Exhibit 10.8

 

EXECUTION VERSION

 

Confidential Materials omitted and filed separately with the
Securities and Exchange Commission.  Double 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

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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

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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

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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

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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

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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

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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

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(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

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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

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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

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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

 

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(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.

 

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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)

 

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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

 

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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

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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

 

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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

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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 SIX (6) 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

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REGULATIONS, INCLUDING THOSE OF THE FDA AND EMEA, (II) BIOLINERX SHALL BEAR ALL
EXPENSES REQUIRED TO ESTABLISH AND QUALIFY THE BIOLINERX MANUFACTURING SITE,
INCLUDING THE COSTS OF SCALE-UP BATCHES, PROCESS VALIDATION BATCHES AND
STABILITY BATCHES, (III) BIOLINERX SHALL NOT BE ENTITLED TO ASSIGN SUCH OPTION
OR TO UTILIZE SUBCONTRACT MANUFACTURING, AND (IV) NEITHER PARTY SHALL HAVE ANY
OBLIGATION TO ENTER INTO SUCH AGREEMENT UNLESS ALL OF THE TERMS AND CONDITIONS
THEREOF ARE ACCEPTABLE TO BOTH PARTIES.  IF BIOLINERX LTD. EXERCISES SUCH OPTION
AND THE PARTIES ENTER INTO A SUPPLY AGREEMENT, (X) IKARIA SHALL BE REQUIRED TO
PURCHASE NO LESS THAN TWENTY PERCENT (20%) OF ITS REQUIREMENTS FOR THE PRODUCT
FROM BIOLINERX, AND (Y) THE PER UNIT PRICE FOR THE PRODUCT SHALL BE THE [**],
PROVIDED THAT THE PRICE SHALL NOT EXCEED [**] 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

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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.

[**]

 

$

[**]

 

 

 

 

 

[**]

 

$

12,500,000

 

 

 

 

 

 

 

 

 

[**]

 

$

[**]

 

 

 

 

 

 

4.

[**]

 

$

[**]

 

 

 

 

5.

[**]

 

$

[**]

 

 

 

 

6.

[**]

 

$

[**]

 

 

 

 

Total Development and Regulatory Milestone Payments

 

132,500,000

 

15

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(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 $250 Million

 

11

%

 

 

>$250 Million to $1 Billion

 

13

%

 

 

>$1 Billion

 

15

%

 

 

(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

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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

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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 TEN PERCENT (10%) OF
ANY SUCH PAYMENT WITHIN 30 DAYS AFTER ACTUAL RECEIPT THEREOF FROM THE THIRD
PARTY.

 

ARTICLE V
INTELLECTUAL PROPERTY OWNERSHIP, PROTECTION AND RELATED MATTERS

 

SECTION 5.1            OWNERSHIP OF INVENTIONS.

 

(A)           INTENTIONALLY OMITTED.

 

(B)           INTENTIONALLY OMITTED.

 

(C)           INVENTORSHIP.  QUESTIONS OF INVENTORSHIP SHALL BE RESOLVED IN
ACCORDANCE WITH UNITED STATES PATENT LAWS.  IN THE EVENT OF A DISPUTE REGARDING
INVENTORSHIP, IF THE PARTIES ARE UNABLE TO RESOLVE THE DISPUTE, THE PARTIES
SHALL JOINTLY ENGAGE MUTUALLY ACCEPTABLE INDEPENDENT PATENT COUNSEL NOT
REGULARLY EMPLOYED BY EITHER PARTY TO RESOLVE SUCH DISPUTE.  THE DECISION OF
SUCH INDEPENDENT PATENT COUNSEL SHALL BE BINDING ON THE PARTIES WITH RESPECT TO
THE ISSUE OF INVENTORSHIP.

 

18

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(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.  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), [**].

 

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(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

 

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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

 

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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

 

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(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

 

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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

 

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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.

 

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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

 

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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

 

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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:

 

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(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.

 

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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

 

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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).

