
                7.5.2

              	
                Pre-defined
      SAEs

              


      

       

      For the
purposes of this study, the following events will be defined as
serious:

      


      
        	
                 
      

              	
                ·

              	
                re-infarction

              


      

       

      
        	
                 
      

              	
                ·

              	
                stroke
      or transient ischemic attack (TIA)

              


      

       

      
        	
                 
      

              	
                ·

              	
                acute
      heart failure (decompensation)

              


      

      


      The
occurrence of any of these events after implantation of BL-1040 will be
considered an SAE; they are to be reported and followed up as specified in
Sections 7.5.3 and 7.5.4.


       

      
        	
                7.5.3

              	
                Reporting
      serious adverse events

              


      

       

      All
Serious Adverse Events (SAEs) must be reported immediately by the Investigator
without filtration, whether considered to be associated with BL-1040 and whether
or not considered related to BL-1040. The Investigator must report SAEs within
one calendar day of becoming aware of the event by telephone, fax or e-mail to
the Study Contact for Reporting Serious Adverse Events as indicated below. This
initial notification should include minimal, but sufficient information to
permit identification of the reporter, the patient, study device, any
medications administered, AEs, causality assessment and date of onset. The
Investigator should not wait for additional information to fully document the
event before providing notification. An acknowledgement letter will confirm the
first notification. The report is then to be followed by submission of a
completed SAE Report Form provided by Averion International as soon as possible
but at latest within 3 calendar days of the initial telephone/fax or e-mail
report detailing relevant aspects of the AEs in question. All actions taken by
the Investigator and the outcome of the event must also be reported immediately.
For documentation of the SAE, any actions taken, outcome and follow-up reports,
the SAE Report Forms are to be used. Where applicable, hospital case records and
autopsy reports should be obtained.

      


      Investigators
must report SAEs to the appropriate ethics committee if requested by the
committee and/or according to local legal requirements.

      


      


      
        	
                Study
      Contact for Reporting Serious Adverse Events.

              
	
                 

                 

                 

                 

                Fax:

                e-mail:

                Tel:

                 

              	
                 

                Averion
      International

                Gewerbestrasse
      24, CH-4123 Allschwil, Switzerland

                 

                +41-61-487-1421

                SAE@averionintl.com

                +41-61-487-1681

                 

                24/24
      hour and 7/7 day availability

              


      

      
         

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4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                7.5.4

              	
                Follow-up
      of serious adverse events

              


      

       

      All SAEs
must be collected and documented until the end of the long term follow-up (Month
60), and followed up until the event either resolved, subsided, stabilized,
disappeared or is otherwise explained or the study patient is lost to follow-up.
All follow-up activities must be reported, if necessary on one or more
consecutive SAE report forms, in a timely manner. All fields with additional or
changed information must be completed and the report form should be forwarded to
the Study Contact for Reporting Serious Adverse Events as soon as possible but
latest within 7 calendar days after receipt of the new information. Clinically
significant laboratory abnormalities will be followed up until they have
returned to normal, or a satisfactory explanation has been provided. Reports
relative to the subsequent course of an AE noted for any patient must be
submitted to Averion International.

       

      
        	
                7.6

              	
                Treatment
      of adverse events

              


      

       

      Treatment
of any AE is at the sole discretion of the Investigator and according to current
available best treatment. The applied measures should be recorded in the CRF of
the patient.

       

      
        	
                7.7

              	
                Pregnancy

              


      

       

      The
Sponsor must be notified immediately of any pregnancy that occurs during the
study. The SAE report form should be used to report the pregnancy, even though
the pregnancy is not considered an SAE. Women who become pregnant during the
study will be followed up until birth of the child. The health status of the
newborn will be reported in the patient’s CRF.

      
         

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4 

        01 December
2008


      

      
        
          
          

        

        
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                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                
                  8

                

              	
                Data
      Evaluation and Statistics

              


      

       

      In all
analyses where a change from baseline is performed, baseline is defined as the
last available value before device implantation.

       

      
        	
                8.1

              	
                Endpoints

              


      

       

      The primary endpoints are
occurrence of all adverse events including but not limited to:

      


      
        	
                 
      

              	
                ·

              	
                all
      MIs

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                cardiovascular
      hospitalization

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                serious
      ventricular arrhythmias sustained

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                VT
      (symptomatic or sustained VT [duration longer than 30 seconds or 100
      beats, or associated with hemodynamic collapse]

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                VF

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                symptomatic
      bradycardia, pauses of longer than 3.0 seconds, complete atrioventricular
      block, Mobitz II atrioventricular block

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                symptomatic
      heart failure (NYHA criteria + physical examination OR hospitalization due
      to heart failure)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                renal
      failure

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                stroke

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                death

              


      

      


      Secondary
Endpoints include the parameters:

       

      
        	
                 
      

              	
                ·

              	
                change
      from baseline in LV dimensions (end-systolic volume index, end-diastolic
      volume index, left ventricular mass)

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                change
      from baseline in regional (infarct related) and global wall motion
      score

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                change
      from baseline in ejection fraction

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                cardiac
      rupture

              
	 	 	 


      

      
        	
                 
      

              	
                ·

              	
                NT-proBNP

              


      

      


       

      
        	
                8.2

              	
                Estimated
      sample size

              


      

       

      No formal
sample size calculation was performed. Twenty patients followed up to Day 180
were deemed necessary to meet the objectives of this Phase I study. Taking into
account drop-outs after the device implantation, thirty patients will be
enrolled.


       

      
        	
                8.3

              	
                Planned
      methods of analysis

              


      

       

      All data
recorded will be presented in data listings and summary tables, as appropriate.
Missing values will not be replaced. No formal hypothesis testing will be
performed.


       

      
        	
                8.3.1

              	
                Analysis
      population

              


      

       

      All
participants who received the BL-1040 myocardial implant will be included in the
safety analysis. Any excluded cases will be documented together with the reason
for exclusion. All decisions on exclusions from the analysis will be finalized
prior database lock.


       

      
        	
                8.3.2

              	
                Analysis
      of demographics

              


      

       

      Continuous demographic
variables (age, height, weight) will be summarized using mean, median, standard
deviation, minimum, maximum, and number of available observations.

      
         

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4 

        01 December
2008


         

      

      
        
          
          

        

        
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                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      Qualitative
demographic characteristics will be summarized by counts and percentages. Other
patient characteristics (medical history, clinical findings, prior medications,
inclusion/exclusion criteria) will only be listed.


       

      
        	
                8.3.3

              	
                Analysis
      of safety

              


      

       

      AEs will
be described in individual listings and frequency tables by system organ class
and preferred terms (MedDRA version 10.0 or higher), regardless of relationship
as well as for related AEs. The severity of AEs will also be
tabulated.

      


      Vital
signs will be listed and changes from baseline and raw results will be
summarized by means and standard deviations.

      


      Laboratory
test values will be presented by individual listings with flagging of values
outside the normal ranges. Raw laboratory results and changes from baseline will
be summarized by means and standard deviations.

      


      12 lead
ECG findings will be presented by listings and frequency tables, as appropriate.
Continuous ECG data will be summarized using standard descriptive
statistics.

      


      The
change from baseline in cardiac parameter (LV dimensions, wall motion score,
ejection fraction) as well as the NT-proBNP data will be summarized using
standard descriptive statistics.


       

      
        	
                8.4

              	
                Interim
      analysis

              


      

       

      An
interim safety analysis will be performed after 5 patients have completed the
Day 30 visit, on all data collected up to this timepoint.


       

      
        	
                8.5

              	
                Final
      and follow-up reporting

              


      

       

      The final
clinical study report will be prepared based on data from Day 180, or End of
Study, from the final patient. Thereafter, an annual safety report will be
prepared after each yearly safety follow-up visit (Months 12, 24, 36, 48,
60).


       

      
        	
                8.6

              	
                Quality
      assurance

              


      

       

      All data
collected in the CRF will be double entered into a validated computerized
clinical data management system (Clintrial). Laboratory values from the local
lab will be entered into the CRF. Analysis of the data will only be performed
after all queries have been resolved using an appropriate software for analysis
(SAS 8.1).

      
         

        Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment
4 

        01 December
2008


      

      
        
          
          

        

        
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                  Safety
      and Feasibility study of BL-1040

                  Final

                	 	
                  CONFIDENTIAL

                


        

         

      

      
        	
                9

              	
                Ethics
      and regulatory considerations

              


      

       

      The study
will be conducted according to Good Clinical Practice, the Declaration of
Helsinki 2000 (Appendix A), and the rules and regulations of the European Union
and Israel.


       

      
        	
                9.1

              	
                Informed
      Consent

              


      

       

      The
nature, purpose and potential risk of the study as well as the action of the
BL-1040 myocardial implant will be explained to all patients both verbally and
in writing. They will be given adequate time to consider the study before
signing the consent form. Their questions will be actively encouraged. They will
be informed that they may withdraw from the study at any time. This information
is documented in the protocol and participants in the study will sign a consent
form confirming that they have read and understood it; no study activities will
take place until the consent form has been signed. They will also be given a
Patient Information Sheet and copy of the consent form.


       

      
        	
                9.2

              	
                Authorities

              


      

       

      The
procedures laid out by the local regulatory authorities must be followed and all
documents must be submitted to all concerned authorities, and where needed,
approved before a clinical study may commence.


       

      
        	
                9.3

              	
                Protocol
      Amendments

              


      

       

      There
will be no alteration to the protocol without the express written approval of
the Sponsor.

      


      The local
authorities or ethics committees must approve all major protocol amendments
prior to implementation.

      


      No
protocol amendments should be adopted without prior written approval from the
ethics committee except in the following cases:

      


      
        	
                 
      

              	
                ·

              	
                in
      order to eliminate immediate hazard to the
  patients,

              


      

       

      
        	
                 
      

              	
                ·

              	
                changes
      involving only logistical or administrative aspects of the trial. Then
      notification to the relevant authorities should be
    submitted.

              


      

      


      In these
cases, the implemented deviation or change should be submitted as soon as
possible to the relevant authorities for review and approval.

      


      No
protocol deviations are anticipated. However, should any protocol deviations
occur, the Principal Investigator must report the matter to the Sponsor as soon
as reasonably practical. Details of the deviation and, if possible, the reason
for its occurrence must be included in the study report.

      


      Major
modifications will need further approval, and will be submitted to the local
authorities or ethics committees, according to local regulations, in the form of
an Amendment. Minor administrative changes require only that the Chairman of the
Ethics Committee be informed in writing without delay.


       

      
        	
                9.4

              	
                Patient
      confidentiality

              


      

       

      Individual
patient data obtained as a result of this study is considered confidential. A
patient identification number will identify any patient data collected
throughout the study only.

      
         

        Annotated
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        01 December
2008


         

      

      
        
          
          

        

        
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      Data
generated as a result of this study are to be available for inspection on
request by all authorized Sponsor personnel, Averion International personnel,
audit personnel and regulatory authorities. The Informed Consent must clearly
reflect this access.


       

      
        	
                9.5

              	
                Insurance

              


      

       

      The
compensation of the patient in the event of study related injuries will comply
with the applicable obligatory requirements. Details will be included in the
Informed Consent.


       

      
        	
                9.6

              	
                Duration
      of the study

              


      

       

      The
active study phase for each patient is 180 days. Enrolment is expected to begin
in Q1 2008; the study is expected to end Q1 2010.

