Document:

Exhibit 10.26

 

EXECUTION VERSION

 

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”

  	
  1

  
	
  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

  

 

i

 

Table of Contents

 

	
   

  	
   

  	
  Page

  
	
   

  	
   

  	
   

  
	
  Section 1.43

  	
  “Territory”

  	
  7

  
	
  Section 1.44

  	
  “Third Party”

  	
  7

  
	
  Section 1.45

  	
  “Valid Claim”

  	
  8

  
	
  Section 1.46

  	
  Additional Definitions

  	
  8

  
	
  Section 1.47

  	
  Interpretation

  	
  9

  
	
   

  	
   

  	
   

  
	
  Article II Grant of Rights

  	
  9

  
	
  Section 2.1

  	
  BioLineRx License Grant to Ikaria; Consent of OCS

  	
  9

  
	
  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

  	
  10

  
	
  Section 2.6

  	
  Retained Rights

  	
  11

  
	
   

  	
   

  	
   

  
	
  Article III Development;
  Manufacturing; Commercialization

  	
  11

  
	
  Section 3.1

  	
  General

  	
  11

  
	
  Section 3.2

  	
  Joint Development Committee

  	
  11

  
	
  Section 3.3

  	
  On-Going Trials

  	
  12

  
	
  Section 3.4

  	
  Regulatory Matters

  	
  12

  
	
  Section 3.5

  	
  Technology Exchange

  	
  13

  
	
  Section 3.6

  	
  Manufacturing

  	
  13

  
	
  Section 3.7

  	
  Commercialization

  	
  14

  
	
  Section 3.8

  	
  Efforts

  	
  15

  
	
   

  	
   

  	
   

  
	
  Article IV
  Financial Provisions

  	
  15

  
	
  Section 4.1

  	
  Milestone Payments

  	
  15

  
	
  Section 4.2

  	
  Royalties on Net Sales of Products

  	
  16

  
	
  Section 4.3

  	
  Reports and Accounting

  	
  17

  
	
  Section 4.4

  	
  Currency Amounts

  	
  18

  
	
  Section 4.5

  	
  Currency Exchange

  	
  18

  
	
  Section 4.6

  	
  Tax Withholding

  	
  18

  
	
  Section 4.7

  	
  Upfront Payments Received Under Sublicenses

  	
  18

  
	
   

  	
   

  	
   

  
	
  Article V Intellectual
  Property Ownership, Protection and Related Matters

  	
  18

  
	
  Section 5.1

  	
  Ownership of Inventions

  	
  18

  
	
  Section 5.2

  	
  Prosecution and Maintenance of Patent Rights

  	
  19

  
	
  Section 5.3

  	
  Third Party Infringement

  	
  20

  
	
   

  	
   

  	
   

  
	
  Article VI Confidentiality;
  Non-Solicitation; Standstill

  	
  23

  
	
  Section 6.1

  	
  Confidential Information

  	
  23

  
	
  Section 6.2

  	
  Disclosures to Employees, Consultants, Advisors, Etc

  	
  23

  
	
  Section 6.3

  	
  Non-Solicitation

  	
  24

  
	
  Section 6.4

  	
  Standstill

  	
  24

  

 

ii

 

Table of Contents

 

	
   

  	
  Page

  
	
   

  	
   

  
	
  Section 6.5

  	
  Term

  	
  24

  
	
  Section 6.6

  	
  Publicity

  	
  24

  
	
  Section 6.7

  	
  Publications

  	
  25

  
	
   

  	
   

  	
   

  
	
  Article VII Representations
  and Warranties 

  	
  25 

  
	
  Section 7.1

  	
  Representations of Authority

  	
  25

  
	
  Section 7.2

  	
  Consents

  	
  25

  
	
  Section 7.3

  	
  No Conflict

  	
  26

  
	
  Section 7.4

  	
  Enforceability

  	
  26

  
	
  Section 7.5

  	
  Additional BioLineRx Representations

  	
  26

  
	
  Section 7.6

  	
  BGN License Agreement

  	
  27

  
	
  Section 7.7

  	
  Employee, Consultant and Advisor Legal Obligations

  	
  27

  
	
  Section 7.8

  	
  Accuracy of Representations and Warranties on Effective
  Date

  	
  28

  
	
  Section 7.9

  	
  No Warranties

  	
  28

  
	
   

  	
   

  	
   

  
	
  Article VIII Term and
  Termination

  	
  28

  
	
  Section 8.1

  	
  Term

  	
  28

  
	
  Section 8.2

  	
  Termination for Material Breach

  	
  28

  
	
  Section 8.3

  	
  Development-Related Termination

  	
  28

  
	
  Section 8.4

  	
  Effect of Certain Terminations and Expiration

  	
  28

  
	
  Section 8.5

  	
  Survival

  	
  29

  
	
  Section 8.6

  	
  Termination Prior to Effective Date

  	
  29

  
	
   

  	
   

  	
   

  
	
  Article IX Dispute
  Resolution

  	
  29

  
	
  Section 9.1

  	
  Negotiation

  	
  29

  
	
  Section 9.2

  	
  Escalation

  	
  30

  
	
  Section 9.3

  	
  Mediation

  	
  30

  
	
  Section 9.4

  	
  Litigation

  	
  30

  
	
  Section 9.5

  	
  Equitable Relief

  	
  30

  
	
   

  	
   

  	
   

  
	
  Article X Miscellaneous
  Provisions

  	
  30

  
	
  Section 10.1

  	
  Indemnification

  	
  30

  
	
  Section 10.2

  	
  Governing Law

  	
  31

  
	
  Section 10.3

  	
  Submission to Jurisdiction

  	
  32

  
	
  Section 10.4

  	
  Assignment

  	
  32

  
	
  Section 10.5

  	
  Entire Agreement; Amendments

  	
  32

  
	
  Section 10.6

  	
  Notices.

  	
  32

  
	
  Section 10.7

  	
  Force Majeure

  	
  33

  
	
  Section 10.8

  	
  Independent Contractors

  	
  34

  
	
  Section 10.9

  	
  Limitations of Liability

  	
  34

  
	
  Section 10.10

  	
  No Implied Waivers; Rights Cumulative

  	
  34

  
	
  Section 10.11

  	
  Severability

  	
  34

  
	
  Section 10.12

  	
  Execution in Counterparts; Facsimile Signatures

  	
  34

  

 

iii

 

Table of Contents

 

	
  Schedules

  	
   

  	
   

  
	
  Schedule 1.30

  	
  Protocol
  for On-Going Phase I/II Trial

  	
   

  
	
  Schedule 1.31

  	
  Descriptions
  of Other On-Going Trials

  	
   

  
	
  Schedule 1.35

  	
  Outline
  of Initial Pivotal Clinical Trial

  	
   

  
	
  Schedule 1.42(a)

  	
  Independent
  Safety Monitoring Board Charter

  	
   

  
	
  Schedule 2.3

  	
  Existing
  Product Agreements

  	
   

  
	
  Schedule 3.1

  	
  Initial
  Development Plan

  	
   

  
	
  Schedule 3.3

  	
  Independent
  Safety Monitoring Board

  	
   

  
	
  Schedule 3.7

  	
  Preliminary
  Commercialization Plan

  	
   

  
	
  Schedule 4.3(a)

  	
  Wire
  Transfer Information

  	
   

  
	
   

  	
   

  	
   

  
	
  Exhibits

  	
   

  	
   

  
	
  Exhibit A

  	
  Technology Exchange Plan

  	
   

  
	
  Exhibit B

  	
  BioLineRx Patent Rights

  	
   

  

 

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 

 

1

 

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.

 

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) [**].

 

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.

 

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

 

7

 

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

  
	
  “Technology
  Exchange Plan”

  	
   

  	
  Section 3.5

  
	
  “Third
  Party Payment”

  	
   

  	
  Section 4.2(b)

  

 

8

 

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.

 

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 

 

9

 

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.

 

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 

 

10

 

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: [**]

 

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 

 

11

 

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.

 

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 

 

12

 

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.

 

(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 

 

13

 

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 [**] percent ([**]%) 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 [**] percent
([**]%) 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.

 

(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 

 

14

 

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.

 

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

  

 

15

 

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

 

 

	
  MILESTONE

  	
   

  	
  PAYMENT

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

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

  	
   

  	
  $

  	
  [**]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

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

  	
   

  	
  $

  	
  [**]

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  3.  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.

 

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 $[**]

  	
   

  	
  [**]

  	
  %

  	
   

  
	
   

  	
  >$[**] 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
[**] percent ([**]%) 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 [**] percent ([**]%). 
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 [**] percent ([**]%), 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 

 

16

 

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.

 

(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 

 

17

 

to reduce any subsequent payments by the amount of the
overpayment.  If the underpayment to
BioLineRx is equal to or greater than [**] percent ([**]%) 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.

 

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 [**] percent ([**]%) 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.

 

18

 

(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), then [**].

 

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.  [**].

 

19

 

(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 

 

20

 

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.

 

(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.

 

(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 

 

21

 

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:

 

(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

 

22

 

(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, [**] percent ([**]%) 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 [**] percent ([**]%) 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.

 

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 

 

23

 

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.

 

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 

 

24

 

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.

 

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.

 

25

 

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;

 

(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 

 

26

 

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);

 

(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 

 

27

 

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.

 

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:

 

28

 

(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.

 

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.

 

29

 

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.

 

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 

 

30

 

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.

 

(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).

 

31

 

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.

 

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:

 

32

 

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

 

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 

 

33

 

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.

 

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

 

34

 

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

  	
   

  	
   

  

 

35

 

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:

  	
  Venn Life Sciences AG

  
	
  Address:

  	
  Elisabethenstrasse
  23/3, CH- 4051 Basel

  
	
  Phone:

  	
  +41 61 201 11 00Fax:     +41
  61 273 42 50

  
	
   

  	
   

  
	
  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

  
			

 

Page 2 of 52

 

	
  Medical Monitor, US
  (ISMB support only)

  
	
  Name:

  	
  Sanjay Machado,
  MD

  
	
  Address:

  	
  Venn Life
  Sciences Group

  
	
   

  	
  7355 TransCanada Hwy

  
	
   

  	
  Suite 200

  
	
   

  	
  Saint-Laurent, Quebec, Canada H4T 1T3

  
	
   

  	
   

  
	
  Phone:

  	
  +1 514.315.2992
  ext 117

  
	
  Fax:

  	
  +1 514.315.0995

  
	
  e-mail:

  	
  sanjay.machado@vlsworldwide.com

  
	
   

  	
   

  
	
  Medical Monitor, Europe

  	
   

  
	
  Name:

  	
  Andrea
  Kempf-Mueller, MD

  
	
  Address:

  	
  Venn Life Sciences
  AG

  
	
   

  	
  Elisabethenstrasse
  23/3, 4051 Basel, Switzerland

  
	
  Phone:

  	
  +41 61 201 11 83

  
	
  Fax:

  	
  +41 61 273 42 50

  
	
  e-mail:

  	
  andrea.kempf-mueller@vlsworldwide.com

  

 

Page 3 of 52

 

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)

  

 

Page 4 of 52

 

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

  	
  27 Jan 2009

  	
   

  	
  Signature

  	
  /s/ Moshe Phillip

  
	
   

  	
   

  	
   

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

  
	
   

  	
   

  	
   

  	
   

  
	
  Date/Place

  	
  27 Jan 2009

  	
   

  	
  Signature

  	
  /s/ Shmuel Tuvia

  
	
   

  	
   

  	
   

  	
  (Shmuel Tuvia, PhD, Project Manager)

  
	
   

  	
   

  	
   

  	
   

  
	
  Date/Place

  	
  27 Jan 2009

  	
   

  	
  Signature

  	
  /s/ Moti Gal

  
	
   

  	
   

  	
   

  	
  (Moti Gal, Clinical Operations Manager)

  

 

Page 5 of 52

 

Medical
Advisor Signature Page

 

	
  Name:

  	
  Prof Jonathan Leor, MD

  
	
  Address:

  	
  Head, Neufeld Cardiac
  Research Institute.

  
	
   

  	
  Tel-Aviv University

  
	
   

  	
  Sheba Medical Center

  
	
   

  	
  Tel-Hashomer 52621

  
	
   

  	
  Israel

  
	
  Phone:

  	
  +972-3-534-8685

  
	
  Fax:

  	
  +972-3-5351139

  

 

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

 

	
  Date/Place

  	
  28/1/09

  	
   

  	
  Signature

  	
  /s/ Jonathan Leor

  
	
   

  	
   

  	
   

  	
  (Jonathan Leor, MD,
  Medical Advisor)

  

 

Page 6 of 52

 

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, possibly
  Switzerland

  
	
   

  	
   

  	
   

  
	
  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

  

 

Page 7 of 52

 

	
   

  	
   

  	
  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:

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

  ·                  Biomarkers: peak CK > 2000 IU

  ·                  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

  

 

Page 8 of 52

 

	
   

  	
   

  	
   

  	
   

  	
  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

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  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

  ·                  lst 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)

  

 

Page 9 of 52

 

	
   

  	
   

  	
  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 Failure® 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.