 

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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]

 

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

 

[g80101mq09ai001.jpg]

 

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

 

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

 

[g80101mq09ai002.jpg]

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

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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

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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

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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

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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

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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

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1         Introduction

 

1.1      Background

 

1.1.1   Acute Myocardial Infarction- Definition

 

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

 

1.1.2   Infarction types and pathogenesis

 

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

 

1.1.3    Mechanisms of myocardial damage

 

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

 

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

 

1.1.4    Treatment of AMI

 

The goal of treatment for AMI is early reperfusion by rapid revascularization of
the occluded culprit coronary artery both by medical means to dissolve the clot
with thrombolytics or by cardiac catheterization with primary coronary
intervention (PCI) and deployment of stents to

 

Page 15 of 52

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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

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2      Study Objectives

 

The objectives of this study are:

 

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

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

 

Page 17 of 52

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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

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4       Investigational Plan

 

4.1    Summary of study design

 

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

 

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

 

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

 

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

 

4.1.1  Estimated study duration

 

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

 

4.1.2  Number of Patients

 

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

 

4.2  Sequential enrollment

 

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

 

4.3  Responsibilities of the Independent Safety Monitoring Board

 

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

 

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

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·                  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

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·      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

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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

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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.

 

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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

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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].

 

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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.

 

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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

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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

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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

 

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·                  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

 

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·      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.

 

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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

 

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·                  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.

 

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

 

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7                                         Adverse and Serious Adverse Events

 

7.1                               Adverse event definition

 

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

 

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

 

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

 

7.2                               Recording adverse events

 

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

 

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

 

·                  a malfunction or deterioration in the characteristics or
performance

·                  an incorrect or out of specification test result

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

·                  use error

 

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

 

7.3                               Pre-device events

 

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

 

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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

 

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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

 

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·                  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

 

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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.

 

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8                                         Data Evaluation and Statistics

 

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

 

8.1                               Endpoints

 

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

 

·                  all MIs

·                  cardiovascular hospitalization

·                  serious ventricular arrhythmias sustained

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

·              VF

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

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

·                  renal failure

·                  stroke

·                  death

 

Secondary Endpoints include the parameters:

 

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

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

·                  change from baseline in ejection fraction

·                  cardiac rupture

·                  NT-proBNP

 

8.2                               Estimated sample size

 

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

 

8.3                               Planned methods of analysis

 

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

 

8.3.1                   Analysis population

 

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

 

8.3.2                   Analysis of demographics

 

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

 

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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).

 

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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.

 

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

 

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10                                  Data Handling and Record Keeping

 

10.1                        Documentation

 

Records must be retained for 15 years after study completion

 

10.2                        Case Report Forms

 

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

 

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

 

10.3                        Monitoring and quality control

 

To ensure compliance with relevant regulations, data generated by this study
must be available for inspection upon request by representatives of BioLine
Innovations Jerusalem, 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.

 

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11                                  References

 

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

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

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

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

5.         Van de Werf et 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.

 

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Appendix A: Declaration of Helsinki

 

Initiated: 1964
17.C                                                           Original: English

 

WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI

Ethical Principles

for

 

Medical Research Involving Human Subjects

 

Adopted by the 18th WMA General Assembly

Helsinki, Finland, June 1964

and amended by the

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

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

41st WMA General Assembly, Hong Kong, September 1989

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

and the

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

 

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

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

 

A. INTRODUCTION

 

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

 

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

 

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

 

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

 

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

 

6.              The primary purpose of medical research involving human subjects
is to improve prophylactic, diagnostic and therapeutic procedures and the
understanding of the aetiology and pathogenesis of disease. Even the best proven
prophylactic, diagnostic, and

 

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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.

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

27.       Both authors and publishers have ethical obligations. In publication
of the results of research, the Investigators are obliged to preserve the
accuracy of the results. Negative as well as positive results should be
published or otherwise publicly available. Sources of funding, institutional
affiliations and any possible conflicts of interest should be declared in

 

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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.