      
         

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                10

              	
                Data
      Handling and Record Keeping

              


      

       

      
        	
                10.1

              	
                Documentation

              


      

       

      Records
must be retained for 15 years after study completion.


       

      
        	
                10.2

              	
                Case
      Report Forms

              


      

       

      The
Investigator is responsible for maintaining adequate and accurate medical
records from which accurate information will be transferred into the study
database. Case Report Forms (CRFs) should be completed by the Investigator or
delegated personnel.

      


      CRFs will
be provided for each patient. All data will be entered in black ink.
Data/corrections entered will be signed or initialed by the study personnel
undertaking that procedure. Overwriting data or use of liquid correcting fluid
is not allowed. Detailed instructions are provided with the
CRF.


       

      
        	
                10.3

              	
                Monitoring
      and quality control

              


      

       

      To ensure
compliance with relevant regulations, data generated by this study must be
available for inspection upon request by representatives of BioLine Innovations
Jerusalem, Averion International (CRO), auditing personnel and relevant local
regulatory authorities.

      


      Regular
on-site visits for monitoring of study activities and data recording will be
scheduled. Formal reports of these visits will be generated and copies provided
to relevant Sponsor and study personnel.


       

      
        	
                10.4

              	
                Publication
      policy

              


      

       

      The
results of the study are the property of the Sponsor. All manuscripts, abstracts
or other modes of presentation arising from the results of the study must be
reviewed and approved in writing by the Sponsor, in advance of submission.
Co-authorship with any Sponsor personnel will be discussed and mutually agreed
upon before submission of a manuscript to a publisher.

      
         

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4 

        01 December
2008


         

      

      
        
          
          

        

        
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                11

              	
                References

              


      

      


      
        	
                1.

              	
                GMP
      guideline Volume 4, Annex 13 Manufacture of Investigational Medicinal
      Products (July 2003 Revision 1)

              
	 	 


      

      
        	
                2.

              	
                Marcus
      ML, Wilson RF and White CW. Methods of measurement of myocardial blood
      flow in patients: a critical review, Circulation 1987, 76;
      245-253

              
	 	 


      

      
        	
                3.

              	
                Bassand
      et al., Guidelines for the diagnosis and treatment of patients with
      non-ST-segment elevation acute coronary syndromes. European Heart Journal
      2007, 27; 1598-1660

              
	 	 


      

      
        	
                4.

              	
                Silber
      S et al. ESC
      Guidelines: Guidelines for percutaneous coronary interventions. European Heart Journal
      2005, 26; 804-847

              
	 	 


      

      
        	
                5.

              	
                Van
      de Werf et al., Management of acute myocardial infarction in patients
      presenting with ST-segment elevation. European Heart Journal
      2003, 24; 28-66.

              
	 	 


      

      
        	
                6.

              	
                Rector
      TS, Francis GS, Cohn JN. Patients’ self-assessment of their congestive
      heart failure. Part 1 Patient perceived dysfunction and its poor
      correlation with maximal exercise tests. Heart Failure 1987, Oct/Nov;
      192-196.

              
	 	 


      

      
        	
                7.

              	
                Rector
      TS, Kubo SH, Cohn JN: patients’ self-assessment of their congestive heart
      failure. Part 2: Content, reliability and validity of a new measure, the
      Minnesota Living with Heart Failure questionnaire. Heart Failure 1987,
      Oct/Nov; 198-209.

              
	 	 


      

      
        	
                8.

              	
                Rector
      TS. A conceptual model of the quality of life in relation to heart
      failure. J Cardiac
      Failure 2006.

              


      

      
         

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      Appendix A: Declaration of Helsinki

      


      
        	
                Initiated:
      1964 17.C

              	
                Original:
      English

              


      

       

      WORLD
MEDICAL ASSOCIATION DECLARATION OF HELSINKI

      
        Ethical
Principles

      

      
        for

      

      
        Medical
Research Involving Human Subjects

      

       

      Adopted
by the 18th WMA General Assembly

      
         
Helsinki,
Finland, June 1964

      

      
         
and
amended by the

      

      
         
29th WMA
General Assembly, Tokyo, Japan, October 1975

      

      
         
35th WMA
General Assembly, Venice, Italy, October 1983

      

      
         
41st WMA
General Assembly, Hong Kong, September 1989

      

      
         
48th WMA
General Assembly, Somerset West, Republic of South Africa, October
1996

      

       

      
         
and
the

      

       

      
         
52nd WMA
General Assembly, Edinburgh, Scotland, October 2000

      

      
         
Note of
Clarification on Paragraph 29 added by the WMA General Assembly, Washington
2002

      

      
         
Note of
Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo
2004

      

       

      A.
INTRODUCTION


       

      
        	
                1.

              	
                The
      World Medical Association has developed the Declaration of Helsinki as a
      statement of ethical principles to provide guidance to physicians and
      other participants in medical research involving human subjects. Medical
      research involving human subjects includes research on identifiable human
      material or identifiable data.

              


      

       

      
        	
                2.

              	
                It
      is the duty of the physician to promote and safeguard the health of the
      people. The physician’s knowledge and conscience are dedicated to the
      fulfillment of this duty.

              


      

       

      
        	
                3.

              	
                The
      Declaration of Geneva of the World Medical Association binds the physician
      with the words, "The health of my patient will be my first consideration,"
      and the International Code of Medical Ethics declares that, "A physician
      shall act only in the patient's interest when providing medical care which
      might have the effect of weakening the physical and mental condition of
      the patient."

              


      

       

      
        	
                4.

              	
                Medical
      progress is based on research which ultimately must rest in part on
      experimentation involving human
subjects.

              


      

       

      
        	
                5.

              	
                In
      medical research on human subjects, considerations related to the
      well-being of the human subject should take precedence over the interests
      of science and society.

              


      

       

      
        	
                6.

              	
                The
      primary purpose of medical research involving human subjects is to improve
      prophylactic, diagnostic and therapeutic procedures and the understanding
      of the aetiology and pathogenesis of disease. Even the best proven
      prophylactic, diagnostic, and therapeutic methods must continuously be
      challenged through research for their effectiveness, efficiency,
      accessibility and quality.

              


      

      
         

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                7.

              	
                In
      current medical practice and in medical research, most prophylactic,
      diagnostic and therapeutic procedures involve risks and
      burdens.

              


      

       

      
        	
                8.

              	
                Medical
      research is subject to ethical standards that promote respect for all
      human beings and protect their health and rights. Some research
      populations are vulnerable and need special protection. The particular
      needs of the economically and medically disadvantaged must be recognised.
      Special attention is also required for those who cannot give or refuse
      consent for themselves, for those who may be subject to giving consent
      under duress, for those who will not benefit personally from the research
      and for those for whom the research is combined with
  care.

              


      

       

      
        	
                9.

              	
                Research
      Investigators should be aware of the ethical, legal and regulatory
      requirements for research on human subjects in their own countries as well
      as applicable international requirements. No national ethical, legal or
      regulatory requirement should be allowed to reduce or eliminate any of the
      protections for human subjects set forth in this
    Declaration.

              


      

       

      B.
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH

       

      
        	
                10.

              	
                It
      is the duty of the physician in medical research to protect the life,
      health, privacy, and dignity of the human
  subject.

              


      

       

      
        	
                11.

              	
                Medical
      research involving human subjects must conform to generally accepted
      scientific principles, be based on a thorough knowledge of the scientific
      literature, other relevant sources of information, and on adequate
      laboratory and, where appropriate, animal
  experimentation.

              


      

       

      
        	
                12.

              	
                Appropriate
      caution must be exercised in the conduct of research which may affect the
      environment, and the welfare of animals used for research must be
      respected.

              


      

       

      
        	
                13.

              	
                The
      design and performance of each experimental procedure involving human
      subjects should be clearly formulated in an experimental protocol. This
      protocol should be submitted for consideration, comment, guidance, and
      where appropriate, approval to a specially appointed ethical review
      committee, which must be independent of the Investigator, the sponsor or
      any other kind of undue influence. This independent committee should be in
      conformity with the laws and regulations of the country in which the
      research experiment is performed. The committee has the right to monitor
      ongoing trials. The researcher has the obligation to provide monitoring
      information to the committee, especially any serious adverse events. The
      researcher should also submit to the committee, for review, information
      regarding funding, sponsors, institutional affiliations, other potential
      conflicts of interest and incentives for
  subjects.

              


      

       

      
        	
                14.

              	
                The
      research protocol should always contain a statement of the ethical
      considerations involved and should indicate that there is compliance with
      the principles enunciated in this
Declaration.

              


      

       

      
        	
                15.

              	
                Medical
      research involving human subjects should be conducted only by
      scientifically qualified persons and under the supervision of a clinically
      competent medical person. The responsibility for the human subject must
      always rest with a medically qualified person and never rest on the
      subject of the research, even though the subject has given
      consent.

              


      

       

      
        	
                16.

              	
                Every
      medical research project involving human subjects should be preceded by
      careful assessment of predictable risks and burdens in comparison with
      foreseeable benefits to the subject or to others. This does not preclude
      the participation of healthy volunteers in medical research. The design of
      all studies should be publicly
available.

              


      

      
         

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                17.

              	
                Physicians
      should abstain from engaging in research projects involving human subjects
      unless they are confident that the risks involved have been adequately
      assessed and can be satisfactorily managed. Physicians should cease any
      investigation if the risks are found to outweigh the potential benefits or
      if there is conclusive proof of positive and beneficial
      results.

              


      

       

      
        	
                18.

              	
                Medical
      research involving human subjects should only be conducted if the
      importance of the objective outweighs the inherent risks and burdens to
      the subject. This is especially important when the human subjects are
      healthy volunteers.

              


      

       

      
        	
                19.

              	
                Medical
      research is only justified if there is a reasonable likelihood that the
      populations in which the research is carried out stand to benefit from the
      results of the research.

              


      

       

      
        	
                20.

              	
                The
      subjects must be volunteers and informed participants in the research
      project.

              


      

       

      
        	
                21.

              	
                The
      right of research subjects to safeguard their integrity must always be
      respected. Every precaution should be taken to respect the privacy of the
      subject, the confidentiality of the patient’s information and to minimise
      the impact of the study on the subject's physical and mental integrity and
      on the personality of the subject.

              


      

       

      
        	
                22.

              	
                In
      any research on human beings, each potential subject must be adequately
      informed of the aims, methods, sources of funding, any possible conflicts
      of interest, institutional affiliations of the researcher, the anticipated
      benefits and potential risks of the study and the discomfort it may
      entail. The subject should be informed of the right to abstain from
      participation in the study or to withdraw consent to participate at any
      time without reprisal. After ensuring that the subject has understood the
      information, the physician should then obtain the subject's freely given
      informed consent, preferably in writing. If the consent cannot be obtained
      in writing, the non-written consent must be formally documented and
      witnessed.

              


      

       

      
        	
                23.

              	
                When
      obtaining informed consent for the research project the physician should
      be particularly cautious if the subject is in a dependent relationship
      with the physician or may consent under duress. In that case the informed
      consent should be obtained by a well-informed physician who is not engaged
      in the investigation and who is completely independent of this
      relationship.

              


      

       

      
        	
                24.

              	
                For
      a research subject who is legally incompetent, physically or mentally
      incapable of giving consent or is a legally incompetent minor, the
      Investigator must obtain informed consent from the legally authorised
      representative in accordance with applicable law. These groups should not
      be included in research unless the research is necessary to promote the
      health of the population represented and this research cannot instead be
      performed on legally competent
persons.