  

 

Page 10 of 52

 

Schedule of Events

	
  Visits/Week

  	
   

  	
  Hospitalization

  	
   

  	
  Post
  discharge follow-up

  	
   

  
	
  Study days

  	
   

  	
  Screening

  (Day) (-7) to

  Day (-1)

  	
   

  	
  Day 1

  Day of application(1)

  	
   

  	
  Daily during

  hospitalization(2)

  	
   

  	
  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

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Coronary
  angiography, PCI, stent(1)

  	
   

  	
  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

  	
   

  	
  X

  	
  (4)

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Laboratory
  safety parameters

  	
   

  	
  X

  	
  (5)

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Total
  CK/CK MB

  	
   

  	
  X

  	
   

  	
  X

  	
  (7)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  NT-proBNP

  	
   

  	
  X

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  
	
  Echocardiography/MRI

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Continuous
  ECG monitoring

  	
   

  	
   

  	
   

  	
  X

  	
  (9)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Cardiac
  catheterization; application of BL- 1040; coronary angiography

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  PTT
  or ACT measurements

  	
   

  	
   

  	
   

  	
  X

  	
  (10)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  24-hour
  ambulatory Holter monitoring

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Safety
  contact for discharged patients

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Minnesota
  Living with Heart Failure

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Serious/Adverse
  events and concomitant medication

  	
   

  	
  X

  	
   

  	
  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

 

Page 11 of 52

 

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

  	
  19

  
	
  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

  
									

 

Page 12 of 52

 

	
  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

  	
  35

  
	
  7.1

  	
  Adverse event
  definition

  	
  35

  
	
  7.2

  	
  Recording adverse
  events

  	
  35

  
	
  7.3

  	
  Pre-device events

  	
  35

  
	
  7.4

  	
  General adverse events

  	
  36

  
	
  7.4.1

  	
  Assessment of severity
  of general adverse events

  	
  36

  
	
  7.4.2

  	
  Assessment of causality
  of adverse events

  	
  36

  
	
  7.4.3

  	
  Follow-up of adverse
  events and assessment of outcome

  	
  36

  
	
  7.5

  	
  Serious Adverse Events

  	
  37

  
	
  7.5.1

  	
  Definition of Serious
  Adverse Event (SAE)

  	
  37

  
	
  7.5.2

  	
  Pre-defined SAEs

  	
  38

  
	
  7.5.3

  	
  Reporting serious
  adverse events

  	
  38

  
	
  7.5.4

  	
  Follow-up of serious
  adverse events

  	
  38

  
	
  7.6

  	
  Treatment of adverse
  events

  	
  39

  
	
  7.7

  	
  Pregnancy

  	
  39

  
	
  8

  	
  Data Evaluation and Statistics

  	
  40

  
	
  8.1

  	
  Endpoints

  	
  40

  
	
  8.2

  	
  Estimated sample size

  	
  40

  
	
  8.3

  	
  Planned methods of
  analysis

  	
  40

  
	
  8.3.1

  	
  Analysis population

  	
  40

  
	
  8.3.2

  	
  Analysis of
  demographics

  	
  40

  
	
  8.3.3

  	
  Analysis of safety

  	
  41

  
	
  8.4

  	
  Interim analysis

  	
  41

  
	
  8.5

  	
  Final and follow-up
  reporting

  	
  41

  
	
  8.6

  	
  Quality assurance

  	
  41

  
	
  9

  	
  Ethics and regulatory
  considerations

  	
  42

  
	
  9.1

  	
  Informed Consent

  	
  42

  
	
  9.2

  	
  Authorities

  	
  42

  
	
  9.3

  	
  Protocol Amendments

  	
  42

  
	
  9.4

  	
  Patient confidentiality

  	
  42

  
	
  9.5

  	
  Insurance

  	
  43

  
	
  9.6

  	
  Duration of the study

  	
  43

  
	
  10

  	
  Data Handling and Record
  Keeping

  	
  44

  
	
  10.1

  	
  Documentation

  	
  44

  
	
  10.2

  	
  Case Report Forms

  	
  44

  
	
  10.3
  

  	
  Monitoring and quality
  control

  	
  44

  
	
  10.4
  

  	
  Publication policy

  	
  44

  
	
  11

  	
  References

  	
  45

  
								

 

Appendix A: Declaration
of Helsinki

 

Appendix B: Minnesota
Living with Heart Failure® questionnaire

 

Page 13 of 52

 

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 natnuretic peptide

  
	
  NYHA

  	
  New York Heart
  Association

  
	
  °C

  	
  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

  

 

Page 14 of 52

 

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

 

Page 15 of 52

 

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.

 

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.

 

Page 16 of 52

 

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.

 

Page 17 of 52

 

3
     Safety Endpoints

 

3.1   Primary
endpoints

 

Primary safety endpoints
include:

 

·      occurrence
of all adverse events including but not limited to

·         all
MLs

·         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

 

Page 18 of 52

 

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.

 

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:

 

Page 19 of 52

 

·                  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

 

Page 20 of 52

 

·      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:

·      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)

·      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])

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

·      one or more of the following:

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

·      Biomarkers: peak CK > 2000 IU

·      infarct size > 25% as measured by MRI

·      successful revascularization with PCI
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

 

 

Page 21 of 52

 

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.

 

Page 22 of 52

 

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.

 

Page 23 of 52

 

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

 

Page 24 of 52

 

Investigator will
determine the dose and time of intake, and document the medication(s) in
the patient’s CRF.

 

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].

 

Page 25 of 52

 

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 questionnaire®. 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.

 

Page 26 of 52

 

Table 6.1           Schedule of Events

 

	
   

  	
   

  	
  Hospitalization

  	
   

  	
  Post discharge follow-up

  	
   

  
	
  Visits/Week

  Study days

  	
   

  	
  Screening

  Day (-7) to

  Day (-1)

  	
   

  	
  Day 1

  Day of application(1)

  	
   

  	
  Daily during

  hospitalization(2)

  	
   

  	
  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)

  	
   

  
	
  AM1

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Hospitalization

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Coronary
  angiography, PCI, stent(1)

  	
   

  	
  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

  	
   

  	
  X

  	
  (4)

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Laboratory
  safety parameters

  	
   

  	
  X

  	
  (5)

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Total
  CK/CK MB

  	
   

  	
  X

  	
   

  	
  X

  	
  (7)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  NT-proBNP

  	
   

  	
  X

  	
   

  	
  X

  	
  (8)

  	
   

  	
   

  	
  X

  	
  (6)

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
   

  	
   

  
	
  Echocardiography/MRI

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Continuous
  ECG monitoring

  	
   

  	
   

  	
   

  	
  X

  	
  (9)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Cardiac
  catheterization; application of BL- 1040; coronary angiography

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  PTT
  or ACT measurements

  	
   

  	
   

  	
   

  	
  X

  	
  (10)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  24-hour
  ambulatory Holler monitoring

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Safety
  contact for discharged patients

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Minnesota
  Living with Heart Failure®

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  	
  X

  	
   

  
	
  Serious/Adverse
  events and concomitant medication

  	
   

  	
  X

  	
   

  	
  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 net 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

  

 

Page 27 of 52

 

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.

 

Page
28 of 52

 

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 Holtter 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

 

Page
29 of 52

 

·                  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
Failure® 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
Failure® 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

 

Page
30 of 52

 

·      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.

 

Page 31 of 52

 

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

 

·                  urinalysis

 

Page
32 of 52

 

·                  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:

 

Universitatsklinikum Heidelberg

Zentrallabor

Im Neuenheimer Feld 671

69120 Heidelberg, Germany

Tel.: 06221-56-8803

Fax: 06221-56-5205

 

6.4          Minnesota Living with Heart
Failure® questionnaire

 

The
Minnesota Living with Heart Failure® 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.

 

Page 34 of 52

 

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).

 

Page 35 of 52

 

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

 

Page 36 of 52

 

Page 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.

 

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

 

Page 37 of 52

 

·                  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 Venn Life Sciences AG 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.

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Venn Life
  Sciences AG, Elisabethenstrasse 23/3, CH-4051 Basel

  
	
   

  	
   

  	
   

  
	
  Fax:

  	
   

  	
  00800 201 11 011

  
	
  e-mail:

  	
   

  	
  SAE@vlsworldwide.com

  
	
  Tel:

  	
   

  	
  +41 61 201 11 83

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
  24/24 hour and
  7/7 day availability

  

 

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

 

Page 38 of 52

 

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 Venn Life Sciences AG.

 

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.

 

Page 39 of 52

 

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.

 

Page 40 of 52

 

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).

 

Page 41 of 52

 

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.

 

Page 42 of 52

 

Data generated as a
result of this study are to be available for inspection on request by all
authorized Sponsor personnel, Venn Life Sciences AG 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.

 

Page 43 of 52

 

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, Venn Life Sciences AG(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.

 

Page 44 of 52

 

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 at., 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.

 

Page 45 of 52

 

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

 

Page 46 of 52

 

therapeutic methods must
continuously be challenged through research for their effectiveness,
efficiency, accessibility and quality.

 

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.

 

Page 47 of 52

 

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

 

Page 48 of 52

 

the publication. Reports
of experimentation not in accordance with the principles laid down in this
Declaration should not be accepted for publication.

 

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.

 

§  §  §

 

Page 49 of 52

 

Appendix
B: Minnesota Living with Heart Failure® questionnaire

 

Page 50 of 52

 

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.

 

Page 51 of 52

 

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

 

Page 52 of 52

 

SCHEDULE 1.31

 

DESCRIPTIONS OF OTHER
ON-GOING TRIALS

 

	
  Name
  of Study

  	
   

  	
  Estimated Duration

  	
   

  	
  Estimated End Date

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  

 

 

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

 

A total of twelve pages were
omitted pursuant to a request for confidential treatment.

[**]

 

 

SCHEDULE 2.3

 

EXISTING PRODUCT AGREEMENTS

 

[**]

 

 

SCHEDULE 3.1

 

INITIAL DEVELOPMENT PLAN

 

[**]

 

A total of four pages were omitted pursuant to
a request for confidential treatment.

 

 

SCHEDULE 3.7

 

PRELIMINARY
COMMERCIALIZATION PLAN

 

 

[**]

 

A total of ten pages were
omitted pursuant to a request for confidential treatment.

 

 

SCHEDULE 4.3(a)

 

BIOLINERX WIRE TRANSFER
INFORMATION

 

	
  Bank
  Name:

  	
  [**]

  
	
   

  	
   

  
	
  Bank
  Address:

  	
  [**]

  
	
   

  	
   

  
	
   

  	
   

  
	
  SWIFT
  Number:

  	
  [**]

  
	
   

  	
   

  
	
  IBAN
  Number:

  	
  [**]

  
	
   

  	
   

  
	
  Account
  Number:

  	
  [**]

  
	
   

  	
   

  
	
  Account Name:

  	
  [**]

  

 

 

EXHIBIT A

 

TECHNOLOGY EXCHANGE PLAN

 

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

 

7.                                      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.

 

8.                                      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

·                  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

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

·                  master batch record(s)

·                  filling/packaging process

·                  aseptic and process development and
validation documents

·                  facility and equipment requirements and
design documents

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

·                  product test methods, specifications and
justification of specifications

·                  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

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  	
  [**]

  
	
  [**]

  	
   

  	
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Family 2

 

A METHOD
OF TREATING MUSCLE TISSUES

 

	
  Country

  	
   

  	
  Earliest

  Priority

  	
   

  	
  Entry

  Date

  	
   

  	
  Filing Date

  Application No.

  	
   

  	
  Issue Date

  Patent No.

  	
   

  	
  Status

  	
   

  	
  Owner

  
	
  [**]

  	
   

  	
  [**]

  	
   

  	
   

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  	
   

  	
  [**]

  

 

 

PAYMENT DATE EXTENSION AMENDMENT

 

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”) are party to an
Amended and Restated License and Commercialization Agreement dated as of the
26th day of August, 2009 (the “Agreement”).  Any defined terms used herein shall have them
meaning ascribed thereto in the Agreement.