 

§ § §

 

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Appendix B: Minnesota Living with Heart Failure® questionnaire

 

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LIVING WITH HEART FAILURE QUESTIONNAIRE

 

Instructions for Use

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

APPROVING OFFICIALS

 

Name

 

Title

 

Signature

 

Date

 

 

 

 

 

 

 

Lincoff, A. Michael, M.D

 

Chairman ISMB

 

 

 

 

 

 

 

 

 

 

 

Moti Gal

 

Sponsor Contact Person

 

 

 

 

 

 

 

 

 

 

 

Andrea Kempf-Müller, M.D

 

Drug Safety Officer

 

 

 

 

 

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

 

Contact details ISMB members

 

Lincoff, A. Michael, M.D.

 

ISMB Chairman

The Cleveland Clinic Foundation

 

 

9500 Euclid Avenue - F25

 

 

Cleveland, OH  44195

 

 

Phone:  216.444.2367

 

 

FAX:  216.636.0609

 

 

lincofa@ccf.org

 

 

 

 

 

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

 

 

Hopital Bichat-Claude BernadService de Cardiologie

 

 

46 Rue Henri Huchard

 

 

75018 Paris

 

 

FRANCE

 

 

gabriel.steg@bch.aphp.fr

 

 

 

 

 

Michael Marber BSc, MB.BS, PhD, FRCP

 

 

Professor of Cardiology

 

 

King’s College London

 

 

Honorary Consultant Cardiologist

 

 

Guy’s & St Thomas’ Hospitals

 

 

The Rayne Institute, St Thomas’ Hospital

 

 

Lambeth Palace Rd, London SE1 7EH

 

 

mike.marber@kcl.ac.uk

 

 

 

 

 

Kerry Lee, Ph.D.

 

 

Duke Clinical Research Institute

 

 

2400 Pratt Street

 

 

Room 0311 Terrace Level

 

 

Durham, NC  27705

 

 

Ph: 919-668-8725

 

 

Fx: 919-668-7055

 

 

kerry.lee@duke.edu

 

 

 

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

 

Contact details BioLine and Averion

 

Project Manager

 

Address: 2268 chemin de Sourdaine

Averion:

 

F-84140 Montfavet

Frederic Liegeois, Msc

 

Phone: +33 (0)490140997

 

 

Mobile: +33 (0)681607626

 

 

Email: frederic.liegeois@averionintl.com

 

 

 

Senior Drug Development Manager

Bioline:

Tuvia Shmuel, PhD

 

 

Address: BioLine Innovations Jerusalem,

19 Hartum St., POB 45158 Jerusalem, 

Israel 91450

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

Fax: +972-2-548-9101

e-mail: shmuelt@biolinerx.com

 

 

 

ISMB Sponsor Representative

Bioline:

Adina Porat

 

Address: BioLine Innovations Jerusalem,

19 Hartum St., POB 45158

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

Mobile: +972-54-5594613

Fax: +972-2-548-9101

E-Mail: adinap@biolinerx.com

 

 

 

Clinical Operations Manager

Bioline:

Moti Gal

 

Address: BioLine Innovations Jerusalem,

19 Hartum St., POB 45158

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

Mobile: +972-54-5933127

Fax: +972-2-548-9101

E-Mail: motig@biolinerx.com

 

 

 

ISMB Coordinator

Venn Life Sciences AG

 

 

Medical Monitor, Europe

Andrea Kempf-Müller, MD

Venn Life Sciences AG

Elisabethenstrasse 23/3

4051 Basel, Switzerland

 Tel: +41 61 201 11 83

Mobile: + 41 79 348 54 59

Fax: +41 61 273 42 50

Email: andrea.kempf-

mueller@vlsworldwide.com

 

Medical Monitor, US (only for ISMB contact)

 Sanjay Machado, MD

Venn Life Sciences

7355 Trans-Canada Suite 200

 

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

 

 

 

St-Laurent, QC, Canada

H4T-1T3

Tel: (541) 315-2992 117

Mobile: (514) 946-7678

Fax: (514) 315-0995

Email: sanjaym@vlscanada.com

 