              


      

       

      
        	
                25.

              	
                When
      a subject deemed legally incompetent, such as a minor child, is able to
      give assent to decisions about participation in research, the Investigator
      must obtain that assent in addition to the consent of the legally
      authorised representative.

              


      

       

      
        	
                26.

              	
                Research
      on individuals from whom it is not possible to obtain consent, including
      proxy or advance consent, should be done only if the physical/mental
      condition that prevents obtaining informed consent is a necessary
      characteristic of the research population. The specific reasons for
      involving research subjects with a condition that renders them unable to
      give informed consent should be stated in the experimental protocol for
      consideration and approval of the review committee. The protocol should
      state that consent to remain in the research should be obtained as soon as
      possible from the individual or a legally authorised
      surrogate.

              


      

       

      
        	
                27.

              	
                Both
      authors and publishers have ethical obligations. In publication of the
      results of research, the Investigators are obliged to preserve the
      accuracy of the results. Negative as well as positive results should be
      published or otherwise publicly available. Sources of funding,
      institutional affiliations and any possible conflicts of interest should
      be declared in the publication. Reports of experimentation not in
      accordance with the principles laid down in this Declaration should not be
      accepted for publication.

              


      

      
         

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A

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2008


         

      

      
        
          
          

        

        
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      C.
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL
CARE

      
         

        
          	
                  28.

                	
                  
                    The
      physician may combine medical research with medical care, only to the
      extent that the research is justified by its potential prophylactic,
      diagnostic or therapeutic value. When medical research is combined with
      medical care, additional standards apply to protect the patients who are
      research subjects.

                  

                


        

         

        
          	
                  29.

                	
                  
                    The
      benefits, risks, burdens and effectiveness of a new method should be
      tested against those of the best current prophylactic, diagnostic, and
      therapeutic methods. This does not exclude the use of placebo, or no
      treatment, in studies where no proven prophylactic, diagnostic or
      therapeutic method exists.

                  

                


        

         

        
          	
                  30.

                	
                  
                    At
      the conclusion of the study, every patient entered into the study should
      be assured of access to the best proven prophylactic, diagnostic and
      therapeutic methods identified by the
  study.

                  

                


        

         

        
          	
                  31.

                	
                  
                    The
      physician should fully inform the patient which aspects of the care are
      related to the research. The refusal of a patient to participate in a
      study must never interfere with the patient-physician
      relationship.

                  

                


        

         

        
          	
                  32.

                	
                  
                    In
      the treatment of a patient, where proven prophylactic, diagnostic and
      therapeutic methods do not exist or have been ineffective, the physician,
      with informed consent from the patient, must be free to use unproven or
      new prophylactic, diagnostic and therapeutic measures, if in the
      physician’s judgement it offers hope of saving life, re-establishing
      health or alleviating suffering. Where possible, these measures should be
      made the object of research, designed to evaluate their safety and
      efficacy. In all cases, new information should be recorded and, where
      appropriate, published. The other relevant guidelines of this Declaration
      should be followed.

                  

                


        

         

      

      
        	
                § §
      §

              


      

       

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A

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      Appendix
B: Minnesota Living with Heart FailureÒ questionnaire

      
         

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Appendix B

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      LIVING
WITH HEART FAILURE QUESTIONNAIRE

      


      Instructions for
Use

      


      
        	
                1.

              	
                Patients
      should respond to the questionnaire prior to other assessments and
      interactions that may bias responses. You may tell the patient that you
      would like to get his or her opinion before doing other medical
      assessments.

              


      

      


      
        	
                2.

              	
                Ample,
      uninterrupted time should be provided for the patient to complete the
      questionnaire.

              


      

      


      
        	
                3.

              	
                The
      following instructions should be given to the patient each time the
      questionnaire is completed.

              


      

      


      
        	
                 
      

              	
                a.

              	
                Read
      the introductory paragraph at the top of the questionnaire to the
      patient.

              


      

      


      
        	
                 
      

              	
                b.

              	
                Read
      the first question to the patient - "Did your heart failure prevent you
      from living as you wanted during the past month by causing swelling in
      your ankles or legs"? Tell the patient, "If you did not have any ankle or
      leg swelling during the past month you should circle the zero after this
      question to indicate that swelling was not a problem during the past
      month". Explain to the patient that if he or she did have swelling that
      was caused by a sprained ankle or some other cause that was definitely not
      related to heart failure he or she should also circle the zero. Tell the
      patient, "If you are not sure why you had the swelling or think it was
      related to your heart condition, then rate how much the swelling prevented
      you from doing things you wanted to do and from feeling the way you would
      like to feel". In other words, how bothersome was the swelling? Show the
      patient how to use the 1 to 5 scale to indicate how much the swelling
      affected his or her life during the past month - from very little to very
      much.

              


      

      


      
        	
                4.

              	
                Let
      the patient read and respond to the other questions. The entire
      questionnaire may be read directly to the patient if one is careful not to
      influence responses by verbal or physical
cues.

              


      

      


      
        	
                5.

              	
                Check
      to make sure the patient has responded to each question and that there is
      only one answer clearly marked for each question. If a patient elects not
      to answer a specific question(s) indicate so on the
      questionnaire.

              


      

      


      
        	
                6.

              	
                Score
      the questionnaire by summating the responses to all 21 questions. In
      addition, physical (items 2, 3, 4, 5, 6, 7, 12 and 13) and emotional
      (items 17, 18, 19, 20, and 21) dimensions of the questionnaire have been
      identified by factor analysis, and may be examined to further characterize
      the effect of heart failure on a patient's
life.

              


      

      
        
           

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Appendix B

          01 December
2008


           

        

      

      
        
          
          

        

        
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      LIVING
WITH HEART FAILURE QUESTIONNAIRE

      


      These
questions concern how your heart failure (heart condition) has prevented you
from living as you wanted during the last month. The items listed below describe
different ways some people are affected. If you are sure an item does not apply
to you or is not related to your heart failure then circle 0 (No) and go on to
the next item. If an item does apply to you, then circle the number rating how
much it prevented you from living as you wanted.

      


      Did
your heart failure prevent you from

      living
as you wanted during the last

      month
by:

      


      
        	 	 	 
      	 	
                No

              	 	 	
                Very
      little

              	 	 	 	 	 	 	 	 	 	 	 	
                Very
      

                much

              	 
	1.	 	
                Causing
      swelling in your ankles, legs, etc.?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	2.	 	
                Making
      you sit or lie down to rest during the day?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	3.	 	
                Making
      your walking about or climbing stairs difficult?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	4.	 	
                Making
      your working around the house or yard difficult?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	5.	 	
                Making
      your going places away from home difficult?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	6.	 	
                Making
      your sleeping well at night difficult?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	7.	 	
                Making
      your relating to or doing things with your friends or family
      difficult?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	8.	 	
                Making
      your working to earn a living difficult?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	9.	 	
                Making
      your recreational pastimes, sports or hobbies difficult?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	10.	 	
                Making
      your sexual activities difficult?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	11.	 	
                Making
      you eat less of the foods you like?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	12.	 	
                Making
      you short of breath?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	13.
      	 	
                Making
      you tired, fatigued, or low on energy?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	14.
      	 	
                Making
      you stay in a hospital?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	15.
      	 	
                Costing
      you money for medical care?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	16.	 	
                Giving
      you side effects from medications?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	17.
      	 	
                Making
      you feel you are a burden to your family or friends?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	18.	 	
                Making
      you feel a loss of self-control in your life?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	19. 	 	
                Making
      you worry?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	20.	 	
                Making
      it difficult for you to concentrate or remember things?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 
	21.	 	
                Making
      you feel depressed?

              	 	 	0	 	 	 	1	 	 	 	2	 	 	 	3	 	 	 	4	 	 	 	5	 


      

       

      Copyright
University of Minnesota 1986.

      
        
           

          Annotated
Protocol incorporating Amendment 1, Amendment 2, Amendment 3, and Amendment 4  
Appendix B

          01 December
2008


           

        

      

      
        
          
          

        

        
          Page 52
of 52

          
            

          

        

        
          
          

        

      

    

    


    SCHEDULE
1.31

     

    DESCRIPTIONS OF OTHER
ON-GOING TRIALS

     

    
      
        
          
            
              
                
                  
                    
                      
                        	
                                Name of Study

                              	 	
                                Estimated Duration

                              	 	
                                Estimated End Date

                              
	
                                [***]

                              	 	
                                [***]

                              	 	
                                [***]

                              
	
                                [***]

                              	 	
                                [***]

                              	 	
                                [***]

                              
	
                                [***]

                              	 	
                                [***]

                              	 	
                                [***]

                              


                      

                    

                  

                

              

            

          

        

      

    

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          
          

          
            

          

        

        
           


        

      

    

    


    SCHEDULE
1.35

     

    OUTLINE OF STRUCTURE FOR
PIVOTAL CLINICAL TRIAL FOR PRIMARY INDICATION

     

    (see
Schedule 3.1)

    


    
      
        
           


        

        
          
          

          
            

          

        

        
           


        

      

    

    


    SCHEDULE
1.42(a)

     

    
      INDEPENDENT
SAFETY MONITORING BOARD CHARTER

    

     

    Independent
Safety Monitoring Board

    


    Charter

    


    For

    


    Bioline
Innovations Jerusalem

    


    Protocol
No. BL-1040

    


    
      
        	
                 

                A
      Phase I, multi-center, open label study designed to assess the safety and
      feasibility of the injectable BL-1040 implant to provide scaffolding to
      infarcted myocardial tissue

                 

              


      

    

    


    
      
        
           


        

        
          
          

          
            

          

        

        
           


        

      

    

     

    

      APPROVING
OFFICIALS

       

      
        
          
            
              
                
                  
                    
                      
                        	
                                Name

                              	 
      	
                                Title

                              	 
      	
                                Signature

                              	 
      	
                                Date

                              
	 
      	 
      	 
      	 
      	 
      	 
      	 
      
	
                                Lincoff,
      A. Michael, M.D

                              	 
      	
                                Chairman
      ISMB

                              	 
      	
                                  

                              	 
      	
                                  

                              
	 
      	 
      	 
      	 
      	 
      	 
      	 
      
	
                                Moti
      Gal

                              	 
      	
                                Sponsor
      Contact Person

                              	 
      	
                                  

                              	 
      	
                                  

                              
	 
      	 
      	 
      	 
      	 
      	 
      	 
      
	
                                Andrea
      Kempf-Müller, M.D

                              	
                                  

                              	
                                 Drug
      Safety Officer

                              	
                                  

                              	
                                  

                              	
                                  

                              	
                                  

                              


                      

                    

                  

                

              

            

          

        

      
 

      
        
           


        

        
           


          
            

          

        

        
           


        

      


      Contact
details ISMB members

      


      Lincoff,
A. Michael,
M.D.                                                                                          ISMB
Chairman

      The
Cleveland Clinic Foundation

      9500
Euclid Avenue - F25

      Cleveland,
OH  44195

      Phone: 
216.444.2367

      FAX: 
216.636.0609

      lincofa@ccf.org

       

      Philippe
Gabriel Steg, M.D., F.A.C.C

      Hopital
Bichat-Claude BernadService de Cardiologie

      46 Rue
Henri Huchard

      75018
Paris

      FRANCE

      gabriel.steg@bch.aphp.fr

       

      Michael
Marber BSc, MB.BS, PhD, FRCP

      Professor
of Cardiology

      King's
College London

      Honorary
Consultant Cardiologist

      Guy’s
& St Thomas’ Hospitals

      The Rayne
Institute, St Thomas' Hospital

      Lambeth
Palace Rd, London SE1 7EH

      mike.marber@kcl.ac.uk

       

      Kerry
Lee, Ph.D.