 

Pursuant
to Section 4.1(a) the Agreement, Ikaria is required to make a
milestone payment to BioLineRx of USD $10,000,000 upon the Successful
Completion of the On-Going Phase I/II Trial (the “Second Milestone Payment”)
on or before [**].  BioLine and Ikaria
are currently in discussions to determine whether Ikaria is required to
withhold United States federal income taxes from the Second Milestone
Payment.  In order to enable the parties
to complete those discussions, Ikaria and BioLine hereby agree that the due
date for the Second Milestone Payment is hereby extended to [**].

 

Sections
10.2 (“Governing Law”) and 10.3 (“Submission to Jurisdiction”) of the Agreement are hereby
incorporated herein by reference.

 

Acknowledged,
Agreed, and Confirmed

 

 

	
  /s/
  Daniel Tassé

  	
   

  	
  /s/
  Kinneret Savitsky

  
	
  Daniel
  Tassé

  	
   

  	
  Kinneret
  Savitsky,

  
	
  Chief
  Executive Officer

  	
   

  	
  Chief
  Executive Officer

  
	
  Ikaria
  Development Subsidiary One LLC

  	
   

  	
  On behalf of, and as authorized representative of, both BioLineRx
  Ltd. and BioLine Innovations Jerusalem L.P.

  

 

 

AMENDMENT TO THE AMENDED AND RESTATED LICENSE AND COMMERCIALIZATION
AGREEMENT

 

This
Amendment (this “Amendment”) is entered into this 21st day of April 2010 (the “Amendment
Effective Date”) by and between Ikaria Development
Subsidiary One LLC, a Delaware limited liability company with a
place of business at 6 Route 173, Clinton, NJ, 08809 USA (“Ikaria”), and
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., “BioLine Rx”) . 
This Amendment amends the Amended and Restated License and
Commercialization Agreement entered into by and between Ikaria and BioLineRx
dated as of the 26th day of August 2009 (the “Agreement”).  Any defined term used in this Amendment not
expressly defined herein shall have the meaning ascribed thereto in the
Agreement.

 

1.             Modification of Payee. All payments to be made
under the Agreement shall be made to BiolineRx Ltd. or any Third Party assignee
of BioLineRx Ltd. permitted under Section 10.4 of the Agreement.

 

2.             Modification of Assignment.
The last two sentences of Section 10.4 of the Agreement are hereby
amended and restated as follows:

 

“BioLineRx
Ltd. may assign its right to receive payments hereunder to a Third Party, in its
sole discretion, provided that BioLineRx Ltd. provides Ikaria with prior
written notice of the assignment and the name and address of the assignee.  Any such Third Party assignee may not further
assign the right to receive payments hereunder without providing Ikaria with
prior written notice of the assignment and the name and address of the
assignee. Ikaria shall maintain a written record of any such assignments. The
parties intend that this Agreement shall be considered to be in “registered
form” as defined in United States Treasury Regulations Section 5f.103-1(c).  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 assignment in contravention
of this Section 10.4 shall be null and void.”

 

3.             Ratification of Agreement.  Except as set forth in this Amendment, all of
the other terms and conditions of the Agreement are hereby ratified and
confirmed to be of full force and effect, and shall continue in full force and
effect.  This Amendment is hereby
integrated into and made a part of the Agreement.

 

4.             Counterparts. 
This Amendment may be executed in two or more counterparts, each of
which shall be effective as of the Amendment Effective Date, and all of which
shall constitute one and the same instrument. 
Each such counterpart shall be deemed an original, and it shall not be
necessary in making proof of this Amendment to produce or account for more than
one such counterpart.

 

Page
1 of 2

 

5.             Execution and Delivery.  This Amendment shall be deemed executed by
the parties when any one or more counterparts hereof, individually or taken
together, bears the signatures of each of the parties hereto.

 

 

Acknowledged
and Agreed to:

 

	
  BIOLINERX
  LTD.

  	
   

  	
  IKARIA
  DEVELOPMENT SUBSIDIARY ONE LLC

  
	
   

  	
   

  	
   

  
	
  By:
  /s/  Kinneret L. Savitsky /s/ Philip Serlin

  	
   

  	
  By:
  /s/ Matthew M. Bennett

  
	
  Signature

  	
   

  	
  Signature

  
	
   

  	
   

  	
   

  
	
  Kinneret
  L. Savitsky                 Philip
  Serlin

  	
   

  	
  Matthew
  M. Bennett

  
	
  Printed Name

  	
   

  	
  Printed Name

  
	
   

  	
   

  	
   

  
	
  CEO                                          CFO

  	
   

  	
  Vice
  President and Secretary

  
	
  Title

  	
   

  	
  Title

  
	
   

  	
   

  	
   

  
	
  April 21,
  2010

  	
   

  	
  April 21,
  2010

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  BIOLINE
  INNOVATIONS JERUSALEM L.P., BY ITS GENERAL PARTNER BIOLINE INNOVATIONS
  JERUSALEM, LTD.

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  By:
  /s/  Kinneret L. Savitsky /s/ Philip Serlin

  	
   

  	
   

  
	
  Signature

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  Kinneret
  L. Savitsky                 Philip
  Serlin

  	
   

  	
   

  
	
  Printed Name

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  CEO                                          CFO

  	
   

  	
   

  
	
  Title

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
  April 21,
  2010

  	
   

  	
   

  

 

Page
2 of 2Exhibit
10.27

 

EXECUTION
VERSION

 

Confidential
Materials omitted and filed separately with the

Securities and Exchange Commission. 
Asterisks denote omissions.

 

 

LICENSE AGREEMENT

 

BY AND AMONG

 

IKARIA DEVELOPMENT
SUBSIDIARY TWO LLC

 

AND

 

FIBREX MEDICAL, INC.

 

AND

 

FIBREX MEDICAL RESEARCH &
DEVELOPMENT GESMBH

 

 

DATED

 

AS OF

 

JULY 17, 2009

 

 

TABLE OF CONTENTS

	
  Article I
  Definitions; Interpretation

  	
  1

  
	
  Section 1.1

  	
  “Affiliate”

  	
  1

  
	
  Section 1.2

  	
  “Business Day”

  	
  1

  
	
  Section 1.3

  	
  “Commercialization” or “Commercialize”

  	
  1

  
	
  Section 1.4

  	
  “Compound”

  	
  2

  
	
  Section 1.5

  	
  “Commercially Reasonable Efforts”

  	
  2

  
	
  Section 1.6

  	
  “Confidential Information”

  	
  2

  
	
  Section 1.7

  	
  “Control”

  	
  2

  
	
  Section 1.8

  	
  “Development” or “Develop”

  	
  2

  
	
  Section 1.9

  	
  “EU”

  	
  3

  
	
  Section 1.10

  	
  “Executive Officers”

  	
  3

  
	
  Section 1.11

  	
  “FDA”

  	
  3

  
	
  Section 1.12

  	
  “Fibrex Know-How”

  	
  3

  
	
  Section 1.13

  	
  “Fibrex Patent Rights”

  	
  3

  
	
  Section 1.14

  	
  “Fibrex Intellectual Property”

  	
  3

  
	
  Section 1.15

  	
  “Field”

  	
  3

  
	
  Section 1.16

  	
  “F.I.R.E. Study”

  	
  3

  
	
  Section 1.17

  	
  “First Commercial Sale”

  	
  3

  
	
  Section 1.18

  	
  “Generic Version”

  	
  3

  
	
  Section 1.19

  	
  “Ikaria Product Improvements”

  	
  3

  
	
  Section 1.20

  	
  “Ikaria Product IP”

  	
  4

  
	
  Section 1.21

  	
  “Indication”

  	
  4

  
	
  Section 1.22

  	
  “Joint Intellectual Property”

  	
  4

  
	
  Section 1.23

  	
  “Joint Know-How”

  	
  4

  
	
  Section 1.24

  	
  “Joint Patent Rights”

  	
  4

  
	
  Section 1.25

  	
  “Know-How”

  	
  4

  
	
  Section 1.26

  	
  “Knowledge”

  	
  4

  
	
  Section 1.27

  	
  “MAA”

  	
  4

  
	
  Section 1.28

  	
  “Manufacturing” or “Manufacture”

  	
  4

  
	
  Section 1.29

  	
  “NDA”

  	
  4

  
	
  Section 1.30

  	
  “Net Sales”

  	
  4

  
	
  Section 1.31

  	
  “Party”

  	
  6

  
	
  Section 1.32

  	
  “Patent Rights”

  	
  6

  
	
  Section 1.33

  	
  “Person”

  	
  6

  
	
  Section 1.34

  	
  “Phase I Clinical Trial”

  	
  6

  
	
  Section 1.35

  	
  “Phase IIa Clinical Trial”

  	
  6

  
	
  Section 1.36

  	
  “Phase IIb Clinical Trial”

  	
  6

  
	
  Section 1.37

  	
  “Phase III Clinical Trial”

  	
  6

  
	
  Section 1.38

  	
  “Product”

  	
  6

  
	
  Section 1.39

  	
  “Regulatory Approval”

  	
  6

  
	
  Section 1.40

  	
  “Regulatory Authority”

  	
  6

  
	
  Section 1.41

  	
  “Royalty Term”

  	
  7

  
	
  Section 1.42

  	
  “Sublicensee”

  	
  7

  
	
  Section 1.43

  	
  “Successful Completion”:

  	
  7

  
	
  Section 1.44

  	
  “Territory”

  	
  7

  

 

 

Table of Contents

(Continued)

 

	
   

  	
   

  	
  Page

  
	
   

  	
   

  	
   

  
	
  Section 1.45

  	
  “Third Party”

  	
  7

  
	
  Section 1.46

  	
  “Valid Claim”

  	
  7

  
	
  Section 1.47

  	
  Additional Definitions

  	
  7

  
	
  Section 1.48

  	
  Interpretation

  	
  8

  
	
   

  	
   

  	
   

  
	
  Article II Grant of
  Rights

  	
  9

  
	
  Section 2.1

  	
  Fibrex License Grant to Ikaria

  	
  9

  
	
  Section 2.2

  	
  Non-Competition

  	
  9

  
	
  Section 2.3

  	
  Section 365(n) of the Bankruptcy Code

  	
  9

  
	
  Section 2.4

  	
  Sublicenses

  	
  10

  
	
  Section 2.5

  	
  Retained Rights

  	
  10

  
	
   

  	
   

  	
   

  
	
  Article III Development;
  Manufacturing; Commercialization

  	
  10

  
	
  Section 3.1

  	
  General

  	
  10

  
	
  Section 3.2

  	
  Regulatory Matters

  	
  10

  
	
  Section 3.3

  	
  Technology Transfer

  	
  10

  
	
  Section 3.4

  	
  Diligence and Reports

  	
  11

  
	
  Section 3.5

  	
  Manufacturing

  	
  11

  
	
  Section 3.6

  	
  Commercialization

  	
  11

  
	
  Section 3.7

  	
  On-Going Studies

  	
  11

  
	
  Section 3.8

  	
  Consulting Agreements

  	
  12

  
	
   

  	
   

  	
   

  
	
  Article IV Financial
  Provisions

  	
  12

  
	
  Section 4.1

  	
  Milestone Payments

  	
  12

  
	
  Section 4.2

  	
  Royalties on Net Sales of Products

  	
  14

  
	
  Section 4.3

  	
  Reports and Accounting

  	
  15

  
	
  Section 4.4

  	
  Currency Amounts

  	
  16

  
	
  Section 4.5

  	
  Currency Exchange

  	
  16

  
	
  Section 4.6

  	
  Tax Withholding

  	
  16

  
	
  Section 4.7

  	
  Blocked Payments

  	
  16

  
	
  Section 4.8

  	
  Freedom to Operate

  	
  16

  
	
   

  	
   

  	
   

  
	
  Article V Intellectual
  Property Ownership, Protection and Related Matters

  	
  17

  
	
  Section 5.1

  	
  Ownership of Inventions

  	
  17

  
	
  Section 5.2

  	
  Prosecution and Maintenance of Patent Rights

  	
  18

  
	
  Section 5.3

  	
  Third Party Infringement

  	
  18

  
	
   

  	
   

  	
   

  
	
  Article VI
  Confidentiality

  	
  20

  
	
  Section 6.1

  	
  Confidential Information

  	
  20

  
	
  Section 6.2

  	
  Disclosures to Employees, Consultants, Advisors, Etc.