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

 

1.                        PROTOCOL BL-1040

 

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

 

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

 

2.                        SCOPE OF THE ISMB CHARTER

 

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

 

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

 

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

 

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

 

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

 

3.                        COMPOSITION OF THE ISMB

 

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

 

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

 

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

 

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

 

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

 

ISMB Administration

 

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

 

ISMB Contacts & Consultants

 

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

 

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

 

From Venn Life Sciences AG, the ISMB Coordinator will serve as the primary
contact person for any questions the ISMB members have regarding the contents of
the ISMB Data Reports. This individual is not considered to be a member of the
ISMB and will

 

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

 

only attend open and final sessions of ISMB Data Review Meetings. Additional
individuals may also be invited to attend the open and final sessions of the
ISMB Data Review meetings, as deemed appropriate.

 

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

 

4.                        ISMB ROLE & RESPONSIBILITIES

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

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

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

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

 

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

 

 

promptly by the ISMB. The ISMB will review this information and may decide to
interrupt, alter, or terminate the trial.

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

 

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

 

5.                        VENN LIFE SCIENCES AG ROLE & RESPONSIBILITIES

 

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

 

·             To identify a specific individual to interface with the ISMB.

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

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

·             To provide specific meeting issues in advance of the meeting.

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

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

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

 

6.                        BIOLINE INNOVATIONS JERUSALEM’S RESPONSIBILITIES

 

Bioline Innovations Jerusalem will be responsible for the following:

 

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

 

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

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

 

7.                        ONGOING COMMUNICATIONS & NOTIFICATIONS

 

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

 

8.                        DATA REVIEW MEETINGS

 

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

 

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

 

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

 

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

 

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

 

Voting

 

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

 

Meeting Minutes

 

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

 

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

 

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

 

9.                        RECORDS RETENTION

 

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

 

Data Source and Content

 

10.                 ISMB COMMUNICATION OF FINAL CONCLUSIONS

 

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

 

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

 

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

 

11.                 IMPLEMENTATION OF THE ISMB RECOMMENDATIONS

 

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

 

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

 

12.                 CONFIDENTIALITY

 

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

 

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

 

 

SCHEDULE 2.3

 

EXISTING PRODUCT AGREEMENTS

 

[**]

 

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

 

SCHEDULE 3.1

 

INITIAL DEVELOPMENT PLAN

 

Project Boston Clinical Development Plan

 

Objective

 

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

 

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

 

Strategy

 

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

 

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

 

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

 

Endpoint and sample size

 

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

 

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

 

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

 

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

 

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

 

Control Group
Event Rate

 

Treatment Group
Event Rate

 

Sample size per arm
90% power and type
1 error < 5%

 

Total

[**]

 

[**]

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

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

 

Budget

 

 

 

2009

 

2010

 

2011

 

2012

 

2013

 

2014

 

2015

 

2016

 

TOTAL

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

 

 

 

 

 

[**]

 

 

 

 

 

 

 

 

 

 

 

[**]

 

 

 

 

 

 

[**]

 

 

 

 

 

 

 

 

 

 

 

 

 

[**]

 

 

 

 

[**]

 

 

 

 

 

 

 

 

 

 

 

 

 

[**]

 

[**]

 

 

[**]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[**]

 

 

TOTAL

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

Phase III Study

 

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

 

Clinical:

 

 

 

 

 

Monitoring:

 

 

 

[**]

 

Per Patient total:

 

[**]

 

[**]

 

Pre Clinical

 

[**]

 

[**]

 

Total

 

 

 

[**]

 

 

Given that 15-20% of the total clinical costs are committed before the first
patient is enrolled, we estimate that cost to decision point is approximately
[**]. It may be possible to reduce cost to the

 

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

 

decision point by [**], trading off for time-to-launch. This alternative
scenario has not been modeled.