      Duke
Clinical Research Institute

      2400
Pratt Street

      Room 0311
Terrace Level

      Durham,
NC  27705

      Ph:
919-668-8725

      Fx:
919-668-7055

      kerry.lee@duke.edu
 

      
        
           


        

        
           


          
            

          

        

        
           


        

      


      Contact
details BioLine and Averion

      


      
        	
                Project
      Manager

                Averion:

                Frederic
      Liegeois, Msc

              	 
      	
                Address:
      2268 chemin de Sourdaine

                F-84140
      Montfavet

                Phone:
      +33 (0)490140997

                Mobile:
      +33 (0)681607626

                Email:
      frederic.liegeois@averionintl.com

              
	 
      	 
      	 
      
	
                Senior
      Drug Development Manager

                Bioline:

                Tuvia
      Shmuel, PhD

                 

              	 
      	
                Address:
      BioLine Innovations Jerusalem,

                19
      Hartum St., POB 45158 Jerusalem,

                Israel
      91450

                Phone:
      +972-2-548-9100, ext. 124

                Fax:
      +972-2-548-9101

                e-mail:
      shmuelt@biolinerx.com

              
	 
      	 
      	 
      
	
                ISMB
      Sponsor Representative

                Bioline:

                Adina
      Porat

              	 
      	
                Address:
      BioLine Innovations Jerusalem,

                19
      Hartum St., POB 45158

                Phone:
      +972-2-548-9100 ex. 135

                Mobile:
      +972-54-5594613

                Fax:
      +972-2-548-9101

                E-Mail:
      adinap@biolinerx.com

              
	 
      	 
      	 
      
	
                Clinical
      Operations Manager

                Bioline:

                Moti
      Gal

              	 
      	
                Address:
      BioLine Innovations Jerusalem,

                19
      Hartum St., POB 45158

                Telephone:
      +972-2-548-9100 ex. 147

                Mobile:
      +972-54-5933127

                Fax:
      +972-2-548-9101

                E-Mail:
      motig@biolinerx.com

              
	 
      	 
      	 
      
	
                ISMB
      Coordinator

                Venn
      Life Sciences AG

                 

              	 
      	
                Medical
      Monitor, Europe

                Andrea
      Kempf-Müller, MD

                Venn
      Life Sciences AG

                Elisabethenstrasse
      23/3

                4051
      Basel, Switzerland

                 Tel:
      +41 61 201 11 83

                Mobile:
      + 41 79 348 54 59

                Fax:
      +41 61 273 42 50

                Email:
      andrea.kempf-mueller@vlsworldwide.com
      
 

                Medical
      Monitor, US (only for ISMB contact)

                 Sanjay
      Machado, MD

                Venn
      Life Sciences

                7355
      Trans-Canada Suite 200

                St-Laurent,
      QC, Canada

                H4T-1T3

                Tel:
      (541) 315-2992 117

                Mobile:
      (514) 946-7678

                Fax:
      (514) 315-0995

                Email:
      sanjaym@vlscanada.com

              


      

       

      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

      
        	
                1.

              	
                PROTOCOL
      BL-1040

              


      

      A Phase
I, multi-center, open label study designed to assess the safety and feasibility
of the injectable BL-1040 implant to provide scaffolding to infarcted myocardial
tissue.

       

      
      

      Venn Life
Sciences AG has been contracted by Bioline Innovations Jerusalem to provide
services as the Contract Research Organization (CRO) for the trial.

       

      
        	
                2.

              	
                SCOPE
      OF THE ISMB CHARTER

              


      

      The
International Independent Safety Monitoring Board (ISMB) was formed to monitor
the safety of patients participating in this trial on an ongoing
basis.

       

      The ISMB
will evaluate quality, accuracy and timeliness of data flow and assure
confidentiality of data.

       

      The ISMB
will develop stopping rules for the termination of the study prior to the
initiation.

       

      Bioline
Innovations Jerusalem will forward the charter to Regulatory Authorities, and/or
Ethics Committees as necessary.


       

      The
objective of the ISMB Charter is to outline the specific purposes and functions
of the ISMB. In addition, it describes the procedures for data abstraction and
data delivery conventions to and from the ISMB members for review
purposes.

       

      
        	
                3.

              	
                COMPOSITION
      OF THE ISMB

              


      

      The ISMB
is composed of three members, three voting members including the Chairman. In
addition a bio-statistician will consult the ISMB however will not attend as a
voting member. The members are independent physicians in the field of cardiology
and a bio-statistician experienced in evaluating safety data from cardiology
clinical studies. Prof. Lincoff will serve as Chairman of the ISMB. All ISMB
members have been approved by the sponsor, Bioline Innovations
Jerusalem.

      


      By
signing the ISMB Charter, voting ISMB members verify that they do not have a
vested interest in the outcome of the study, nor do they have a financial
conflict of interest. ISMB members are not employees of Bioline Innovations
Jerusalem have outside employment and will not be involved in patient
recruitment or as investigators in the study.


      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

      The ISMB
members are expected to serve until the study is completed. Should a member
resign, the reason and effective date of resignation must be submitted in
writing to Bioline Innovations Jerusalem and the ISMB Chairman. A replacement
member will be sought by Bioline Innovations Jerusalem in consultation with the
ISMB Chairman.

       

      Except
for the initial meeting of the ISMB where the background data on BL-1040 and the
study design will be discussed by Bioline Innovations Jerusalem’s’
representatives, Bioline Innovations Jerusalem will not participate in the ISMB
meetings unless requested by the ISMB.

       

      ISMB
Administration

      From Venn
Life Sciences AG, the ISMB Coordinator will arrange for the provision of the
data and narratives required by the ISMB. Bioline Innovations Jerusalem will
provide administrative, logistical and coordinating services to the
ISMB.

       

      ISMB
Contacts & Consultants

      The
Chairman will be the representative of the ISMB who will be responsible for
timely official communications between the ISMB and Bioline Innovations
Jerusalem. The Chairman will provide leadership and oversee that the direction
of ISMB meeting operations are in accordance with the ISMB charter.

       

      From the
sponsor, Bioline Innovations Jerusalem, an identified representative will serve
as the primary contact person for the ISMB. The sponsor primary contact is named
on the ISMB charter. This individual is not considered to be a member of the
ISMB and will only attend open and final sessions of ISMB Data Review
Meetings.

       

      From Venn
Life Sciences AG, the ISMB Coordinator will serve as the primary contact person
for any questions the ISMB members have regarding the contents of the ISMB Data
Reports. This individual is not considered to be a member of the ISMB and will
only attend open and final sessions of ISMB Data Review Meetings. Additional
individuals may also be invited to attend the open and final sessions of the
ISMB Data Review meetings, as deemed appropriate.
 

      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

      The ISMB
Chairman will ensure that ISMB contacts are not
exposed to the ISMB review of the data until the ISMB has arrived at a
conclusion. ISMB contacts may not be present during
closed sessions, when the ISMB Data Report is reviewed, ISMB deliberations are
made, ISMB recommendations are discussed and/or ISMB voting procedures are
conducted.

       

      
        	
                4.

              	
                ISMB
      ROLE & RESPONSIBILITIES

              


      

      The ISMB
is an independent expert advisory group commissioned and charged with the
responsibility of evaluating accumulating data at regular intervals and ensuring
the safety of the subjects enrolled in the study by monitoring cumulative safety
data collected in the clinical program and providing recommendations to Bioline
Innovations Jerusalem based on review of this data. The ISMB will contribute to
efficient conduct of the trial by providing a fast review of emerging findings
from the study. This ISMB will consist of physicians with expertise in
cardiovascular disease, particularly in the area of coronary artery disease and
with experience monitoring safety of drugs and/or devices for cardiovascular
applications, and will have no participation in the trial in any other
capacity.

       

      These
reviews in subsets of patients will have the objective of searching for signals
of clinically important adverse safety findings that may be indicative of risk
to currently enrolled patients as well as increased risk for future patients. In
these reviews, the ISMB will assume a conservative approach in assessing
safety.

       

      
      

      The
Chairman will be directly responsible for reporting the outcome of all ISMB
meetings and be the primary contact for any emergency meetings, as appropriately
convened. He will be a voting member of the ISMB. The Chairman will also be
responsible for the preparation of the report and/or recommendations to Bioline
Innovations Jerusalem.

       

      
      

      The three
voting members of the ISMB (along with the Chairman) will be responsible for
evaluating the safety data and making recommendations on the continuation of the
study as set out in the protocol. They may also make other pertinent safety
recommendations for the conduct of the study. They will be guided by the ISMB
Biostatistician’s evaluation of the data, as required.


      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

      The
bio-statistician will be involved in conducting any analysis that the ISMB
recommends. The Bio-statistician will be responsible for designing and
maintaining the safety database that the ISMB will use for its analysis. This
database may differ from the database by Venn Life Sciences AG and, as such, is
meant only for the use of the ISMB. The database will be created in such a way
that it is reproducible and can be audited, if necessary. If the ISMB is
considering a recommendation of premature termination of the study, the
bio-statistician can contact Venn Life Sciences AG for additional data and/or
for the performance of confirmatory analysis. The Bio-statistician can also
arrange for the necessary ISMB communications to be documented and stored and
only to be released after study completion.

       

      The ISMB
will ensure that this study meets the highest standards of patient safety. In
their analysis of the data from the patients, the ISMB will be focused on
determining if there is a signal of clinically significant pattern of change in
safety parameters that may lead to termination of study. This may require the
ISMB to perform/request additional data/analyses prior to making a
decision.

       

      The
operating procedures of the ISMB are based on and are in compliance with
guidance and definitions of the International Conference on Harmonization and
the Food and Drug Administration. The ISMB will conduct all of its operations
under the ICH Good Clinical Practices (GCP).


       

      Specifically,
the ISMB is authorized and charged to perform the following
functions:

      


      
        	
                 
      

              	
                ·

              	
                review
      30 day safety data patients from the first 2 sequentially enrolled
      patients to determine whether 3 additional patients may be enrolled; after
      reviewing the 30 day safety data from these 3 additional patients, will
      determine whether the rest of patients may be
  enrolled

              


      

      
        	
                 
      

              	
                ·

              	
                within
      30 days of enrolment of each successive group of 5 patients receiving the
      device, will review all Serious and Severe Adverse Events occurring to
      date and will recommend continuation, discontinuation, or modification of
      the procedure or protocol, based on a determination of whether the
      occurrence of serious, unexpected, or device-related adverse events (Sec.
      7 in protocol) might outweigh the potential benefit achievable with the
      device

              


      

      
        	
                 
      

              	
                ·

              	
                review
      emerging findings in patients and identify potential safety concerns with
      BL-1040

              


      

      
        	
                 
      

              	
                ·

              	
                will
      receive information, on an expedited basis, on all Serious and Severe
      Adverse Events, clinically significant laboratory values (as defined in
      the study safety plan), ECG abnormalities and vital signs that are
      associated with Serious and Severe Adverse Events, and data from patients
      who decided to withdraw from the study due to Serious and Severe Adverse
      Events. All Serious and Severe Adverse Events that occur in the catheter
      lab during the administration of BL-1040 or the hospitalization period
      after the procedure should be reviewed promptly by the ISMB. The ISMB will
      review this information and may decide to interrupt, alter, or terminate
      the trial.