  	
  21

  
	
  Section 6.3

  	
  Terms of this Agreement

  	
  21

  
	
  Section 6.4

  	
  Term

  	
  21

  
	
  Section 6.5

  	
  Publicity

  	
  21

  

 

ii

 

Table of Contents

(Continued)

 

	
   

  	
   

  	
  Page

  
	
   

  	
   

  	
   

  
	
  Article VII
  Representations and Warranties

  	
  22

  
	
  Section 7.1

  	
  Representations of Authority

  	
  22

  
	
  Section 7.2

  	
  Consents

  	
  22

  
	
  Section 7.3

  	
  No Conflict

  	
  22

  
	
  Section 7.4

  	
  Enforceability

  	
  22

  
	
  Section 7.5

  	
  Additional Fibrex Representations

  	
  22

  
	
  Section 7.6

  	
  Employee, Consultant and Advisor Legal Obligations

  	
  23

  
	
  Section 7.7

  	
  No Warranties

  	
  23

  
	
   

  	
   

  	
   

  
	
  Article VIII Term and
  Termination

  	
  23

  
	
  Section 8.1

  	
  Term

  	
  23

  
	
  Section 8.2

  	
  Termination for Material Breach

  	
  23

  
	
  Section 8.3

  	
  Development-Related Termination by Ikaria

  	
  23

  
	
  Section 8.4

  	
  Effect of Certain Terminations and Expiration

  	
  24

  
	
  Section 8.5

  	
  Survival

  	
  25

  
	
   

  	
   

  	
   

  
	
  Article IX
  Dispute Resolution

  	
  25

  
	
  Section 9.1

  	
  Negotiation

  	
  25

  
	
  Section 9.2

  	
  Escalation

  	
  25

  
	
  Section 9.3

  	
  Litigation

  	
  25

  
	
  Section 9.4

  	
  Equitable Relief

  	
  26

  
	
   

  	
   

  	
   

  
	
  Article X
  Miscellaneous Provisions

  	
  26

  
	
  Section 10.1

  	
  Indemnification

  	
  26

  
	
  Section 10.2

  	
  Governing Law

  	
  27

  
	
  Section 10.3

  	
  Submission to Jurisdiction

  	
  27

  
	
  Section 10.4

  	
  Assignment

  	
  27

  
	
  Section 10.5

  	
  Entire Agreement; Amendments

  	
  27

  
	
  Section 10.6

  	
  Notices

  	
  28

  
	
  Section 10.7

  	
  Force Majeure

  	
  28

  
	
  Section 10.8

  	
  Independent Contractors

  	
  29

  
	
  Section 10.9

  	
  Limitations of Liability

  	
  29

  
	
  Section 10.10

  	
  No Implied Waivers; Rights
  Cumulative; Joint and Several Liability

  	
  29

  
	
  Section 10.11

  	
  Severability

  	
  29

  
	
  Section 10.12

  	
  Fibrex Medical R&D

  	
  29

  
	
  Section 10.13

  	
  Execution in Counterparts; Facsimile Signatures

  	
  30

  
	
  Section 10.14

  	
  Ikaria Affiliates

  	
  30

  
	
  Section 10.15

  	
  Parent Guarantee

  	
  30

  

 

iii

 

Table of Contents

(Continued)

 

	
   

  	
   

  	
  Page

  
	
   

  	
   

  	
   

  
	
  Schedules

  	
   

  	
   

  
	
  Schedule
  1.4

  	
  Compounds

  	
   

  
	
  Schedule
  3.7

  	
  On-Going
  Studies

  	
   

  
	
  Schedule
  4.3(a)

  	
  Wire
  Transfer Information

  	
   

  
	
   

  	
   

  	
   

  
	
  Exhibits

  	
   

  	
   

  
	
  Exhibit A

  	
  Fibrex
  Patent Rights

  	
   

  
	
  Exhibit B

  	
  Technology
  Transfer Plan

  	
   

  
	
  Exhibit C

  	
  Milestone
  Payment Examples

  	
   

  
	
  Exhibit D

  	
  Form of Guarantee

  	
   

  

 

iv

 

LICENSE AGREEMENT

 

This License Agreement (the “Agreement”)
is entered into this 17th day of July, 2009 (the “Effective Date”), by
and among Ikaria Development Subsidiary Two LLC, a Delaware limited liability
company having a principal place of business at 6 State Route 173, Clinton, NJ
08809, USA (“Ikaria”), Fibrex Medical, Inc., a Delaware corporation
having a principal place of business at 245 First Street, Suite 1800,
Cambridge, MA 02142 (“Fibrex Medical”), and Fibrex Medical Research &
Development GesmbH, a corporation organized and existing under the laws of the
Republic of Austria, having a principal place of business at Gastgebgasse 5-13,
A-1230 Vienna, Austria (“Fibrex Medical R&D”; together with Fibrex
Medical, “Fibrex”).

 

INTRODUCTION

 

WHEREAS, Fibrex owns or controls certain
intellectual property rights covering an investigational portfolio of compounds
designated by Fibrex as FX06, FX201, FX107, and back-up compounds, which
inhibit the binding of fibrin E1 fragment to vascular endothelial cadherin;

 

WHEREAS, Fibrex desires to grant to Ikaria
the worldwide exclusive rights (except as set forth herein) to Develop,
Manufacture, use, 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, Fibrex 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 or shares 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.

 

Section 1.2             “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 or Vienna, Austria are authorized by law to remain closed.

 

Section 1.3             “Commercialization” or “Commercialize”
shall mean any activities directed to marketing, promoting, distributing,
importing, exporting, or selling a product.

 

1

 

Section 1.4             “Compound” means (a) FX06,
(b) FX201, (c) FX107 (each of (a), (b) and (c) as more
fully described on Schedule 1.4 to this Agreement), and (d) any backup
compounds Controlled by Fibrex during the term of this Agreement that inhibit
the binding of fibrin E1 fragment to vascular endothelial cadherin, including
second generation fibrin E1 fragment inhibitors.

 

Section 1.5             “Commercially Reasonable Efforts”
means the use of efforts and resources commonly used by Ikaria and its
Affiliates with its other pharmaceutical products of similar commercial
potential at a similar stage in its product life, but no less than active commitment
of efforts and resources (financial and otherwise) consistent with those
normally applied in the biopharmaceutical industry to accomplish a similar
objective under similar circumstances for products of similar commercial
potential at a similar stage in their product development.

 

Section 1.6             “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, 
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:

 

(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 1.7             “Control” shall mean, as to
a Party, the legal authority or right of such Party or any of 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.

 

Section 1.8              “Development” or “Develop”
shall mean research, discovery, and development activities, including test
method development and stability testing, toxicology, 

 

2

 

formulation, optimization, quality
assurance/quality control development, statistical analysis, clinical studies,
regulatory affairs, product approval, and registration.

 

Section 1.9             “EU” shall mean the European
Union and all the member states thereof, as it may be comprised from time to
time.

 

Section 1.10            “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 Fibrex (or a
senior executive officer of Fibrex designated by Fibrex).

 

Section 1.11           “FDA” shall mean the United
States Food and Drug Administration or any successor agency thereof.

 

Section 1.12           “Fibrex Know-How” shall mean
all Know-How necessary or useful for the Development, Manufacture, use or
Commercialization of Products that (a) is Controlled by Fibrex as of the
Effective Date or (b) Fibrex comes to Control during the term of this
Agreement.

 

Section 1.13           “Fibrex Patent Rights” shall
mean Patent Rights Controlled by Fibrex that claim or are directed to any of
the Compounds or their method of manufacture or use, including the Patent
Rights listed in Exhibit A.

 

Section 1.14           “Fibrex Intellectual Property”
shall mean, collectively, Fibrex Patent Rights, Fibrex Know-How, and Fibrex’s
rights in and to any Joint Intellectual Property.

 

Section 1.15           “Field” shall mean any and all
therapeutics uses.

 

Section 1.16           “F.I.R.E. Study” shall mean
the Phase II clinical trial conducted by Fibrex using FX06 in AMI patients
using a bolus dosing regimen titled “A Multi-center, Double-blind, Randomized,
Placebo-Controlled Study to Measure the Effect of FX06 on Ischemia-Reperfusion
Injury in Patients Undergoing Primary Percutaneous Coronary Intervention (March 08,
2006),” as amended by Amendments 1- 4.

 

Section 1.17           “First Commercial Sale” shall
mean, with respect to a Product in a country, the first commercial sale of such
Product by Ikaria, its Affiliates, or Sublicensees in such country.  Sales for test marketing, clinical trial
purposes, or compassionate or similar use shall not be considered to constitute
a First Commercial Sale.

 

Section 1.18           “Generic Version” shall mean,
with respect to a Product, a product Developed and Manufactured by one or more
Third Parties not licensed under the Fibrex Intellectual Property or the Ikaria
Product IP that comprises the same compound, and is approved for the same
indication as such Product.

 

Section 1.19           “Ikaria Product Improvements”
shall mean any Ikaria Sole Inventions necessary or useful for the Development,
Manufacture, or use of any Product Developed hereunder, the practice of which
would constitute infringement (with respect to Patent Rights) or unauthorized
use (with respect to Know-How) but for ownership of (with a retained right to
exploit), or a license granted under, the Fibrex Intellectual Property.

 

3

 

Section 1.20           “Ikaria Product IP” shall
mean, collectively, all Patent Rights and Know-How necessary or useful for the
Development, Manufacture, use, or Commercialization of Products that (a) is
Controlled by Ikaria as of the Effective Date or (b) Ikaria comes to
Control during the term of this Agreement.

 

Section 1.21           “Indication” shall mean any
disease or condition for which Ikaria Develops a Product.

 

Section 1.22           “Joint Intellectual Property”
shall mean Joint Know-How and Joint Patent Rights, collectively.

 

Section 1.23           “Joint Know-How” shall mean
any Know-How, including any Joint Inventions, that is developed or acquired
jointly by the Parties during the term of this Agreement.

 

Section 1.24           “Joint Patent Rights” shall
mean Patent Rights that claim or disclose Joint Know-How.

 

Section 1.25           “Know-How” shall mean any
information, inventions, discoveries, documents and other works of authorship,
copyrights, trade secrets, data, or materials, whether proprietary or not,
including data generated in clinical trials.

 

Section 1.26           “Knowledge” shall mean, with
respect to a Party, the Party’s actual knowledge as of the Effective Date,
together with any knowledge of any of the Party’s officer- or director-level
employees, that a Person in such Party’s position would be expected to obtain
as of the Effective Date, 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           “MAA” shall mean a Marketing
Authorization Application.

 

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.

 

Section 1.29           “NDA” shall mean a New Drug
Application submitted to the FDA or Japan’s Ministry of Health, Labor and
Welfare.

 

Section 1.30           “Net Sales” shall mean, with
respect to a Product, the gross amounts billed by Ikaria, its Affiliates, or
Sublicensees in respect of sales of such Product by Ikaria and its Affiliates
or Sublicensees 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 and discount programs, third party
rebates and chargebacks, hospital buying group/group purchasing organization
administration fees, and managed care organization rebates) actually allowed and
taken with respect to such sales;

 

4

 

(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, rebates or
retroactive price reductions and allowances for wastage replacement;

 

(d)   Portions of invoiced sales amounts included in Net Sales in prior
periods that are actually written off by Ikaria, its Affiliates, or
Sublicensees as uncollectible up to an aggregate of [**]% of such gross sales;
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 Sublicensees, maintained in accordance
with generally accepted accounting principles, consistently applied.

 

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, Ikaria shall in good faith make a determination of the
respective fair market values of the Product(s) and all other components
included in the Combination Product, and shall notify Fibrex of such
determination and provide Fibrex with data to support such determination.  Fibrex shall have the right to review such
determination of fair market values and, if Fibrex disagrees with such
determination, to notify Ikaria of such disagreement within sixty (60) days
after Ikaria notifies Fibrex of such determination.  If Fibrex notifies Ikaria that Fibrex
disagrees with such determination within such sixty (60) day period and if
thereafter the Parties are unable to agree in good faith as to such respective
fair market values, then such matter shall be resolved as provided in Article IX.  If Fibrex does not notify Ikaria that Fibrex
disagrees with such determination within such sixty (60) day period, such
determination shall be conclusive and binding on the Parties.

 

5

 

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

 

Section 1.31           “Party” shall mean Fibrex, or
Ikaria; “Parties” shall mean Fibrex and Ikaria.

 

Section 1.32           “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 1.33           “Person” shall mean any
natural person or any corporation, company, partnership, joint venture, firm,
university, other entity, governmental authority, or subdivision thereof.

 

Section 1.34           “Phase I Clinical Trial” shall
mean a clinical trial in any country to initially evaluate the safety or
pharmacokinetic effect of a Product in humans 
and that satisfies the criteria set forth in U.S. 21 C.F.R. §312.21(a) or
the equivalent laws, rules or regulations in the EU or Japan.