 

Cost by Year ($M)

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**] Study

 

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

 

Cost by Year ($M)

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

Timeline

 

Phase III Study

 

Enrollment
w/ [**] per site per month

 

Part 1

 

Part 2

Total Enrollment

 

[**]

 

[**]

Active Sites

 

[**]

 

[**]

Enrollment/Site/Month (on average)

 

[**]

 

[**]

Monthly Study Enrollment

 

[**]

 

[**]

Time to Enroll Patient per Part (months)

 

[**]

 

[**]

TOTAL ENROLLMENT TIME (months)

 

[**]

 

Trial Task

 

End Date

Initiate Project

 

[**]

FPI

 

[**]

[**]

 

[**]

LPI

 

[**]

DB Lock

 

[**]

CSR

 

[**]

Submit PMA

 

[**]

 

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

 

Probability of success

 

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

 

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

 

SCHEDULE 3.7

 

PRELIMINARY COMMERCIALIZATION PLAN

 

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

 

 

Preface:

 

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

 

I.                                        Situation Analysis

 

a.              Unmet Medical Need

 

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

 

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

 

Estimates for population and cardiovascular statistics are presented in Table 1

 

Table 1

 

 

 

 

 

Est.
Annual

 

 

 

 

 

 

 

 

 

non-fatal

 

 

 

 

 

Country

 

Population
(000,000)

 

MI
(000)

 

Interventional
Cardiologist

 

Annual PCI
Procedures

 

[**]

 

10.4

 

34.7

 

230

 

28

 

[**]

 

5.5

 

18.3

 

85

 

15

 

[**]

 

5.3

 

17.7

 

80

 

14

 

[**]

 

64.4

 

214.7

 

1,772

 

172

 

[**]

 

82.3

 

274.3

 

1,500

 

219

 

[**]

 

16.7

 

55.7

 

266

 

45

 

[**]

 

0.3

 

1.0

 

14

 

1

 

[**]

 

58.1

 

193.7

 

1,879

 

155

 

[**]

 

40.5

 

135.0

 

730

 

108

 

[**]

 

7.6

 

25.3

 

124

 

20

 

[**]

 

61.1

 

203.7

 

1,000

 

163

 

Total Europe

 

352.2

 

1,174.0

 

7,682

 

939

 

[**]

 

127.0

 

423.3

 

2,500

 

339

 

[**]

 

21

 

70

 

373

 

56

 

Grand Total

 

479.2

 

1,597.3

 

10,182

 

1,278

 

 

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

 

b.              Product

 

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

 

c.               Assessment of current level of CV practice

 

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

 

Hospital admissions

 

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

 

Coronary revascularization and other procedures for CVD

 

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

 

Drugs

 

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

 

d.              Pricing  and reimbursement environment

 

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

 

Pricing

 

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

 

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

 

[**]

 

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

 

Reimbursement

 

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

 

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

 

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

 

II.                                   Commercialization Plan

 

Product Positioning Strategy

 

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

 

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

 

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

 

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

 

·                  NSTEMI (all patients who have an NSTEMI): [**]

 

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

 

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

 

Organization Size and Structure

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Table 2

 

 

 

 

 

Est.
Annual

 

 

 

 

 

 

 

 

 

 

 

non-fatal

 

 

 

 

 

 

 

Country

 

Population
(000,000)

 

MI
(000)

 

Interventional
Cardiologist

 

Annual PCI
Procedures (000)

 

Sales
Reps

 

[**]

 

10.4

 

34.7

 

230

 

28

 

[**]

 

[**]

 

5.5

 

18.3

 

85

 

15

 

[**]

 

[**]

 

5.3

 

17.7

 

80

 

14

 

[**]

 

[**]

 

64.4

 

214.7

 

1,772

 

172

 

[**]

 

[**]

 

82.3

 

274.3

 

1,500

 

219

 

[**]

 

[**]

 

16.7

 

55.7

 

266

 

45

 

[**]

 

[**]

 

0.3

 

1.0

 

14

 

1

 

[**]

 

[**]

 

58.1

 

193.7

 

1,879

 

155

 