              


      


      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

      
        	
                 
      

              	
                ·

              	
                will
      adjudicate whether or not an event is unexpected, based on a pre-specified
      list of expected Serious and Severe Adverse Events  as well as
      clinical judgment within the study population.

              


      

       

      All ISMB
members will review the safety data provided by the CRO. The members will reach
their own individual decision on the relatedness and the potential hazard posed
by the event. The ISMB will then collectively discuss the cases. In the event
the majority opinion of the Board is that the events do not pose any significant
risk then the ISMB will recommend continuing the trial as designed. However, if
the Board decides that undue risk could accrue from continuation of the study as
designed, the ISMB has the freedom to recommend appropriate changes to the study
selection criteria, safety evaluations, etc. In addition, the CRO will provide
datasets and listings capturing disposition, AEs, clinically significant
Echocardiography, MRI, angiography, Holter, ECG vital signs/laboratory changes,
once all patients complete study.

      
 

      
        	
                5.

              	
                VENN
      LIFE SCIENCES AG ROLE &
RESPONSIBILITIES

              


      

      Venn Life
Sciences AG will provide coordinating services for the study. The ISMB
Coordinator will provide information, on an expedited basis, on all Serious and
Severe Adverse Events, clinically significant laboratory values (as defined in
the study safety plan, ECG abnormalities and vital signs that are associated
with Serious and Severe Adverse Events as required, to the ISMB members. Venn
Life Sciences AG will be charged with the following
responsibilities:

       

      
        	
                -

              	
                To
      identify a specific individual to interface with the
  ISMB.

              


      

      
        	
                -

              	
                To
      provide all required information in advance of the meeting in a mutually
      agreeable format approved at the initial meeting of the
    ISMB.

              


      

      
        	
                -

              	
                To
      provide a standard safety narrative for all patients who withdraw from the
      study due to Serious or Severe Adverse
Events.

              


      

      
        	
                -

              	
                To
      provide specific meeting issues in advance of the
  meeting.

              


      

      
        	
                -

              	
                To
      keep the ISMB Chairman informed of any serious safety issues as the study
      progresses

              


      

      
        	
                -

              	
                To
      inform each principal investigator of the ISMB recommendations, as
      required.

              


      

      
        	
                -

              	
                To
      notify Bioline Innovations Jerusalem of any issues related to the ISMB
      which might negatively influence the
study.

              


      

       

      
        
          	
                  6.

                	
                  BIOLINE
      INNOVATIONS JERUSALEM’S
RESPONSIBILITIES

                


        

      

      Bioline
Innovations Jerusalem will be responsible for the following:


      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

      
        	
                -

              	
                To
      make any necessary changes to the protocol recommended by the ISMB and
      approved by Bioline Innovations
Jerusalem.

              


      

      
        	
                -

              	
                To
      ensure that the ISMB is operating as needed for the purpose of the
      study.

              


      

      


      
        
          	
                  7.

                	
                  ONGOING
      COMMUNICATIONS &
NOTIFICATIONS

                


        

      

      The ISMB
Chairman will receive relevant information regarding serious adverse events and
Early Terminations on an ongoing basis. The ISMB Chairman will determine whether
further distribution of this material to the remaining voting ISMB members is
necessary.

       

      
        	
                8.

              	
                DATA
      REVIEW MEETINGS

              


      

      ISMB Data
Review meetings will be held in person or through teleconferences based on the
volume of data to be reviewed. The ISMB Coordinator will establish the agenda
for each ISMB Data Review meeting, with input from Bioline Innovations Jerusalem
and the ISMB Chairman.

       

      It is
expected that there will be one initiation and at least three scheduled ISMB
Data Review meetings. The initiation meeting will be held via face-to-face
format, while the Data Review Meetings may be held via
teleconference.


       

      The
first 2 patients will be sequentially enrolled into the study. After the 1st
patient has completed Day 30 assessments, the Independent Safety Monitoring
Board (ISMB, Sec. 4.3) will review the patient’s data through Day 30 (first ISMB
meeting). The ISMB will then decide whether to give approval to enroll the 2nd
patient. After the 2nd patient has completed Day 30 assessments, the ISMB will
again review the data and provide approval for enrollment of the next 3 patients
(2nd ISMB meeting). After all 3 patients have completed Day 30 assessments, the
ISMB will review the data from these patients and provide approval for opening
enrollment to the rest of the patients (3rd meeting)

       

      The ISMB
may also elect to hold ad hoc meetings outside of the scheduled dates, if deemed
necessary. For instance, as the ISMB Chairman will receive information regarding
reported serious adverse events on a regular basis, ad-hoc ISMB meetings may
also be held on a triggered basis (e.g. in response to a high number of safety
events).


      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

      Voting

      Input
must be obtained from all three ISMB members, for voting purposes. The ISMB will
strive for a consensus opinion regarding the data reviewed. If ISMB consensus is
not possible, a majority vote will be required, to determine the final ISMB
recommendation. If the ISMB vote does not result in a clear majority, the ISMB
Chairman will assemble and present majority and dissenting opinions for all
recommendations considered.

      Meeting
Minutes

       

      ISMB Data
Review meeting minutes will be divided by session and will reflect the
attendance of voting ISMB members, the ISMB Coordinator, ISMB contacts and
consultants and other individuals, as well as whether each individual attended
in person or via teleconference.

       

      Since all
details of ISMB deliberations must be kept strictly confidential among members
of the ISMB, portions of the ISMB Data Review meeting minutes must remain
confidential until the completion of the final study analysis.

       

      The ISMB
Chairman will file all minutes from all sessions, centrally. Once the final
study analysis is complete, the ISMB Chairman will forward the central file of
all ISMB minutes for all sessions to Bioline Innovations Jerusalem for
appropriate filing.


       

      
        	
                9.

              	
                RECORDS
      RETENTION

              


      

      The ISMB
Chairman should maintain a record of all ISMB minutes until the investigation of
the study device is discontinued. After this period, the ISMB Chairman will
forward to the sponsor all records to the sponsor to determine if further
retention and/or archiving is necessary.

       

      Data
Source and Content

       

      
        	
                10.

              	
                ISMB
      COMMUNICATION OF FINAL CONCLUSIONS

              


      

      The ISMB
Chairman will contact Bioline Innovations Jerusalem within two working days
after an ISMB meeting (via facsimile or telephone) to notify them of
recommendations forthcoming from that meeting. Bioline Innovations Jerusalem
will act upon these recommendations as appropriate, i.e., the final decision
will rest with Bioline Innovations Jerusalem. Bioline Innovations Jerusalem’s VP
of Medical Affairs or designee will notify the project team and the CRO of the
ISMB recommendations.

       

      Bioline
Innovations Jerusalem’s VP of Medical Affairs will also write a memo to the
files documenting the recommendations of the ISMB and convey to all
investigators the decision to continue/discontinue the
study.
 

      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

      
        	
                11.

              	
                IMPLEMENTATION
      OF THE ISMB RECOMMENDATIONS

              


      

      The
decision to implement the recommendations of the ISMB will be made by Bioline
Innovations Jerusalem. Bioline Innovations Jerusalem will notify the ISMB of the
actual action taken, in response to all recommendations.

      


      If the
ISMB recommends early study termination or protocol modification and such action
is not accepted or implemented, Bioline Innovations Jerusalem will address this
decision with the ISMB in writing.

       

      
        	
                12.

              	
                CONFIDENTIALITY

              


      

      The ISMB
will maintain a strictly confidential relationship to the study data. The ISMB
will only reveal specific details and information associated with ISMB data
review to appropriate parties, as specified by this ISMB
Charter.
 

      
        
           


        

        
           


          
            

          

        

        
           


        

      

    

     

    SCHEDULE
2.3

     

    EXISTING PRODUCT
AGREEMENTS

     

    [***]

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          
          

          
            

          

        

        
           


        

      

    

     

    
      SCHEDULE
3.1

       

      INITIAL
DEVELOPMENT PLAN

       

      Project
Boston Clinical Development Plan

       

      Objective

       

      This
product is a unique concept, and will require a unique and sophisticated
development plan to satisfy all stakeholders.

       

      This
product has been given a regulatory designation as a device (rather than drug).
The objective of this development plan is to leverage that designation for a
rapid and efficient regulatory approval, while providing adequate evidence for
safety within the intended patient population.

       

      Strategy

       

      The
strategy is to complete a minimal additional amount of preclinical safety in
parallel with the clinical development program. [***]

       

      The
filing will be based on a [***] note that the current phase 2 study has no
control group, and can give only general information about safety and
tolerability, and no real information on efficacy in humans. For this reason the
[***] will be designed with a ‘vanguard’ cohort of
approximately [***] patients. Once the vanguard has completed 6 months of follow
up, and interim analysis will be performed, assessing the study for 1) safety,
2) efficacy or futility and 3) performance of the endpoint. Specific, detailed
and comprehensive criteria will be established to allow for stopping or
continuation, or adjustments in sample size or inclusion criteria. The rules for
the interim analysis will be agreed with regulatory authorities in advance of
any unblinding, and appropriate adjustments will be made for type 1
error.

       

      Following
the interim analysis the number of participating centers will be increased to
speed enrollment, and the study will continue to completion.

       

      Endpoint
and sample size

       

      We will
define [***], and then power the study to show at least a [***] with BL-1040
compared to placebo. This difference is clinically meaningful.

       

      To give
maximum power we want to define an endpoint that has a [***] after treatment,
which would be reduced to [***]. We will design a [***] that ensures an event
rate that is [***] in the control arm.

      
         

        
          

        

      

      [***]
Redacted pursuant to a confidential treatment request.


      
        
           


        

        
           


          
            

          

        

        
           


        

      

       

      Failure
could include [***] Any one of these events
and the patient is [***]’; none of these events
and the patient is considered [***]. It is possible that other clinically
relevant events may be added to the composite.

       

      Next we
will estimate how often each of these events will happen. [***]

       

      
        
          
            
              
                
                  
                    	
                            Control Group

                            Event Rate

                          	
                            Treatment Group

                            Event Rate

                          	
                            Sample size per arm

                            90% power and type 

                            1 error < 5%

                          	
                            Total

                          
	
                            [***]

                          	
                            [***]

                          	
                            [***]

                          	
                            [***]

                          
	
                            [***]

                          	
                            [***]

                          	
                            [***]

                          	
                            [***]

                          
	
                            [***]

                          	
                            [***]

                          	
                            [***]

                          	
                            [***]

                          


                  

                

              

            

          

        

      

       

      Although
not required under device approval regulations, approximately [***] patients
would be desirable for a safety database. If we assume that the placebo event
rate will be approximately [***], we would estimate the sample size of the
pivotal study to be approximately [***] patients, including the [***] patients
in the vanguard cohort.