 

Section 1.35           “Phase IIa Clinical Trial”
shall mean a clinical trial in any country to initially evaluate the
effectiveness of a Product (whether as a primary or secondary endpoint) for a
particular Indication in humans with the disease or indication under study and
that satisfies the criteria set forth in U.S. 21 C.F.R. §312.21(b) or the
equivalent laws, rules or regulations in the EU or Japan.

 

Section 1.36           “Phase IIb Clinical Trial”
shall mean a clinical trial in any country (a) the results of which, if
successful, are designed to provide a sufficient basis for designing and
commencing a Phase III Clinical Trial and (b) that satisfies the criteria
set forth in U.S. 21 C.F.R. §312.21(b) or the equivalent laws, rules or
regulations in the EU or Japan.

 

Section 1.37           “Phase III Clinical Trial”
means a clinical trial in any country the results of which could be used to
establish safety and efficacy of a Product to support Regulatory Approval and
that would otherwise satisfy the requirements of 21 CFR § 312.21(c) or the
equivalent laws, rules or regulations in the EU or Japan.

 

Section 1.38           “Product” shall mean any
preparations in final form, bulk form or other form containing as an active
pharmaceutical ingredient one or more Compounds for sale by prescription,
over-the-counter or any other method.

 

Section 1.39           “Regulatory Approval” shall
mean, with respect to a product, jurisdiction and indication, the approval of
the applicable Regulatory Authority required to market and sell such product in
such jurisdiction for such indication.

 

Section 1.40           “Regulatory Authority” shall
mean any national (e.g., the FDA),
supra-national or other regulatory agency or governmental entity involved in
the granting of 

 

6

 

Regulatory Approval for, or in the regulation
of human clinical studies of, therapeutic pharmaceutical products.

 

Section 1.41           “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 later of (a) the
expiration of the last-to-expire Valid Claim in the Fibrex Patent Rights that
claim the sale or use of such Product in the Field in such country, or (b) the
date on which Regulatory Approval of a Generic Version of any Product has
occurred in such country.

 

Section 1.42           “Sublicensee” means Third
Party granted a right to make, use, sell, offer for sale, or import a Product,
excluding a wholesaler or reseller of a Product that does not market or promote
the sale of such Product.

 

Section 1.43           “Successful Completion” shall
mean:

 

(a)   with respect to the Phase I Clinical Trial, (i) the study has
demonstrated in healthy volunteers that the investigational compound has a
favorable safety profile at the dose levels studied, and that dose and exposure
levels are achieved that are in the range required for expected therapeutic
efficacy or (ii) Ikaria proceeds to continue to Develop the Product
following the completion of such Clinical Trial to the next phase of clinical
development;

 

(b)   with respect to the Phase IIa Clinical Trial, (i) the study
has demonstrated in a target patient population that the investigational
compound has a favorable safety profile at the dose levels studied, that dose
and exposure levels are achieved that are required to mediate therapeutic
efficacy, and has demonstrated biologically meaningful proof-of-concept
efficacy or (ii) Ikaria proceeds to continue to Develop the Product
following the completion of such Clinical Trial to the next phase of clinical
development; and

 

(c)   with respect to the Phase IIb Clinical Trial, (i) the study
has further demonstrated safety and therapeutic efficacy at a dose level range
in a target patient population that enables dose selection and progression to
full (phase III) development or (ii) Ikaria proceeds to continue to
Develop the Product following the completion of such Clinical Trial to the next
phase of clinical development.

 

Section 1.44             “Territory”
shall mean the entire world.

 

Section 1.45           “Third Party” shall mean any
Person other than a Party or any of its Affiliates.

 

Section 1.46           “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 1.47           Additional Definitions.  Each of the following terms is defined in the
section of this Agreement indicated below:

 

7

 

	
  Term

  	
   

  	
  Section

  
	
   

  	
   

  	
   

  
	
  “Agreement”

  	
   

  	
  Preamble

  
	
   

  	
   

  	
   

  
	
  “Bankruptcy
  Code”

  	
   

  	
  Section 2.34

  
	
  “Breaching
  Party”

  	
   

  	
  Section 8.2

  
	
  “Combination
  Product”

  	
   

  	
  Section 1.30

  
	
  “Competitive
  Infringement”

  	
   

  	
  Section 5.3(a)

  
	
  “Effective
  Date”

  	
   

  	
  Preamble

  
	
  “Fibrex”

  	
   

  	
  Preamble

  
	
  “Fibrex
  Medical”

  	
   

  	
  Preamble

  
	
  “Fibrex
  Medical R&D”

  	
   

  	
  Preamble

  
	
  “Fibrex
  Sole Inventions”

  	
   

  	
  Section 5.1(a)

  
	
  “Force
  Majeure Event”

  	
   

  	
  Section 10.7

  
	
  “Ikaria”

  	
   

  	
  Preamble

  
	
  “Ikaria
  Sole Inventions”

  	
   

  	
  Section 5.1(a)

  
	
  “Indemnified
  Party”

  	
   

  	
  Section 10.1(c)

  
	
  “Indemnifying
  Party”

  	
   

  	
  Section 10.1(c)

  
	
  “Invalidity
  Claim”

  	
   

  	
  Section 5.3(d)

  
	
  “Joint
  Inventions”

  	
   

  	
  Section 5.1(b)

  
	
  “Lead
  Party”

  	
   

  	
  Section 5.3(e)

  
	
  “Losses”

  	
   

  	
  Section 10.1(a)

  
	
  “Non-Breaching
  Party”

  	
   

  	
  Section 8.2

  
	
  “On-Going
  Studies”

  	
   

  	
  Section 3.7

  
	
   

  	
   

  	
   

  
	
  “SEC”

  	
   

  	
  Section 6.1

  
	
  “Severed
  Clause”

  	
   

  	
  Section 10.11

  
	
  “Sole
  Inventions”

  	
   

  	
  Section 5.1(a)

  
	
  “Technology
  Transfer”

  	
   

  	
  Section 3.3

  
	
  “Technology
  Transfer Plan”

  	
   

  	
  Section 3.3

  
	
  “Terminated
  Product”

  	
   

  	
  Section 8.4(b)

  
	
  “Third
  Party Payment”

  	
   

  	
  Section 4.2(c)

  

 

Section 1.48           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 

 

8

 

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, (f) all references herein to Articles, Sections, Exhibits, or
Schedules shall be construed to refer to Articles, Sections, Exhibits, and
Schedules of this Agreement, and (g) wherever this Agreement requires
either Party’s approval or consent, unless otherwise indicated, such approval
or consent shall not be unreasonably withheld, conditioned, or delayed.

 

Article II

Grant of Rights

 

Section 2.1             Fibrex License Grant to Ikaria.  Subject to the terms and conditions of this
Agreement, Fibrex hereby grants to Ikaria the exclusive, irrevocable (except as
provided in Article VIII), royalty-bearing right and license in the
Territory under the Fibrex Intellectual Property to Develop, use, Manufacture
and Commercialize Products for use in the Field.  The foregoing license includes the
unrestricted right to grant sublicenses under the Fibrex Intellectual Property
in accordance with Section 2.4.

 

Section 2.2             Non-Competition.  During the term of and except as provided for
in this Agreement (and provided that Ikaria is complying in all material
respects with its obligations hereunder), Fibrex shall not, directly or
indirectly (including through its Affiliates), Develop, Manufacture,
Commercialize, or grant any rights or options or provide assistance to any
Third Party to Develop, Manufacture or Commercialize, any compound, substance,
or product that inhibits the binding of fibrin E1 fragment to vascular
endothelial cadherin.

 

Section 2.3             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, Section 8.4 and with respect to any
Fibrex Intellectual Property subject to Technology Transfer under Section 3.3,
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 Fibrex 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 a Party
(the “First Party”) of any assignment for the benefit of creditors,
composition, or any bankruptcy, reorganization, arrangement, insolvency, or
similar proceedings under the laws of any jurisdiction, the other Party shall
further be entitled to a complete duplicate of, or complete 

 

9

 

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 such other Party, unless the First Party elects to continue, and
continues, to perform all of its obligations under this Agreement; provided ̧that Fibrex’ rights to such intellectual property
rights and embodiments of Ikaria shall be subject to the terms of Section 8.4.

 

Section 2.4               Sublicenses.  The sublicensing of Ikaria’s rights  under Section 2.1 or appointment of other
Sublicensees shall be
subject to the following provisions: (a) Ikaria shall be primarily liable for any
failure by its Sublicensees  to comply with all relevant restrictions, limitations, and obligations in  this Agreement; (b) each Sublicensee
shall comply in all
material respects with the same level of efforts required to be
performed by Ikaria hereunder with respect to the specific rights that are the
subject of the applicable sublicense.

 

Section 2.5             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, and shall have the sole
right to Develop, Manufacture, and Commercialize Products in the Field in the
Territory.

 

Section 3.2             Regulatory Matters.  Ikaria shall prepare and submit all filings
with Regulatory Authorities relating to Products, which filings shall be in
Ikaria’s name.  With respect to
regulatory matters concerning Products in the Field, Fibrex 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, it being understood that such assistance may include providing
Ikaria with the right to cross-reference INDs or any other filings with
Regulatory Authorities or Regulatory Approval made or held by Fibrex with
respect to the Product or Compounds. Fibrex’ obligations to provide assistance
under this Section 3.2 and Section 3.3 shall continue until December 31,
2009; provided, that such date shall be
accelerated to October 31, 2009 if Ikaria enters into the consulting
agreements referred to in Section 3.8(a) and (b).

 

Section 3.3             Technology Transfer.

 

(a)   As soon as reasonably practicable after Ikaria’s written request,
Fibrex shall complete the activities assigned to Fibrex as set forth on the
technology transfer plan attached hereto as Exhibit B (the “Technology
Transfer Plan”) (“Technology Transfer”).  Fibrex shall make available to Ikaria (or
Ikaria’s designee(s)) such number of technical personnel as may be set forth in
the Technology Transfer 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 3.3, in connection with the
Development, use, Manufacture and Commercialization of Products hereunder.  Each Party shall bear its own costs with
respect to the Technology Transfer.

 

10

 

(b)   One individual nominated by each Party shall be responsible for
coordinating the technology transfer activities under the Technology Transfer
Plan.  Each Party shall cooperate with
the other Party in such other Party’s conduct of technology transfer activities
under the Technology Transfer Plan.

 

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

 

Section 3.4             Diligence and Reports.  Ikaria shall use Commercially Reasonable
Efforts to Develop and Commercialize at least one (or more in Ikaria’s
discretion) Products for a total of at least [**] Indications in the United
States and at least each of the following countries: France, Germany, Italy,
Spain, and the United Kingdom; provided, that
Ikaria may defer clinical development of the [**] Indications until Successful
Completion of the Phase IIb Clinical Trial for the first Indication.  Ikaria shall establish and maintain a
development plan with respect to each Indication it elects to Develop.  Ikaria shall disclose such plans (including
any amendments) to Fibrex and consider in good faith any comments made by
Fibrex; provided, that Ikaria shall remain
solely responsible for Development. Ikaria shall Develop the Products in
accordance with all applicable regulatory requirements, including then current
cGLP, cGCP and cGMP.   Ikaria shall keep
Fibrex reasonably informed about its efforts to Develop the Products, including
annual written reports containing summaries of all results and data from such
development efforts, progress towards meeting all goals and milestones in each
development plan, significant findings and developments, and any reasons for
any delays in meeting milestones or timelines in any development plan.  Subject to Section 3.8, any reports or
information that Ikaria may provide to Fibrex under this Section 3.4 shall
be deemed Confidential Information of Ikaria and shall be treated as such in
accordance with the provisions of Article VI.

 

Section 3.5             Manufacturing.  Ikaria shall be solely responsible for the
Manufacture of Products for Development use or for Commercialization in the
Field in the Territory, which Ikaria may conduct itself or through Affiliates,
Sublicensees, or contractors.

 

Section 3.6             Commercialization.  Ikaria shall be solely responsible for
conducting, itself or through Affiliates, Sublicensees or contractors, 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 1.30, Section 4.2(c),
Section 5.2(d), Section 5.3(e) and Section 10.1(b), as
between the Parties, Ikaria shall bear all costs associated therewith. In performing all such Commercialization activities
and disseminating Product information, Ikaria will comply with all applicable
laws, regulations, and guidelines concerning such activities.