[**]

 

[**]

 

40.5

 

135.0

 

730

 

108

 

[**]

 

[**]

 

7.6

 

25.3

 

124

 

20

 

[**]

 

[**]

 

61.1

 

203.7

 

1,000

 

163

 

[**]

 

Total Europe

 

352.2

 

1,174.0

 

7,682

 

939

 

[**]

 

[**]

 

127.0

 

423.3

 

2,500

 

339

 

[**]

 

[**]

 

21.0

 

70.0

 

373

 

56

 

[**]

 

Grand Total

 

479.2

 

1,597.3

 

10,182

 

1,278

 

[**]

 

 

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

 

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

 

Launch Timelines

 

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

 

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

 

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

 

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

 

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

 

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

 

[**]

 

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

 

Proposed European Structure

 

Headquarters

 

[g80101mq13ai001.jpg]

 

Human Resources

 

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

 

Anticipated headcount:     2

 

Government Affairs

 

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

 

Anticipated headcount:     1

 

Commercial Development

 

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

 

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

 

Anticipated headcount:     5

 

Medical Affairs

 

Development of a strong base of key opinion leaders will be critical to the
success of BL-1040.  Cardiology is a fast moving, highly technical field, and
for Ikaria to be a credible player we will need to make a significant commitment
to supporting the medical community through education, research support, etc. 

 

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

 

The European Medical Affairs team will take the lead in formulating strategy for
the engagement of key opinion leaders in the formulation of brand development
strategy, the development of brand champions and building high-level
relationships between Ikaria and the medical community.  The HQ Medical Affairs
team will work closely with LOC Medical Affairs teams to align strategy across
Europe and ensure a consistent medical approach.

 

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

 

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

 

Anticipated headcount:     3

 

Regulatory Affairs

 

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

 

Anticipated headcount:     2

 

Finance

 

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

 

Anticipated headcount:     9

 

Information Technology

 

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

 

Anticipated headcount:     3

 

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

 

Local Operating Country (LOC) Structure

 

[g80101mq13ai002.jpg]

 

Human Resources

 

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

 

Anticipated headcount:     None

 

Commercial Development

 

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

 

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

 

Anticipated headcount:     Various

 

Medical Affairs

 

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

 

Anticipated headcount:     1-2

 

Regulatory Affairs (RA)

 

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

 

Anticipated headcount:     1-2

 

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

 

Finance

 

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

 

Anticipated headcount:     None

 

Information Technology

 

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

 

Anticipated headcount:     None

 

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

 

 

SCHEDULE 4.3(a)

 

BIOLINERX WIRE TRANSFER INFORMATION

 

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

[**]

 

[**]

 

 

 

[**]

 

 

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

 

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

 

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

 

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

 

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

 

 

[**]

 

[**]

[**]

 

[**]

 

[**]

 

[**]

 

 

 

[**]

 

[**]

[**]

 

[**]

 

 

 

[**]

 

[**]

 

[**]

 

[**]

 

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

 

Family 2

 

A METHOD OF TREATING MUSCLE TISSUES

 

Country

 

Earliest
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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.

 

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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

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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 2

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Execution copy

 

AMENDMENT

TO

AMENDED AND RESTATED LICENSE AND COMMERCIALIZATION AGREEMENT

 

Amendment to Amended and Restated License and Commercialization Agreement (this
“Amendment”), dated as of January 8, 2015 (the “Amendment Effective Date”), by
and among Bellerophon BCM LLC, a Delaware limited liability company formerly
known as Ikaria Development Subsidiary One LLC (“Bellerophon”), on the one hand,
and BioLineRx Ltd., a corporation organized and existing under the laws of the
State of Israel (“BioLineRx”), on the other hand.  Each of Bellerophon and
BioLineRx may be referred to herein as a “Party” and Bellerophon and BioLineRx
may be referred to herein collectively as the “Parties.”