       

      Budget

       

      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              	 
      	
                                      2009

                                    	
                                      2010

                                    	
                                      2011

                                    	
                                      2012

                                    	
                                      2013

                                    	
                                      2014

                                    	
                                      2015

                                    	
                                      2016

                                    	
                                      TOTAL

                                    
	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	 
      	 
      	 
      
	
                                      [***]

                                    	 
      	 
      	 
      	 
      	 
      	
                                      [***]

                                    	 
      	 
      	 
      
	
                                      [***]

                                    	 
      	 
      	 
      	 
      	 
      	 
      	
                                      [***]

                                    	 
      	 
      
	
                                      [***]

                                    	 
      	 
      	 
      	 
      	 
      	 
      	
                                      [***]

                                    	
                                      [***]

                                    	 
      
	
                                      [***]

                                    	 
      	 
      	 
      	 
      	 
      	 
      	 
      	
                                      [***]

                                    	 
      
	
                                      TOTAL

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    	
                                      [***]

                                    


                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

       

      Phase III
Study

       

      Budget
will assume [***] of [***] patients, with a primary endpoint at [***], major
adverse cardiac outcomes at [***], and a safety follow up annually for
[***].

       

      
        
[***]
Redacted pursuant to a confidential treatment request.

      


      
        
          
             


          

          
             


            
              

            

          

          
             


          

        

      

      


      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  	
                                          Clinical:

                                        	 
      	 
      	 
      	 
	 	 	 	 	 
	
                                          Monitoring:

                                        	
                                           

                                        	 
      	
                                          [***]

                                        	 
	
                                          Per
      Patient total:

                                        	
                                          [***] 
      

                                        	 
      	
                                          [***]

                                        	 
	 	 	 	 	 
	
                                          Pre
      Clinical

                                        	
                                          [***]

                                        	
                                          [***]

                                        	 
      	 
	 	 	 	 	 
	 	 	 	 	 
	
                                          Total

                                        	 
      	 
      	
                                           

                                        	
                                          [***] 

                                        


                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

       

      Given
that 15-20% of the total clinical costs are committed before the first patient
is enrolled, we estimate that cost to decision point is
approximately [***]. It may be possible to reduce cost to the decision
point by [***], trading off for time-to-launch. This alternative scenario has
not been modeled.

       

      Cost
by Year ($M)

      
        
          
            
              
                
                  
                    
                      	
                              [***]

                            	
                              [***]

                            	
                              [***]

                            	
                              [***]

                            	
                              [***]

                            	
                              [***]

                            
	
                              [***]

                            	
                              [***]

                            	
                              [***]

                            	
                              [***]

                            	
                              [***]

                            	
                              [***]

                            


                    

                  

                

              

            

          

        

      

      


      [***] Study

       

      Budget
will assume a [***] (including ethnicity) of [***] patients. Study will start in
[***] and end [***].

       

      Cost by Year ($M)

      
        
          
            
              
                
                  
                    
                      
                        	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              
	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              	
                                [***]

                              


                      

                    

                  

                

              

            

          

        

      

       

      Timeline

       

      Phase III
Study

       

      
        
          
            
              
                
                  
                    	
                            Enrollment

                            w/
      [***]per site per month

                          	
                            Part
      1

                          	
                            Part 2

                          
	
                            Total
      Enrollment

                          	
                            [***]

                          	
                            [***]

                          
	
                            Active
      Sites

                          	
                            [***]

                          	
                            [***]

                          
	
                            Enrollment/Site/Month
      (on average)

                          	
                            [***]

                          	
                            [***]

                          
	
                            Monthly
      Study Enrollment

                          	
                            [***]

                          	
                            [***]

                          
	
                            Time
      to Enroll Patient per Part (months)

                          	
                            [***]

                          	
                            [***]

                          
	
                            TOTAL
      ENROLLMENT TIME (months)

                          	
                            [***]

                          


                  

                

              

            

          

        

      

       

      
        

      

      [***]
Redacted pursuant to a confidential treatment request.

      


      
        
          
             


          

          
             


            
              

            

          

          
             


          

        

      

      


      
        
          
            
              	
                      Trial Task

                    	
                      End Date

                    
	
                      Initiate
      Project

                    	
                      [***]

                    
	
                      FPI

                    	
                      [***]

                    
	
                      [***]

                    	
                      [***]

                    
	
                      LPI

                    	
                      [***]

                    
	
                      DB
      Lock

                    	
                      [***]

                    
	
                      CSR

                    	
                      [***]

                    
	
                      Submit
      PMA

                    	
                      [***]

                    


            

          

        

      

       

      Probability
of success

       

      Based on
the available preclinical data it is not possible to come to a firm estimate of
POS at this time. However, there is evidence of efficacy in preclinical models,
and a consensus among experts that the mechanism is plausible. Given the
existing data on the prior use of this class of compounds in humans, the
likelihood of adequate safety and tolerability seems higher than would otherwise
be possible at this stage, and given the device designation, the probability of
clinical and regulatory success is likewise higher than it might otherwise be.
Assuming the likelihood of adequate safety at [***] and the likelihood of
adequate efficacy at [***], the overall POS to filing is in the range of
[***].

       

      
        
[***]
Redacted pursuant to a confidential treatment request.

      


      
        
          
             


          

          
             


            
              

            

          

          
             


          

        

      

       

      
        SCHEDULE
3.7

         

        PRELIMINARY
COMMERCIALIZATION PLAN

         

        Preface:

         

        This
document is prepared for the management of BioLineRx as a basis for discussion
only, and is intended to be indicative of Ikaria’s current intent
with respect to global commercialization of BL-1040. Actual launch plans will
continue to evolve over time, in accordance with the evolution of market
dynamics, the global environment for cardiovascular drugs and devices, and the
emerging product profile of BL-1040.

         

        
          	
                   
      

                	
                  I.

                	
                  Situation
      Analysis

                


        

         

        
          	
                   
      

                	
                  a.

                	
                  Unmet
      Medical Need

                


        

         

        Each year
cardiovascular disease (CVD) causes over 4.3 million deaths in Europe. CVD is
estimated to cost the European Union (EU) economy €192 billion a year. The main
forms of CVD are coronary heart disease (CHD) and stroke. Just under half of
all deaths from CVD are from CHD. CV is also a large problem in Japan, and is
emerging as a public health issue even in the developing countries.

         

        Each year
smoking kills over 1.2 million people in Europe (450,000 from CVD)). Dietary
patterns across Europe are playing an increasing role in CVD. Levels of physical
inactivity are high in many European countries and levels of obesity are
increasing across Europe in both adults and children. Over 48 million adults in
Europe have diabetes and the prevalence is increasing.

         

        Estimates for population and
cardiovascular statistics are presented in Table 1

         

        Table 1

        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    	 
      	 
      	 
      	 
      	
                                            Est.

                                          	 
      	 
      	 
      	 
      
	 
      	 
      	 
      	 
      	
                                            Annual

                                          	 
      	 
      	 
      	 
      
	 
      	 
      	 
      	 
      	
                                            non-fatal

                                          	 
      	 
      	 
      	 
      
	 
      	 
      	
                                            Population

                                          	 
      	
                                            Ml

                                          	 
      	
                                            Interventional

                                          	 
      	
                                            Annual PCI

                                          
	
                                            Country

                                          	 
      	
                                            (000,000)

                                          	 
      	
                                            (000)

                                          	 
      	
                                            Cardiologist

                                          	 
      	
                                            Procedures

                                          
	
                                            [***]

                                          	 
      	
                                            10.4

                                          	 
      	
                                            34.7

                                          	 
      	
                                            230

                                          	 
      	
                                            28

                                          
	
                                            [***]

                                          	 
      	
                                            5.5

                                          	 
      	
                                            18.3

                                          	 
      	
                                            85

                                          	 
      	
                                            15

                                          
	
                                            [***]

                                          	 
      	
                                            5.3

                                          	 
      	
                                            17.7

                                          	 
      	
                                            80

                                          	 
      	
                                            14

                                          
	
                                            [***]

                                          	 
      	
                                            64.4

                                          	 
      	
                                            214.7

                                          	 
      	
                                            1,772

                                          	 
      	
                                            172

                                          
	
                                            [***]

                                          	 
      	
                                            82.3

                                          	 
      	
                                            274.3

                                          	 
      	
                                            1,500

                                          	 
      	
                                            219

                                          
	
                                            [***]

                                          	 
      	
                                            16.7

                                          	 
      	
                                            55.7

                                          	 
      	
                                            266

                                          	 
      	
                                            45

                                          
	
                                            [***]

                                          	 
      	
                                            0.3

                                          	 
      	
                                            1.0

                                          	 
      	
                                            14

                                          	 
      	
                                            1

                                          
	
                                            [***]

                                          	 
      	
                                            58.1

                                          	 
      	
                                            193.7

                                          	 
      	
                                            1,879

                                          	 
      	
                                            155

                                          
	
                                            [***]

                                          	 
      	
                                            40.5

                                          	 
      	
                                            135.0

                                          	 
      	
                                            730

                                          	 
      	
                                            108

                                          
	
                                            [***]

                                          	 
      	
                                            7.6

                                          	 
      	
                                            25.3

                                          	 
      	
                                            124

                                          	 
      	
                                            20

                                          
	
                                            [***]

                                          	 
      	
                                            61.1

                                          	 
      	
                                            203.7

                                          	 
      	
                                            1,000

                                          	 
      	
                                            163

                                          
	
                                            Total
      Europe

                                          	 
      	
                                            352.2

                                          	 
      	
                                            1,174.0

                                          	 
      	
                                            7,682

                                          	 
      	
                                            939

                                          
	
                                            [***]

                                          	 
      	
                                            127.0

                                          	 
      	
                                            423.3

                                          	 
      	
                                            2,500

                                          	 
      	
                                            339

                                          
	
                                            [***]

                                          	 
      	
                                            21

                                          	 
      	
                                            70

                                          	 
      	
                                            373

                                          	 
      	
                                            56

                                          
	
                                            Grand
      Total

                                          	
                                              

                                          	
                                            479.2

                                          	
                                              

                                          	
                                            1,597.3

                                          	
                                              

                                          	
                                            10,182

                                          	
                                              

                                          	
                                            1,278

                                          


                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    
                                      
                                        
                                          
                                            
                                               

                                            

                                          

                                        

                                      

                                    

                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

          
            
[***]
Redacted pursuant to a confidential treatment request.


          
            
               


            

            
               


              
                

              

            

            
               


            

          

           

          
            	
                     
      

                  	
                    b.

                  	
                    Product

                  


          

           

          BL-1040,
a novel, injectable, biodegradable polymer designed to be used in conjunction
with Percutaneous coronary intervention (PCI) to provide mechanical scaffolding
and reduce the risk of structural remodeling and heart failure in
post-myocardial infarction (post-MI) patients, is currently in development and
could be on the market as early as [***] If successful, BL-1040 could be a
breakthrough in the management of patients with cardiovascular disease and could
represent a large commercial opportunity for Ikaria and BioLineRx.

           

          
            	
                     
      

                  	
                    c.

                  	
                    Assessment
      of current level of CV practice

                  


          

           

          There is
significant variability around the medical management of CHD across Europe.
Theses groupings give a high level overview of the most common
interventions:

           

          Hospital
admissions

           

          Rates of
admission for CVD vary considerably across Europe. In general, higher admission
rates are found in Eastern European and Scandinavian countries. Similar
geographical trends are seen for CHD.

           

          Coronary revascularization
and other procedures for CVD

           

          While
rates of revascularization vary widely across Europe, all countries have seen
rates increase significantly since the 1990s. For example, since 1990 rates of
PCI have increased fifteen-fold in Italy and twelve-fold in Finland. We expect
that advances in medical technique and continued development of medical
infrastructure around the world will drive continued growth in the coronary
revascularization market.