 

Section 3.7             On-Going Studies.  Fibrex shall retain control of and shall bear
all costs relating to the on-going studies listed in Schedule 3.7 (the “On-Going
Studies”), and shall exercise commercially reasonable efforts to continue
and complete the On-Going Studies, which 

 

11

 

shall be managed by Fibrex.  Fibrex shall not modify the On-Going Studies
without the prior written consent of Ikaria. 
Without limiting the generality of Section 2.1, any results or
other information resulting from any of the Ongoing Studies shall be deemed to
be included in the scope of the license rights granted to Ikaria by Fibrex
under Section 2.1.

 

Section 3.8             Consulting Agreements.

 

(a)   Ikaria shall discuss in good faith with Mr. Rainer Henning
whether there are consulting services that Ikaria would like Mr. Henning
to (either directly or through a consulting group) to perform for Ikaria in
connection with the Development of Products.

 

(b)   Ikaria shall discuss in good faith with Mr. Peter Petzelbauer
whether there are consulting services that Ikaria would like Mr. Petzelbauer
(either directly or through a consulting group) to perform for Ikaria in connection
with the Development of Products.

 

(c)   Ikaria shall discuss in good faith with Mr. Peter Petzelbauer
whether there are Development services that Ikaria would like Mr. Petzelbauer’s
laboratory to perform for Ikaria in connection with the Development of
Products.

 

 

 

Article IV

Financial Provisions

 

Section 4.1             Milestone Payments.  With respect to each of the following
milestones (other than the milestone payment specified in Section 4.1(a),
which is addressed in Section 4.8), Ikaria shall pay Fibrex the
corresponding payment set forth below within [**] days after the achievement by
Ikaria, its Affiliates or Sublicensees of such milestone:

 

	
   

  	
  a.

  	
  Signing
  of Definitive Agreement

  	
  $5,250,000

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  b.

  	
  Successful
  Completion of Phase I Clinical Trial in healthy volunteers per Compound
  (excluding FX06)

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  c.

  	
  Milestones
  Relating to Development, Regulatory Filing,

  and
  Approval in First Indication

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Successful Completion of Phase IIa Clinical Trial

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Successful Completion of Phase IIb Clinical Trial

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Acceptance of NDA Filing in the U.S.

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Acceptance of MAA Filing in the EU

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Approval of the NDA in the U.S.

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Approval of an MAA in Europe

  	
  $[**]

  

 

12

 

	
   

  	
   

  	
  Approval of an NDA in Japan

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  d.

  	
  Milestones
  Relating to Development, Regulatory Filing, and Approval in Second Indication

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Successful Completion of Phase IIa Clinical Trial

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Successful Completion of Phase IIb Clinical Trial

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Acceptance of NDA Filing in the U.S.

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Acceptance of MAA Filing in the EU

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Approval of the NDA in the U.S.

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Approval of an MAA in Europe

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Approval of an NDA in Japan

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  e.

  	
  Milestones
  Relating to Development, Regulatory Filing, and Approval in Third Indication

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Successful Completion of Phase IIa Clinical Trial

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Successful Completion of Phase IIb Clinical Trial

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Acceptance of NDA Filing in the U.S.

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Acceptance of MAA Filing in the EU

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Approval of the NDA in the U.S.

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Approval of an MAA in Europe

  	
  $[**]

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
  Approval of an NDA in Japan

  	
  $[**]

  

 

(1) If no Phase IIa Clinical
Trial is conducted in this Indication, this milestone payment shall be paid
upon the successful achievement of an interim analysis of a  Phase IIb Clinical Trial in that Indication
or if an interim analysis is not performed, upon Successful Completion of a
Phase IIb Clinical Trial.  This milestone
payment would not be triggered or paid with respect to FX06 at any time.

 

Ikaria shall notify Fibrex promptly after the
achievement of each such milestone. All such payments are non-refundable and,
except as provided in clause (v) below, non-creditable. Payment of
milestones shall be subject to the following:

 

(i)                                     Each of the
milestones set forth in this Section 4.1 (other than Section 4.1(b) shall
be paid only once regardless of the number of Products that achieve such
milestone or the number of times a given Product achieves such milestone.  

 

13

 

Accordingly,
the maximum amount payable under all of the foregoing milestones is
$104,000,000 (excluding the milestone payment to be paid under (b) above).

 

(ii)                                  Milestone
payments payable under Section 4.1(c) shall be paid for the first
Product to achieve the applicable milestone for any Indication.

 

(iii)                               If a Product reaches a development milestone for
any Indication, and if that milestone was already reached for another
Indication, Ikaria shall pay the applicable amount set forth in Section 4.1(d).

 

(iv)                              If a Product reaches a development milestone for
any Indication, and if that milestone was already reached for two other
Indications, Ikaria shall pay the applicable amount set forth in Section 4.1(e).

 

(v)                                 Notwithstanding the foregoing, any milestone
payment paid in respect of an Indication that is no longer under Development
may be credited against that same milestone for any other Indication that Ikaria
may pursue.

 

(vi)                              Payment of the foregoing milestones
is illustrated by the examples set forth in Exhibit C.

 

Section 4.2             Royalties on Net Sales of
Products.

 

(a)   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(c), Ikaria
shall pay to Fibrex 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:

 

	
   

  	
  Aggregate
  Worldwide Calendar Year Net Sales

  	
   

  	
  Royalty

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Up to $[**]

  	
   

  	
  [**]

  	
  %

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Greater than $[**] to $[**]

  	
   

  	
  [**]

  	
  %

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Greater than $[**]

  	
   

  	
  [**]

  	
  %

  	
   

  

 

(b)   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.

 

(c)   Royalty Reductions for Third Party Payments.  If Ikaria is required to obtain a license or
immunity from suit from any Third Party in order for Ikaria, its Affiliates, or
any Sublicensee to exercise or use the rights granted to Ikaria herein in
respect of any Product in any country or to Develop or Commercialize Products
in any country, and Ikaria, its Affiliates, or any Sublicensee pays any Third
Party any up-front fee, milestone, royalty, or other payment (each, a “Third
Party Payment”) in consideration of obtaining such license or immunity from
suit, Ikaria shall have the right to offset up to [**] percent ([**]%) of such
Third Party Payments that are allocable to a Product against royalties payable
to Fibrex under this Section 4.2 in respect of sales of such Product; provided, that such offset shall not exceed [**]% of the

 

14

 

royalties otherwise payable in respect of
sale of such Product; and provided further that any portion of the [**]% of
such Third Party Payments that may be offset against royalties payable to
Fibrex under this Section 4.2 may be applied against royalties to be paid
in respect of such Product in subsequent periods until fully depleted. Not less
than [**] Business Days prior to entering into any agreement providing for
payment of Third Party Payments, Ikaria shall send Fibrex a written notice
describing in reasonable detail the terms of the proposed agreement and reasons
for entering into such agreement.  If
requested by Fibrex, the Parties shall then discuss such terms and Ikaria shall
consider in good faith any views expressed by Fibrex.

 

(d)   Duration of Payments. 
The amounts payable to Fibrex under this 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.

 

Section 4.3             Reports and Accounting.

 

(a)   Reports; Payments. 
Ikaria shall deliver to Fibrex, 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 Fibrex 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 Fibrex from such gross sales and Net
Sales, and (iii) any amounts set off pursuant to Section 4.2(c) against
payments owed to Fibrex.  When Ikaria
delivers such accounting to Fibrex, Ikaria shall also deliver all amounts due
under Section 4.2 to Fibrex for the calendar quarter.  All payments shall be made by wire transfer
to an account to be specified by Fibrex in writing.

 

(b)   Audits by Fibrex. 
Ikaria shall keep, and shall require its Affiliates and Sublicensees 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 Fibrex, Fibrex shall have the right no
more than [**] per calendar year, at Fibrex’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 Sublicensees upon reasonable
notice and during regular business hours. 
Prior to any review conducted pursuant to this Section 4.3(b),
Fibrex’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 Fibrex for a purpose other
than as set forth in this Section 4.3(b). 
Results of such review shall be made available to Ikaria.  If the review reflects an underpayment to
Fibrex, such underpayment shall be promptly remitted to Fibrex.  Likewise, if the review reflects an
overpayment, Ikaria shall be entitled to credit such overpayment against any
subsequent payments. The fees charged by such accountants shall be paid by
Fibrex; provided, that if the audit uncovers an
underpayment of royalties by Ikaria in an amount that exceeds [**]% of the
total royalties owed, then the reasonable fees of such accountants shall be
paid by Ikaria.

 

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

 

15

 

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 Sublicensees 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 Sublicensees 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 reasonable and legal
efforts to reduce tax withholding on payments made to Fibrex.  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 provide to Fibrex documentation
of the payment of any withholding taxes that are paid pursuant to this Section 4.6.

 

Section 4.7                                      Blocked
Payments.  If, by
reason of applicable laws or regulations in any country, it becomes impossible
or illegal for Ikaria or its Affiliates or Sublicensees, to transfer, or have
transferred on its behalf, royalties or other payments to Fibrex, such
royalties or other payments shall be deposited in local currency in the
relevant country to the credit of Fibrex in a recognized banking institution
designated by Fibrex or, if none is designated by Fibrex within a period of
[**] days, in a recognized banking institution selected by Ikaria or its
Affiliate or Sublicensee, as the case may be, and identified in a written
notice given to Fibrex.

 

Section 4.8                                      Freedom to
Operate.

 

(a)          Promptly following the
Effective Date, Ikaria shall conduct a freedom to operate search (the “FTO”)
to verify that the Fibrex Patents Rights do not infringe upon the intellectual
property rights of any Third Party and that Ikaria’s ability to fully exercise
its rights to Develop, use, Manufacture and Commercialize Products for use in
the Field is not otherwise impinged, prevented, blocked, or hindered by or due
to or by the intellectual property rights of a Third Party, other than Patent
Rights relating to the pegylation of any Compound.

 

(b)         Ikaria shall have the sole
right to select counsel to conduct the FTO (so long Fibrex does not reasonably
object to such selection), and shall have the sole right to interact with and
direct such counsel; provided, however, that in order to afford both Ikaria and
Fibrex the benefit of attorney-client privilege with respect to any written
work product resulting from the FTO, Ikaria and Fibrex shall be joint clients
of the counsel selected by Ikaria to conduct the FTO (which shall be reflected
in an engagement letter with the applicable counsel).  Ikaria shall bear the expense of the FTO.

 

(c)          Ikaria shall have [**] days
following the Effective Date in which to complete the FTO (the “FTO Period”).  Ikaria shall provide a copy of the final
results of the FTO to Fibrex and shall discuss such final results with Fibrex.

 

(d)         If Ikaria determines, in its
sole discretion, that the final results of the FTO are acceptable to Ikaria,
Ikaria shall pay to Fibrex the “Signing of the Definitive Agreement” 

 

16

 

milestone payment specified in Section 4.1(a) in
accordance with Section 4.1.  If
Ikaria determines, in its sole discretion, that the final results of the FTO
are unacceptable to Ikaria, Ikaria shall have the right to terminate this Agreement
upon written notice to Fibrex, provided that such notice is given within the
FTO Period.

 

(e)          During the FTO Period,
Ikaria and Fibrex agree that (i) Fibrex will not (either directly or
indirectly) solicit, encourage, respond to, or discuss any proposal for a
transaction that would conflict with or impede the transaction reflected in
this Agreement, or provide any non-public information to any third party in
connection with such a proposal and (ii) Ikaria and its Affiliates will
not (either directly or indirectly) solicit, encourage, respond to, or discuss
any proposal for, or enter into a transaction under which it acquires rights to
a compound or other biopharmaceutical product or that would conflict with or
impede the transaction reflected in this Agreement, or provide any non-public
information to any third party in connection with such a proposal.

 

Article V

Intellectual Property
Ownership, Protection and Related Matters

 

Section 5.1                                      Ownership of
Inventions.

 

(a)          Sole Inventions.  Each Party shall exclusively own all
inventions made solely by such Party, its employees, agents and consultants in
the conduct of the Parties’ activities pursuant to this Agreement (“Sole
Inventions”).  Sole Inventions made
solely by Ikaria, its employees, agents and consultants are referred to herein
as “Ikaria Sole Inventions”.  Sole
Inventions made solely by Fibrex, its employees, agents and consultants are
referred to herein as “Fibrex Sole Inventions”.

 

(b)         Joint Inventions.  The Parties shall jointly own all inventions
made jointly by Ikaria, its employees, agents, and consultants, on the one
hand, and Fibrex, its employees, agents and consultants, on the other hand, in
the conduct of any joint Development activities conducted by the Parties, on
the basis of each Party having an undivided interest in the whole (“Joint
Inventions”).  The Parties shall
jointly own all Joint Inventions on a worldwide basis in accordance with and
bearing with it the same rights as the joint ownership interests of
co-inventors named on U.S. patents under U.S. patent laws.  Such rights of joint ownership are further
implemented by the Parties on a worldwide basis pursuant to this Article V.