 

WHEREAS, Bellerophon, BioLineRx and BioLine Innovations Jerusalem L.P., a
limited partnership organized and existing under the laws of the State of Israel
(“BioLine Innovations”) entered into an Amended and Restated License and
Commercialization Agreement as of August 26, 2009 (the “Agreement”);

 

WHEREAS, BioLine Innovations has assigned all of its rights and obligations
under the Agreement to BioLineRx, and BioLineRx has assumed such rights and
obligations;

 

WHEREAS, Bellerophon has consented to the foregoing assignment and assumption in
accordance with Section 10.4 of the Agreement;

 

WHEREAS, BioLineRx has alleged certain breaches or potential breaches of the
Agreement in correspondence to Bellerophon, and Bellerophon has denied that any
breach of the Agreement exists; and

 

WHEREAS, the Parties desire to amend certain provisions of the Agreement and to
resolve all disputes relating to the Agreement that have arisen between them;

 

NOW, THEREFORE, in consideration of the premises and the mutual covenants
contained herein, and for other good and valuable consideration, the Parties,
intending to be legally bound, hereby agree as follows:

 

1.     Definitions. Capitalized terms used but not otherwise defined herein
shall have the meanings ascribed to such terms in the Agreement.  For the
avoidance of doubt, Bellerophon, as defined in this Amendment, and Ikaria, as
defined in the Agreement, are one and the same entity.

 

2.     Amendment to Agreement Terms.  Section 4.1(a)(3) of the Agreement is
hereby amended and restated to read as follows:

 

“

[**]

 

”

 

3.     Release.  BioLineRx, on its own behalf and on behalf of its predecessors,
successors, assigns, affiliates, agents and representatives, and each of them in
all of their capacities, shall, and hereby does (in such capacity, the
“Releasing Parties”), forever waive, release and discharge Bellerophon and
Bellerophon’s affiliates, and its and their predecessors, successors, assigns,
affiliates, agents, representatives, officers, directors, employees,
stockholders, attorneys and advisors, and each of them in all of their
capacities (in such capacity, the “Released Parties”), of and from any and all
claims, causes of

 

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action, demands, damages, debts, liabilities, obligations, equitable and
provisional remedies, costs, expenses (including attorneys’ and accountants’
fees and expenses) actions and causes of action of any nature whatsoever,
whether now known or unknown, suspected or unsuspected, that such Releasing
Party now has or at any time previously had, based in any way, directly or
indirectly, on the Agreement or the spin-out of Bellerophon from Ikaria
Holdings, Inc. and its affiliates, or based on any act or failure to act, or on
any disclosure or failure to disclose, by Bellerophon under or in connection
with the Agreement (each, a “Claim”).  Each Releasing Party irrevocably
covenants and agrees not to assert directly or indirectly any Claim, or to
commence, institute or cause to be commenced, any proceeding of any kind against
any of the Released Parties, based upon, regarding, related to or arising out of
any matters released in this release, and further covenants and agrees that this
Amendment is a bar to any such Claim.

 

4.     Miscellaneous.  The Parties hereby confirm and agree that, as amended
hereby, the provisions of the Agreement shall remain unchanged and in full force
and effect and the Agreement remains a binding obligation of the Parties.  This
Amendment may be executed in counterparts, each of which shall be deemed an
original, but all of which together shall constitute one and the same
instrument.  Facsimile signatures and signatures transmitted via PDF shall be
treated as original signatures.  Headings used herein are for convenience only
and shall not in any way affect the construction of or be taken into
consideration in interpreting the Agreement.

 

IN WITNESS WHEREOF, the Parties have caused this Amendment to be executed by
their duly authorized representatives.

 

BELLEROPHON BCM LLC

 

BIOLINERX LTD.

 

 

 

By:

/s/ Jonathan Peacock

 

By:

/s/ Kinneret Savitsky /s/ Philip Serlin

 

 

 

 

 

Name:

Jonathan Peacock

 

Name:

Kinneret Savitsky            Philip Serlin

 

 

 

 

 

Title:

Chief Executive Officer

 

Title:

CEO                                CFO/COO

 

2

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