           

          Drugs

           

          The use
of drugs for secondary prevention in CHD patients varies considerably across
populations, except in the case of anti-platelet drugs. Over 80% of patients
took this form of drug (mostly aspirin). The use of beta blockers,
lipid-lowering drugs and ACE inhibitors varies throughout the EU.

           

          
            	
                     
      

                  	
                    d.

                  	
                    Pricing
      and reimbursement environment

                  


          

           

          The
global market for cardiovascular drugs and devices is highly variable in terms
of pricing and reimbursement climates.

           

          Pricing

           

          Pricing
in the developed markets of western Europe tends to be similar to U.S. pricing,
although prices can vary significantly by market, with Northern European markets
having higher prices than
southern European markets. By contrast, pricing in less developed
markets (Eastern Europe, Latin America and the Far East) is highly
variable, and will require careful study to ensure an appropriate price is
selected in order to maximize penetration and profitability. A clear target
product profile will be critical to assessment of pricing strategy in all
markets.

           

          Reference
pricing is common practice in Europe, so timing of local launches must be
carefully coordinated to ensure optimized pricing across the
territory.

           

          
            

          

          [***]
Redacted pursuant to a confidential treatment request.


          
            
               


            

            
               


              
                

              

            

            
               


            

          

          
             

            [***]

             

            [***].

          

           

          Reimbursement

           

          With the
exception of regulatory approval, reimbursement will be the single most
important driver of commercial success.

           

          The
process by which products gain reimbursement can vary greatly from country to
country, and may take a considerable amount of time. A recent study by IMS
suggested that it was common for newly approved drugs to take between one and
three years to gain widespread reimbursement coverage in the top 16 EU markets.
Because most European countries operate centralized, government-financed health
systems, it is not typical for patients to pay for treatments privately. In many
countries where there is virtually no habit of citizens paying for their own
healthcare, initiating selling activity without reimbursement would be virtually
impossible, while inhabitants of some other countries may have no problem paying
for healthcare out of their own disposable income.

           

          Expected
timing of reimbursement will, therefore, be a major driver of the timetable for
building out sales infrastructure, and commencing selling activities. Ikaria
will conduct extensive research between deal closing and launch to ensure that
reimbursement conditions are clearly understood and that plans are in place to
ensure broad and favorable access to major commercial markets.

           

          
            	
                     
      

                  	
                    II.

                  	
                    Commercialization
      Plan

                  


          

           

          Product Positioning
Strategy

           

          Given the
current expectations of the product profile, we aspire to – and expect that –
BL-1040 will be positioned as the de facto standard for prevention of post-MI
remodeling.

           

          While
this depends on the specific results of the clinical trials, the market
conditions, including competitive scenario, and prevailing clinical practice
standards, the goal will be to make BL-1040 use prevalent across a range of
patient sub-groups that are at risk for remodeling. Specifically, the following
patient groups will be addressed in the marketing plan:

           

          
            	
                     
      

                  	
                    ■

                  	
                    High-risk STEMI
      (includes patients with large myocardial Infarctions (MIs), anterior wall
      MIs and long lead time to PCI):
[***]

                  


          

           

          
            	
                     
      

                  	
                    ■

                  	
                    Other STEMI
      (includes all STEMI patients not considered of the highest risk): [***]

                  


          

          


          
            

            [***]
Redacted pursuant to a confidential treatment request.

          


          
            
               


            

            
               


              
                

              

            

            
               


            

          

        

         

        ■    [***]
  

        ■    NSTEMI
[***]

         

        In
addition to the market development efforts listed above, the focus of marketing
strategy will be on creating broad awareness of the significant long-term
effects of remodeling as well as discussing the risks of myocardial damage and
resulting negative consequences for all patients with MIs. In Europe, this will
also require resetting of the current paradigm of treating non-primary PCI
patients with medical therapy alone, and illustrating the benefits of treatment
with a mechanical scaffolding device such as BL-1040.

         

        Organization Size and
Structure

         

        As an
experienced critical care company, Ikaria is committed to providing doctors and
other medical professionals with a high level of customer service. Operating in
a highly specialized, life-or-death environment Ikaria strives to match our
customers own urgency and commitment to patient care.

         

        To be
successful in the area of post-MI care we anticipate creating an organization
capable of delivering both the commercial and medical support desired by our
target customer base. Ikaria intends to establish itself as the leader in
critical care globally, and will use BL-1040 as the platform on which to
establish its international presence. As such, we intend to build a robust but
flexible organization with all the competencies necessary to achieve leadership
of the field. Although BL-1040 will likely be Ikaria’s first global product, we
anticipate that our own internal pipeline candidates IK-1001 and Covox will not
be far behind. The infrastructure envisioned by Ikaria and described in this
document will therefore be sufficient to successfully commercialize all of
Ikaria’s present and future pipeline compounds.

         

        Ikaria
proposed to use a “hub and spoke” approach to commercializing BL-1040 in
Europe—the “hub” being a European headquarters and the “spokes” representing
local operating companies (LOCs) in major markets. The headquarters will provide
overall strategic leadership and will spearhead European product development and
commercial strategy, while local operating companies will be responsible for
selling activity and local tactic implementation.

         

        In
addition to strategic marketing and leadership support, the European
headquarters will be responsible for financial management and reporting of
regional results, management of European regulatory affairs functions,
development of a European clinical development program, development of effective
key opinion leadership, development of compelling health economic data and
development of HR strategies to maintain a strong and vibrant European
organization.

         

        
          
            

          

        

        [***] Redacted
pursuant to a confidential treatment request.

         

        
          
             


          

          
             


            
              

            

          

          
             


          

        

         

        The
primary role of LOCs is to provide the necessary local sales and marketing
efforts necessary to achieve financial objectives for BL-1040. In addition to
the necessary commercial infrastructure, the local operating companies would
also be staffed with the support functions essential to commercial success. This
would include a small local finance team, medical affairs, regulatory affairs
and human resource functions. The role of the local support staff is to
implement strategic initiatives conceived at headquarters level, and support
local initiatives as necessary. The medical affairs staff will be particularly
important in supporting marketing in disseminating the full medical information
on BL-1040 and the clinical specialists will also lead the training of
physicians in using this product appropriately.

         

        The LOC
staffing level will be determined as a function of country population, disease
prevalence and target doctor population. Sales Representatives will be recruited
from companies with a depth of experience in cardiovascular drug and device
sales to ensure we gain rapid access to the necessary prescriber base.
Representatives will be compensated through a blend of base salary and sales
incentive bonus, according to Ikaria’s existing sales force incentive plan. (See
Table 2)


         

        Table 2

        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    
                                      
                                        
                                          
                                            
                                              
                                                
                                                  	 
      	 	 
      	 	
                                                          Est.

                                                        	 	 
      	 	 
      	 	 
      
	 
      	 	 
      	 	
                                                          Annual

                                                        	 	 
      	 	 
      	 	 
      
	 
      	 	 
      	 	
                                                          non-fatal

                                                        	 	 
      	 	 
      	 	 
      
	 
      	 	
                                                          Population

                                                        	 	
                                                          Ml

                                                        	 	
                                                          Interventional

                                                        	 	
                                                          Annual PCI

                                                        	 	
                                                          Sales

                                                        
	
                                                          Country

                                                        	 	
                                                          (000,000)

                                                        	 	
                                                          (000)

                                                        	 	
                                                          Cardiologist

                                                        	 	
                                                          Procedures (000)

                                                        	 	
                                                          Reps

                                                        
	
                                                          [***]

                                                        	 	
                                                          10.4

                                                        	 	
                                                          34.7

                                                        	 	
                                                          230

                                                        	 	
                                                          28

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          5.5

                                                        	 	
                                                          18.3

                                                        	 	
                                                          85

                                                        	 	
                                                          15

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          5.3

                                                        	 	
                                                          17.7

                                                        	 	
                                                          80

                                                        	 	
                                                          14

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          64.4

                                                        	 	
                                                          214.7

                                                        	 	
                                                          1,772

                                                        	 	
                                                          172

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          82.3

                                                        	 	
                                                          274.3

                                                        	 	
                                                          1,500

                                                        	 	
                                                          219

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          16.7

                                                        	 	
                                                          55.7

                                                        	 	
                                                          266

                                                        	 	
                                                          45

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          0.3

                                                        	 	
                                                          1.0

                                                        	 	
                                                          14

                                                        	 	
                                                          1

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          58.1

                                                        	 	
                                                          193.7

                                                        	 	
                                                          1,879

                                                        	 	
                                                          155

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          40.5

                                                        	 	
                                                          135.0

                                                        	 	
                                                          730

                                                        	 	
                                                          108

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          7.6

                                                        	 	
                                                          25.3

                                                        	 	
                                                          124

                                                        	 	
                                                          20

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          61.1

                                                        	 	
                                                          203.7

                                                        	 	
                                                          1,000

                                                        	 	
                                                          163

                                                        	 	
                                                          [***]

                                                        
	
                                                          Total
      Europe

                                                        	 	
                                                          352.2

                                                        	 	
                                                          1,174.0

                                                        	 	
                                                          7,682

                                                        	 	
                                                          939

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          127.0

                                                        	 	
                                                          423.3

                                                        	 	
                                                          2,500

                                                        	 	
                                                          339

                                                        	 	
                                                          [***]

                                                        
	
                                                          [***]

                                                        	 	
                                                          21.0

                                                        	 	
                                                          70.0

                                                        	 	
                                                          373

                                                        	 	
                                                          56

                                                        	 	
                                                          [***]

                                                        
	
                                                          Grand
      Total

                                                        	 	
                                                          479.2

                                                        	 	
                                                          1,597.3

                                                        	 	
                                                          10,182

                                                        	 	
                                                          1,278

                                                        	 	
                                                          [***]

                                                        


                                                

                                              

                                            

                                          

                                        

                                      

                                    

                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

         

        NB: The
number of sales reps anticipated to be needed in each market has been estimated
as a function of [***].

        
          
             

            
              

            

          

          [***] Redacted
pursuant to a confidential treatment request.

           

          
            
              
                 


              

              
                 


                
                  

                

              

              
                 


              

            

          

        

         

        Launch
Timelines

         

        To
maximize the value of BL-1040 Ikaria intends to be ready to launch at the
earliest possible opportunity. As described above, a key driver of launch
readiness in any given market will be the ability to access reimbursement for
BL-1040. Without appropriate reimbursement in place, attempting to launch
BL-1040 would be at best un-productive, and at worst, damaging to the long-term
perception of the product.

         

        Ikaria
proposes to immediately undertake a battery of research and analysis to
understand the market-specific reimbursement environments across major target
markets. Results of this research would guide future launch plans, and help
inform the timing of key investments in people and
infrastructure.


         

        Development
of Ikaria’s ex-US presence will occur differently throughout the
world:

         

        
          	
                   
      

                	
                  1)

                	
                  Ikaria
      already has management structures in place in Canada, Japan and Australia.
      These budding organizations would be expanded in the near term to allow
      essential market preparation activities to begin as soon as possible. As
      the product profile of BL-1040 becomes clearer, and the expectations for
      launch timing crystallize, this existing in-country leadership
      infrastructure will be expanded to include all the local sales and medical
      affairs capability necessary to a successful
  launch.