 

(c)          Inventorship.  For purposes of determining whether an
invention is an Ikaria Sole Invention, a Fibrex Sole Invention or a Joint
Invention, questions of inventorship shall be resolved in accordance with
United States patent laws.

 

Section 5.2                                      Prosecution and
Maintenance of Patent Rights.

 

(a)          Jointly Owned Inventions and
Sole Inventions.  Ikaria
shall have the exclusive right and option for the management of the
preparation, filing, prosecution, and maintenance of any and all patents and
patent applications, including any interference proceedings related thereto,
included in Patent Rights under this Agreement that claim or disclose Jointly
Owned Inventions or, to the extent directed to any Compounds (including their
method of manufacture or use), Sole Inventions owned by either Party.

 

17

 

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

 

(c)          Fibrex 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 Fibrex reasonable notice to this effect
sufficiently in advance to permit Fibrex to undertake such filing and
prosecution without a loss of rights, and thereafter Fibrex may, upon written
notice to Ikaria, file and prosecute such patent applications and maintain such
patents in such country.

 

(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) (including any interference, opposition, and
re-examination proceedings related thereto), provided, however,
that Fibrex shall bear such costs and expenses relating to any Patent Right
with respect to which Fibrex has exercised its step-in right under Section 5.2(c).

 

(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.

 

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 Joint Patent Rights or Fibrex Patent
Rights or (ii) unauthorized use of any of the Joint Know-How or Fibrex
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 

 

18

 

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.

 

(b)         Fibrex Intellectual Property
and Joint 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 Fibrex
Intellectual Property from Competitive Infringement or Joint Intellectual
Property from any infringement.  Ikaria
shall give Fibrex sufficient advance notice of its intent to file any such suit
or take any such action, and the reasons therefor, and shall provide Fibrex
with an opportunity to make suggestions and comments regarding such suit or
action.  Thereafter, Ikaria shall keep
Fibrex informed, and shall from time to time consult with Fibrex regarding the
status of any such suit or action and shall provide Fibrex 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, [**]% of any
remainder shall be paid to Fibrex and the balance retained by Ikaria.

 

(ii)          If Ikaria chooses not to
initiate a suit or take other appropriate action under subsection (b)(i) above
to protect Fibrex Intellectual Property from Competitive Infringement or Joint
Intellectual Property from infringement, Ikaria will so notify Fibrex of its
intention, in which case Fibrex shall have the right to initiate such suit or
take such other appropriate action. 
Fibrex 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, Fibrex
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 equally by the Parties.

 

(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.

 

19

 

(d)         Patent Invalidity Claim.  If a Third Party at any time asserts a claim
that any Joint Patent Right or Fibrex Patent Rights is invalid or otherwise unenforceable
(an “Invalidity Claim”), whether (i) as a defense in an
infringement action brought by Ikaria or Fibrex pursuant to subsection (b) above,
or (ii) in an action brought against Ikaria or Fibrex 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.

 

(e)          Conduct of Certain Actions;
Costs.  For any action to terminate
any infringement of Joint Patent Rights or Fibrex Patent Rights, or any
misappropriation or misuse of Fibrex Know-How, if either Party is unable to
initiate or prosecute such action solely in its own name or to obtain a more effective
remedy, or if required by applicable law, the other Party shall join such
action voluntarily and shall execute all documents necessary to initiate
litigation to prosecute and maintain such action. In connection with any such
action, the parties shall cooperate fully and will provide each other with any
information or assistance that either reasonably requests. 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 Fibrex 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.

 

Article VI

Confidentiality

 

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 the rules or regulations of the United
States Securities and Exchange Commission (the “SEC”) or similar
regulatory agency in a country other than the United States or of any 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 and to the extent practicable under the circumstances, such
Party shall provide the other Party with a copy of the proposed text of such
statements or disclosure (including any exhibits containing this 

 

20

 

Agreement) sufficiently in advance of the
scheduled release or publication thereof to afford such other Party a
reasonable opportunity to review and comment upon the proposed text (including
redacted versions of this Agreement).  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.

 

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 Fibrex 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.  Additionally,
each party is permitted to disclose Confidential Information to actual or
potential licensees, licensors, acquirors or equity or other financing sources;
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                                      Terms of this
Agreement.  Except as
required by applicable laws, treaties, and regulations (including securities
laws), the Parties agree that the terms of this Agreement will be considered
Confidential Information of both Parties to which this Article VI applies.

 

Section 6.4                                      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 6.5                                      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 the rules or
regulations of the SEC or similar regulatory agency in a country other than the
United States or of any 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.

 

21

 

Article VII

Representations and
Warranties

 

Section 7.1                                      Representations
of Authority.  Fibrex and
Ikaria each represents and warrants to the other Party that 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.  Fibrex and Ikaria each represents and
warrants to the other Party that all necessary consents, approvals and
authorizations of all government authorities and other Persons required to be
obtained by it have been obtained.

 

Section 7.3                                      No Conflict.  Fibrex and Ikaria each represents and
warrants to the other Party that, notwithstanding anything to the contrary in
this Agreement, 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 Effective Date 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 Effective Date.

 

Section 7.4                                      Enforceability.  Fibrex 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
Fibrex Representations. 
Fibrex represents and warrants to Ikaria that as of the Effective Date:

 

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

 

(b)         Fibrex 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 Studies;

 

(c)          to Fibrex’s Knowledge, the
issued patents included in the Fibrex Patent Rights listed in Exhibit A
are valid and enforceable;

 

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

 

(e)          Fibrex owns the entire
right, title, and interest in and to the Fibrex Intellectual Property 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
Fibrex Intellectual Property;

 

(f)            to Fibrex’s Knowledge, there
are no anticipated or pending oppositions or re-examinations with respect to
any Fibrex Patent Right;

 

22

 

(g)         to Fibrex’s actual
Knowledge, (i) practice under the Fibrex Patent Rights does and will not
infringe Patent Rights of Third Parties, and (ii) Fibrex did not
misappropriate any intellectual property rights of any Third Party in its
Development of the Products; provided, that this subsection (g) shall not
apply to Patent Rights relating to the pegylation of any Compound.

 

(h)         Fibrex 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 Fibrex Patent Rights or that challenges Fibrex’s ownership
of the Fibrex Intellectual Property or that makes any adverse claim with
respect thereto, and, to the Knowledge of Fibrex, there is no basis for any
such claim, demand or proceeding.

 

Section 7.6                                      Employee,
Consultant and Advisor Legal Obligations.  Fibrex 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.  Fibrex 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 7.7                                      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, OR THAT THE DEVELOPMENT ACTIVITIES WILL BE COMPLETED IN THE EXPECTED
TIMEFRAME.

 

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 upon the date of expiration of the last-to-expire Royalty Term for
all Products in all countries in the Territory.

 

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. 
Such termination shall become effective at the end of the notice period
unless the Breaching Party cures such breach during such notice period.

 

Section 8.3                                      Development-Related
Termination by Ikaria. 
Ikaria shall have the right to terminate this Agreement, on a Product-by-Product
basis, upon sixty (60) days prior written 

 

23

 

notice, if Ikaria at any time determines, in
its sole judgment, that the results of the Development do not warrant further
Development of such 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
Fibrex to Ikaria under Section 2.1 and, notwithstanding any other
provision in this Agreement to the contrary, Ikaria’s obligations under Article IV,
shall survive;

 

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

 

(iii)        Section 5.1, 5.2 and
5.3 shall survive.

 

(b)         If this Agreement is
terminated either by Fibrex under Section 8.2, or by Ikaria under Section 8.3
with respect to a specific Product (the “Terminated Product,” which
shall include all Products in the case of such termination under Section 8.2),

 

(i)                                     the licenses granted under Section 2.1
to the Terminated Product shall terminate as of the effective date of such
termination; provided, that Ikaria, its
Affiliates, and its Sublicensees shall be afforded a commercially reasonable
period of time (but no more than [**] months) to complete any goods in progress
and to sell off any then existing or resulting inventories for finished goods
of the Terminated Product, subject to all royalty and other obligations
hereunder to Fibrex;

 

(ii)                                  Ikaria shall assign and
promptly transfer to Fibrex (A) all regulatory filings, Regulatory
Approvals, and clinical trial agreements (to the extent assignable and not
cancelled) relating to Terminated Product, to the extent that Fibrex elects to
continue Development of such Products; (B) all data, including clinical
data, materials, and information Controlled by Ikaria related to the Terminated
Product; and (C) all trademarks for the Terminated Product (if such
termination occurs after approval of such trademark by a Regulatory Authority);
and (D) other material information, and any other information reasonably
requested and required by Fibrex in order to manufacture the Terminated
Product;

 

(iii)                               Fibrex shall revoke (and
Ikaria shall allow revocation of) all rights granted to Ikaria under Section 5.2
to prosecute and maintain any Fibrex Patent Rights or Joint Patent Rights that
relate solely to the Terminated Product;

 

(iv)                              Subject to commercial
reasonable compensation and for no longer than [**] months after the effective
date of termination with respect to the Terminated Product, Ikaria shall supply
(or use reasonable efforts to cause its Third Party manufacturers to supply the
Terminated Product) to Fibrex to the extent Ikaria or any of its Affiliates
had, prior to such termination, been manufacturing the Terminated Product and,
at Fibrex’s request, shall assist in the transfer of manufacturing processes to
new suppliers; and

 

24

 

(v)                                 if requested by Fibrex,
Ikaria and Fibrex shall negotiate promptly a mutually agreeable license
agreement under which Ikaria would license to Fibrex the exclusive license
under the Ikaria Product Improvements solely to Develop, manufacture and
Commercialize the Terminated Product; provided, however, that,
any such license would be subject to the payment of a reasonable royalty to be
negotiated by the Parties taking into account the development stage of the
terminated Product, the reasons and circumstances for termination, development
costs incurred or estimated to be incurred by each Party and other relevant
factors. If requested by Fibrex, Ikaria shall also provide reasonable
assistance to allow Fibrex to obtain the benefit of any intellectual property
rights embodied in the Terminated Product (or otherwise required for its Manufacture
or Commercialization) that were acquired by Ikaria from Third Parties; provided, that Fibrex shall be responsible for all financial
obligations.

 

(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, in accordance with the reasonable
instructions given by the other Party, with any shipping costs to be borne by
the other Party, provided that a Party may retain any such tangible property
owned by the other Party to the extent included within, or reasonably necessary
to exercise, any of such Party’s surviving rights and licenses.

 

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 provisions set
forth in Section 4.3(b), Section 5.1, Article I, Article VI,
Article IX, Article VIII 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.

 

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 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                                      Litigation.  If the Executive Officers are unable to
settle any dispute after good faith negotiations pursuant to Section 9.2
within [**] days after referral, either Party may seek resolution of the
dispute through remedies available at law or in equity from any court of
competent jurisdiction as set forth in Section 10.3.

 

25

 

Section 9.4             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 Fibrex, its Affiliates and their respective directors,
officers, employees and agents at Ikaria’s cost and expense, and shall
indemnify and hold harmless Fibrex 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, or
other damage or other Losses resulting from the Development, Manufacture, use,
or Commercialization of a Product by or on behalf of Ikaria or its Affiliates
or Sublicensees, excluding any claim for which Fibrex indemnifies Ikaria under
subsection (b) below.

 

(b)   By Fibrex.  Fibrex
agrees to defend Ikaria, its Affiliates and their respective directors,
officers, employees and agents at Fibrex’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
Fibrex of any of its representations, warranties, or obligations pursuant to
this Agreement, (ii) personal injury, property damage, or other damage or
other Losses resulting from the conduct of the F.I.R.E. Study, (iii) any
Losses arising out of the shutdown of operations or winding up or dissolution
of Fibrex Medical R&D or (iv) any allegation that the practice of the
Fibrex Intellectual Property in the Development of the Products under Article III
infringes or misappropriates any Third Party intellectual property rights, to
the extent (x) resulting from Fibrex’s intentional or grossly negligent
acts or omissions or (y) Fibrex had Knowledge on the Effective Date that
such practice would infringe or misappropriate such Third Party intellectual
property rights; provided, that this clause (iii) shall
not apply to any Patent Rights relating to the pegylation of any Compound.

 

(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 

 

26

 

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.  The Indemnifying Party shall not
agree, without the prior written consent of the Indemnified Party, 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 federal court sitting in the Borough of Manhattan in New
York, New York, USA in any action or proceeding arising out of 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 such federal courts 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 this Agreement may be brought in state
courts sitting in the Borough of Manhattan in New York, New York, USA, or if
such courts decline to exercise jurisdiction over any such action or proceeding
or if those courts lack proper jurisdiction, 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.

 

Section 10.4           Assignment.  Each Party may assign this Agreement or any
right hereunder, or delegate any obligation hereunder, in its sole discretion,
to (a) any of its Affiliates, (b) any entity with which or into which
it may consolidate or merge, or (c) any entity acquiring all or
substantially all of its business or assets relating to this Agreement.  Fibrex may also assign its right to receive
payments hereunder.  Neither Party shall
otherwise be permitted to assign this Agreement, in whole or in part, without
the prior written consent of the other Party. 
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 

 

27

 

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.  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.  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 Two 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 Fibrex Medical shall be addressed
to:

 

Fibrex
Medical Inc.

245 First Street, Suite 1800

Cambridge,
MA 02142, USA

Attention:  Chief Executive OfficerNotices to Fibrex
Medical R&D shall be addressed to (with a copy to Fibrex Medical)::

 

Fibrex
Medical Research & Development GesmbH

Gastgebgasse 5-13

A-1230
Vienna, Austria

Attention:  Chief Executive Officer

 

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 with an
original to be followed the same day via a reputable international courier
service, 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; acts or omissions of any government; fire; storm; flood; 

 

28

 

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 Fibrex 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 FIBREX 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.

 

Section 10.10         No Implied Waivers; Rights
Cumulative; Joint and Several Liability. 
No failure on the part of Fibrex 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.  Fibrex Medical and Fibrex Medical R&D
shall be jointly and severally liable for any breach of this Agreement by
either or both of them.

 

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         Fibrex Medical R&D.  Fibrex Medical may shut down the operations
of Fibrex Medical R&D, including the winding down and dissolution of such
entity; provided, that 

 

29

 

all of its rights to all Fibrex Intellectual
Property owned by Fibrex Medical R&D are assigned to Fibrex Medical.

 

Section 10.13         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.

 

Section 10.14         Ikaria Affiliates.  If any
portion of the Development, use, Manufacture, or Commercialization of the
Products is carried out for or behalf of Ikaria by any Affiliate of Ikaria (the
“Affiliate Services”), Ikaria shall, prior to the commencement of the
Affiliate Services, obtain a written assignment by such Affiliate to Ikaria of
all intellectual property and intellectual property rights that may be created
or arise as a result of the Affiliate Services. 
All intellectual property and intellectual property rights that may be
created or arise as a result of the Development, use, Manufacture, or
Commercialization of the Products and that is assigned to an Affiliate of
Ikaria shall be deemed owned by Ikaria for the purpose of this Agreement.

 

Section 10.15         Parent Guarantee.  This Agreement shall not become binding upon
the parties unless and until Ikaria Holdings, Inc. has signed and
delivered the “guarantee” attached hereto as Exhibit D.

 

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

 

30

 

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

 

	
   

  	
  IKARIA
  DEVELOPMENT SUBSIDIARY TWO LLC

  
	
   

  	
   

  
	
   

  	
  By:

  	
  /s/
  Matthew M. Bennett

  
	
   

  	
   

  	
   

  
	
   

  	
  Name:

  	
  Matthew
  M. Bennett

  
	
   

  	
   

  	
   

  
	
   

  	
  Title:

  	
  Senior
  Vice President

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  FIBREX
  MEDICAL INC.

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
  /s/
  Rainer Henning

  
	
   

  	
   

  	
   

  
	
   

  	
  Name:

  	
  Rainer
  Henning

  
	
   

  	
   

  	
   

  
	
   

  	
  Title:

  	
  President
  and CEO

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  FIBREX
  MEDICAL RESEARCH &

  
	
   

  	
  DEVELOPMENT
  GESMBH

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
  /s/
  Rainer Henning

  
	
   

  	
   

  	
   

  
	
   

  	
  Name:

  	
  Rainer
  Henning

  
	
   

  	
   

  	
   

  
	
   

  	
  Title:

  	
  CEO

  

 

31

 

SCHEDULE 1.4

 

COMPOUNDS

 

FX06

 

[**]

 

FX201

 

[**]

 

FX107

 

[**]

 

32

 

SCHEDULE 3.7

 

ON-GOING STUDIES

 

[**]

 

33

 

SCHEDULE 4.3(a)

 

FIBREX WIRE TRANSFER
INFORMATION

 

	
  Bank Name:

  	
   

  	
  [**]

  
	
   

  	
   

  	
   

  
	
  Bank
  Address:

  	
   

  	
  [**]

  
	
   

  	
   

  	
   

  
	
  ABA
  or Routing Number:

  	
   

  	
  [**]

  
	
   

  	
   

  	
   

  
	
  SWIFT
  Number:

  	
   

  	
  (if
  paid to a bank outside of the U.S.)

  
	
   

  	
   

  	
   

  
	
  IBAN
  Number:

  	
   

  	
  (if
  available)

  
	
   

  	
   

  	
   

  
	
  Account
  Number:

  	
   

  	
  [**]

  
	
   

  	
   

  	
   

  
	
  Account Name:

  	
   

  	
  Fibrex Medical, Inc.

  

 

34

 

EXHIBIT A

 

FIBREX PATENT RIGHTS

 

 

	
  Application
  #’s

  	
   

  	
  Patent #

  	
   

  	
  Owner

  	
   

  	
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A
total of two pages were omitted pursuant to a request for confidential
treatment.

 

35

 

EXHIBIT B

 

TECHNOLOGY TRANSFER PLAN

 

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

 

1.                                       All materials
(original or copies as appropriate) in Fibrex’s possession and Control relating
to Product, including documentation relating to Development and all regulatory
filings, clinical information, and data and other documents; provided, that, such materials relating to the F.I.R.E.
Study shall consist of such materials as, within a reasonable period of time
following the Effective Date, the Parties shall establish that are reasonable
necessary for Ikaria to Develop FX06.

 

2.                                       Copies of all
documents and available information in Fibrex’s possession and Control
necessary for Manufacturing of Product at the time of technology transfer.
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

·                  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

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

·                  filling/packaging process

·                  aseptic and process development and
validation documents

·                  facility and equipment requirements and
design documents

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

·                  product test methods, specifications, and
justification of specifications

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

 

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

 

36

 

EXHIBIT C

 

MILESTONE PAYMENT EXAMPLES

 

Solely for the purposes of the examples provided
below to illustrate Ikaria’s payment obligations under Section 4.1, (a) any
three separate Indications will be called “Indication A”, “Indication B” and “Indication
C” and (b) Products containing FX201, FX107 or FX06 Compounds (for uses in
the Field) will be called “FX201 Product”, “FX107 Product”, or “FX06 Product,”
respectively.  For the avoidance of
doubt, the examples provided below are not exhaustive and where FX201 Product,
FX107 Product or FX06 Product is used, such Product may be substituted for a
Product containing any other Compound unless otherwise specified.

 

1)  If an
FX201 Product being Developed for Indication A is the first Product to achieve
Successful Completion of a Phase IIb Clinical Trial, Ikaria would pay Fibrex
$[**] under Section 4.1(c).  If
another FX201 Product or a Product containing any other Compound subsequently
achieves Successful Completion of a Phase IIb Clinical Trial for Indication A,
then Ikaria would not be required to pay Fibrex an additional payment for such
achievement.

 

2)  If an
FX107 Product being Developed for Indication A is the first Product to achieve
Acceptance of NDA Filing in the U.S., Ikaria would pay Fibrex $[**] under Section 4.1(c).  If that same FX107 Product or another FX107
Product or a Product containing any other Compound subsequently becomes the
first Product to achieve that same milestone for Indication B, Ikaria will pay
Fibrex $[**] under Section 4.1(d). 
If that same FX107 Product or another FX107 Product or a Product
containing any other Compound then subsequently becomes the first Product to
achieve that same milestone for Indication C, Ikaria will pay Fibrex $[**]
under Section 4.1(e).

 

3) If any Product (other than an FX06 Product) has
achieved Successful Completion of Phase IIa Clinical Trial for Indication A
(and Fibrex has been paid in accordance with Section 4.1(c) for such
achievement) and an FX201 Product subsequently becomes the first Product (other
than an FX06 Product) to achieve Successful Completion of Phase IIa Clinical
Trial for Indication B, Ikaria would pay Fibrex $[**] under Section 4.1(d).  If that same FX201 Product or another FX201
Product or a Product containing any other Compound is Developed for Indication
C and subsequently achieves Successful Completion of Phase IIb Clinical Trial
for Indication C before that FX201 Product Developed for Indication B achieves
Successful Completion of Phase IIb Clinical Trial, then Ikaria would pay Fibrex
$[**] under Section 4.1(d).  If that
FX201 Product (or any other Product Developed for Indication B) subsequently
achieves Successful Completion of Phase IIb Clinical Trial, then Ikaria would
pay Fibrex $[**] under Section 4.1(e).

 

4)  If an
FX201 Product is the first Product to achieve Successful Completion of a Phase
IIb Clinical Trial for Indication A, Ikaria would pay Fibrex $[**] under Section 4.1(c).  If further Development of that FX201 Product
for Indication A is subsequently terminated, then such amount shall be credited
toward the next achievement of such milestone for any other Indication.

 

37

 

EXHIBIT D

 

FORM OF GUARANTEE

 

GUARANTEE

 

In consideration of Fibrex Medical, Inc. and
Fibrex Medical Research and Development GesmbH (collectively, “Fibrex”)
entering into that certain License Agreement by and among Ikaria Development
Subsidiary Two LLC (“Ikaria”) and Fibrex dated as of July 17, 2009
(the “Agreement”), Ikaria Holdings, Inc., a corporation organized and
existing under the laws of the State of Delaware and the ultimate sole owner of
Ikaria (“Ikaria Parent”), hereby unconditionally and irrevocably
guarantees to Fibrex the payment of all financial obligations of Ikaria,
including milestones and royalty payments set forth in Sections 4.1 and 4.2 of
the Agreement (assuming that any triggering events for such payments have been
met in accordance with the terms and conditions of the Agreement), the
indemnification obligations under Article X and any judgment against
Ikaria in respect to any breach of the Agreement (the “Guaranteed
Obligations”), upon the failure of Ikaria to satisfy a Guaranteed
Obligation when due and payable; provided, that
if Ikaria has failed to satisfy any Guaranteed Obligation, Fibrex shall (a) first
notify both Ikaria and Ikaria Parent of such failure, and provide Ikaria with
the opportunity to cure such failure as set forth in Section 8.2 of the
Agreement, and (b) if Ikaria has not satisfied the Guaranteed Obligation
by the end of the applicable cure period, then Ikaria Parent shall satisfy such
Guaranteed Obligation within fifteen (15) Business Days after written request
therefor from Fibrex. Except as provided above, (a) Ikaria Parent’s
obligations shall in no way be conditioned upon any requirement that Fibrex
first attempt to collect any of the Guaranteed Obligations from Ikaria or
resort to any security or other means of obtaining its payment and (b) to
the extent permitted by law, Ikaria Parent waives presentment, demand, protest,
notice of acceptance, notice of Guaranteed Obligations incurred and all other
notices of any kind, all defenses that may be available by virtue of any
valuation, stay, moratorium law or other similar law now or hereafter in
effect, any right to require the marshaling of assets of Ikaria, and all
suretyship defenses generally.  Without
limiting the generality of the foregoing, Ikaria Parent agrees to the
provisions of the Agreement and agrees that the obligations of Ikaria Parent
hereunder shall not be released or discharged, in whole or in part, or
otherwise affected by (a) any extensions or renewals of any Guaranteed
Obligation; or (b) any rescissions, waivers, amendments or modifications
of any of the terms or provisions of the Agreement or other agreements executed
hereafter evidencing, securing, or otherwise executed in connection with any
Guaranteed Obligation.

 

Ikaria Parent hereby agrees that any and all
disputes, claims, actions, or proceedings arising out of the execution,
delivery, or performance of this Guarantee shall be subject to the provisions
of Article IX and Section 10.2 and 10.3 of the Agreement.

 

	
   

  	
  Ikaria
  Holdings, Inc.

  
	
   

  	
   

  
	
   

  	
   

  
	
   

  	
   

  
	
   

  	
  By:
  Matthew M. Bennett

  
	
   

  	
   

  
	
   

  	
  Its:
  Senior Vice President

  
	
   

  	
   

  
	
   

  	
  Date: July 17, 2009

  

 

38

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