                


        

        
          	
                   
      

                	
                  2)

                	
                  Establishment
      of a European Headquarters function would be a high priority. We
      anticipate filling key leadership positions as early as [***], so that
      high-level reimbursement, medical affairs and commercial strategic
      planning can commence. As a clearer view of the likely launch timeline for
      BL-1040 emerges, remaining HQ infrastructure will be built out to ensure a
      fully operational European headquarters well in advance of launch. In the
      event that a positive result emerges from the interim analysis and a
      decision is made to move up the commercial launch of the product, the
      development of the launch plans – including execution of reimbursement
      strategy and creation of marketing materials – will occur in parallel to
      the ramp up of the LOCs.

                


        

        
          	
                   
      

                	
                  3)

                	
                  Additional,
      2nd-tier
      markets will be evaluated in parallel with [***] commercial infrastructure
      development. Ikaria believes that there will be great potential for
      BL-1040 in markets such as [***], but will need more time to evaluate the
      optimal way to maximize sales in those
  territories.

                


        

         

        [***]

         

        
          
            
              

            

          

          [***] Redacted
pursuant to a confidential treatment request.

           

          
            
              
                 


              

              
                 


                
                  

                

              

              
                 


              

            

          

          


        

        Proposed
European Structure

        


        Headquarters

        


        

         

        Human
Resources

        


        Human
Resources will oversee European benefits programs, ensure compliance with local
employment law, promote employee development and succession planning, and all
functions necessary to building a world-class critical care business in Europe.
The European HQ team will work closely with LOC country managers to ensure local
employee needs are met and compliance with local laws is maintained. Local
in-country contractors may be employed to deliver HR services at the local
level.

        


        Anticipated
headcount:        2

        


        Government
Affairs

        


        Appropriate
reimbursement will be critical to the success of BL-1040. As described above,
reimbursement can be highly variable across Europe. Development of a skilled
government affairs capability within Ikaria Europe will be critical to our
success, for BL-1040 as well as future Ikaria pipeline products.

        


        Anticipated
headcount:        1

        


        Commercial
Development

        


        The
European Commercial Development team is responsible for commercial strategy
formulation across the European area, including both product and sales force
strategy. The HQ marketing team will work closely with the Clinton, NJ-based
marketing team to
develop a cohesive global strategy suitable for implementation in European
markets. The European team will have responsibility to ensure that brand
strategies are implemented consistently across the area, and will perform market
research to monitor performance and adjust strategy as appropriate. The team
will also work in concert with country GMs and local marketing management to
implement large-scale promotional and educations programs.

         

        The
European HQ team will also develop and implement European sales force strategies
including development and maintenance of a customer relationship management
system, sales skills training programs, and sales leadership development. The HQ
team will work closely with LOC commercial management to ensure a top-class
sales effort in each country.

        


        Anticipated
headcount:        5

        


        Medical
Affairs

        


        Development
of a strong base of key opinion leaders will be critical to the success of
BL-1040. Cardiology is a fast moving, highly technical field, and for Ikaria to
be a credible player we will need to make a significant commitment to supporting
the medical community through education, research support, etc. The European
Medical Affairs team will take the lead in formulating strategy for the
engagement of key opinion leaders in the formulation of brand development
strategy, the development of brand champions and building high-level
relationships between Ikaria and the medical community. The HQ


        
          
             


          

          
             


            
              

            

          

          
             


          

        


        Medical
Affairs team will work closely with LOC Medical Affairs teams to align strategy
across Europe and ensure a consistent medical approach.

        


        The HQ Medical Affairs team will
also be responsible for development of health outcome data to support
cost-effectiveness arguments. The HQ team will work closely with
LOC commercial teams to package health outcome data for effective presentation
to in-country prescribers and reimbursement decision makers.

        


        The HQ Medical Affairs team will
also take responsibility for developing responses to requests for medical
information about Ikaria products. The team will work with LOC Commercial and
Medical Affairs teams to ensure a high level of customer support and
satisfaction.

        


        Anticipated
headcount:        3

        


        Regulatory
Affairs

        


        The
European Regulatory Affairs (RA) team will lead all regulatory efforts on behalf
of Ikaria’s European operations. The HQ RA team will work closely
with the Medical Affairs team to ensure development programs have maximal
likelihood of success and that regulatory compliance is maintained at all times.
The RA team will work in concert with in-country RA teams to execute on
regulatory strategies and maintain product registrations with local
authorities.

        


        Anticipated
headcount:        2

         

        Finance

        


        The
European Finance team will support all local operating companies with financial
reporting and planning functions as well as accounts payable and accounts
receivable activities. The HQ
team will consolidate European results and maintain a full European
operating P&L. The HQ
team will perform most of the finance functions on behalf of the European
Area, with LOCs having minimal local requirement for finance
headcount.

        


        Anticipated
headcount:        9

         

        Information
Technology

        


        Ikaria’s
European IT requirements will be delivered by the European HQ team, with local support from
3rd-party
contract services. The HQ
team will liaise with Ikaria’s corporate headquarters IT function in
Clinton, NJ to ensure reliable systems functionality and robust customer
support.

        


        Anticipated
headcount:        3


        
          
             


          

          
             


            
              

            

          

          
             


          

        


        Local
Operating Country (LOC) Structure

        


        

        


        Human
Resources

        


        Human
Resources support will be provided from HQ as described above. Specific local
needs will be coordinated with HQ HR and delivered by local 3rd party
providers

        


        Anticipated
headcount:        None

        


        Commercial
Development

        


        The LOC
Commercial Development team is responsible for implementation of commercial
strategy at the local level. The marketing team is responsible for
implementation of European product strategy and for directing local tactical
marketing in support of BL-1040. The LOC commercial director
is also responsible for the development of a skilled critical care sales
organization, including recruitment, training and management of reps and
managers.

        


        The
number of sales reps required to promote BL-1040 will vary from country
to country according to the market opportunity, the number of prescribing
doctors, and the incidence of PCI procedures. (See Appendix A)

        


        Anticipated
headcount:        Various

        


        Medical
Affairs

        


        Maintenance
of a strong relationships and robust medical affairs response capability will be
essential for success at the local level. The LOC medical director will take
responsibility for development of strong local relationships, coordination of
company response to medical information requests. Clinical Specialists in each
LOC will be responsible for training of physicians on use of product and for
customer service.

        


        Anticipated
headcount:        1-2

        


        Regulatory
Affairs (RA)

        


        The LOC
RA team will work together with HQ RA teams to execute on regulatory strategies
and maintain product registrations with local authorities.

        


        Anticipated
headcount:        1 -2


        
          
             


          

          
             


            
              

            

          

          
             


          

        


        Finance

        


        The HQ
team will perform most of the finance functions on behalf of the European Area,
with LOCs having minimal local requirement for finance headcount.

        


        Anticipated
headcount:        None

        


        Information
Technology

         

        Ikaria’s
European IT requirements will be delivered by the European HQ team, with local
support from 3rd-party
contract services.

         

        Anticipated
headcount:        None


        
          
             


          

          
             


            
              

            

          

          
             


          

        

      

    

     

    SCHEDULE
4.3(a)

     

    BIOLINERX WIRE TRANSFER
INFORMATION

     

    
      [***]

    

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          
          

          
            

          

        

        
           


        

      

    

    


    EXHIBIT
A

     

    TECHNOLOGY EXCHANGE
PLAN

     

    Upon
Ikaria’s request, the following will be provided by BioLineRx to Ikaria or its
designee:

     

    
      	
              10.

            	
              All
      materials (original or copies as appropriate) in BioLineRx’s possession
      and Control relating to Product, including documentation relating to
      Development and all regulatory filings, clinical information, and data and
      other documents relating to the On-Going Phase I/II Trial and the Other
      On-Going Trials.

            


    

     

    
      	
              11.

            	
              Copies
      of all documents and available information in BioLineRx’s possession and
      Control necessary for Manufacturing of Product at the time of technology
      exchange. These documents will include information necessary to assist
      Ikaria or its designee in setting up Manufacturing operations
      for such things as:

            


    

     

    
      	
               
      

            	
              ·

            	
              raw
      material test methods, specifications, qualification and justification for
      use

            


    

    
      	
               
      

            	
              ·

            	
              raw
      material vendor lists with part
numbers

            


    

    
      	
               
      

            	
              ·

            	
              analytical
      methods stated purpose, development, qualification and validation
      reports

            


    

    
      	
               
      

            	
              ·

            	
              process
      development reports, laboratory notebooks and associated electronically
      stored data

            


    

    
      	
               
      

            	
              ·

            	
              Manufacturing
      summary including

            


    

    
      	
               
      

            	
              o

            	
              detailed
      process description with process schematics, operating parameters and
      target ranges, flow charts outlining critical process controls and steps,
      cartoons, verbal description including abbreviations, process scale,
      yield, and standard process
instructions

            


    

    
      	
               
      

            	
              o

            	
              in-process
      controls/tests and acceptance criteria including stated purpose of
      in-process tests

            


    

    
      	
               
      

            	
              o

            	
              master
      batch record(s)

            


    

    
      	
               
      

            	
              o

            	
              filling/packaging
      process

            


    

    
      	
               
      

            	
              o

            	
              aseptic
      and process development and validation
documents

            


    

    
      	
               
      

            	
              o

            	
              facility
      and equipment requirements and design
documents

            


    

    
      	
               
      

            	
              o

            	
              descriptions
      of process equipment, including suppliers, part numbers, and historic
      invoices

            


    

    
      	
               
      

            	
              o

            	
              product
      test methods, specifications and justification of
      specifications

            


    

    
      	
               
      

            	
              o

            	
              product
      stability, test methods and qualification/validation reports, stability
      reports, shelf life recommendations

            


    

    


    As
available and agreed upon by the JDC at the time of a technology exchange,
BioLineRx will provide requested technical manufacturing or engineering advice
to Ikaria or its designee. Ikaria will ensure designee has necessary expertise
in place to exchange the documentation and expertise in an orderly
fashion.

    


    
      
        
           


        

        
          
          

          
            

          

        

        
           


        

      

    

    


    EXHIBIT
B

     

    BIOLINERX PATENT
RIGHTS

     

    Family
1

     

    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    	
                                            INJECTABLE CROSS-LINKED POLYMER PREPARATIONS AND USES THEREOF

                                          
	
                                            Country

                                          	 	
                                            Earliest Priority 

                                          	 	
                                            Entry Date 

                                          	 	
                                            Filing Date

                                            Application No.

                                          	 	
                                            Issue Date 

                                            Patent No. 

                                          	 	
                                            Status

                                          	 	
                                            Owner

                                          
	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      


                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

    

     

    [***]

     

    [***]
Redacted pursuant to a confidential treatment request.

    


    
      
        
           


        

        
          
          

          
            

          

        

        
           


        

      

    

    


    Family
2

     

    
      
        
          
            
              
                
                  
                    
                      
                        
                          
                            
                              
                                
                                  
                                    
                                      	
                                              A METHOD OF TREATING MUSCLE TISSUES

                                            
	 
      
	
                                              Country

                                            	 	
                                              Earliest

                                              Priority

                                            	 	
                                              Entry

                                              Date

                                            	 	
                                              Filing Date

                                              Application No.

                                            	 	
                                              Issue Date

                                              Patent No.

                                            	 	
                                              Status

                                            	 	
                                              Owner

                                            
	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      	 	 
      


                                    

                                  

                                

                              

                            

                          

                        

                      

                    

                  

                

              

            

          

        

      

    

     

    [***]

     

    [***]
Redacted pursuant to a confidential treatment request.