Document:

Exhibit

GIBRALTAR INDUSTRIES, INC.

__________________________________
Award of Restricted Units
__________________________________

THIS AWARD is made to William T. Bosway (the “Recipient”) as of this 2nd day of January, 2019.
Recitals:

Effective as of May 4, 2018, Gibraltar Industries, Inc. (the “Company”) adopted an equity based incentive plan known as the Gibraltar Industries, Inc. 2018 Equity Incentive Plan (the “Plan”).

Under the terms of the Plan, the Committee is authorized to grant equity based compensation awards to Executive Officers of the Company.

The Committee has approved the issuance of an Award of twenty eight thousand twenty seven (28,027) Restricted Units to the Recipient as an incentive for the Recipient in connection with his acceptance of an offer of employment with the Company.

The Plan provides that the terms and conditions of each Award are to be specified in a written instrument.

The Award of Restricted Units to the Recipient on the terms and conditions contained in this instrument has been approved according to the terms of the Plan. 

Grant of Award:

NOW, THEREFORE, the Company hereby grants an Award of Restricted Units to the Recipient on the following terms and conditions:

1.Award of Restricted Units.  Subject to the terms and conditions of this Award instrument (“Instrument”), the Recipient is hereby granted an Award of twenty eight thousand twenty seven (28,027) Restricted Units.  Any reference in this Instrument to Restricted Units shall be deemed to refer only to the Restricted Units granted pursuant to the Award reflected in this Instrument together with any Dividend Equivalent Units attributable to such Restricted Units and any additional Restricted Units credited to the Recipient with respect to the Restricted Units referred to above pursuant to the anti-dilution provisions of the Plan.

2.Restriction on Transfer.  Except as set forth in Section 3, Section 4 and Section 6 below, the Restricted Units shall be subject to the Restrictions on transfer set forth in Section 5.02 of the Plan.

3.Lapse of Restrictions; Expiration of Restricted Period.  On each of the first three (3) anniversaries of the date hereof, the Restrictions shall lapse and the Restricted Period shall expire with respect to one third (1/3) of the total number of Restricted Units which have been awarded to the Recipient pursuant to this Instrument.  With respect to any Restricted Units as to which the Restrictions have not lapsed, prior to the date the Restrictions lapse with respect to any such Restricted Units, the 

Recipient shall not, except as otherwise provided by Section 4 and Section 6 below, have any right to sell, transfer, assign, make subject to gift or otherwise dispose of, or mortgage, pledge otherwise encumber any of such Restricted Units, voluntarily or by operation of law. 

4.Lapse of Restrictions Upon Certain Terminations of Employment.  Notwithstanding any provisions of Section 5.06 of the Plan to the contrary, if, prior to the date that the Restrictions have lapsed with respect to any of the Restricted Units awarded to the Recipient pursuant to this Instrument, the Recipient’s employment is terminated as a result of the Recipient’s death, as a result of the Recipient’s Disability, as a result of a termination of the Recipient’s employment by the Company without “cause” (as defined in the Plan) or a termination of the Recipient’s employment by the Recipient for a “good reason” (as defined in the Plan), the Restrictions on any Restricted Units which have not lapsed as of the date of any such termination of employment, shall lapse on the earlier of: (a) the end of the six (6) month period which begins on the first day following the date the Recipient’s employment is terminated; and (b) the date of the Recipient’s death.

5.Forfeiture of Restricted Units Upon Certain Terminations of Employment.  If the Recipient’s employment is terminated for any reason other than the Recipient’s death, the Recipient’s suffering of a Disability, a termination of the Recipient’s employment by the Company without “cause” (as defined in the Plan) or a termination of the Recipient’s employment by the Recipient for a “good reason” (as defined in the Plan), any Restricted Units credited to the bookkeeping account established for the Recipient in connection with this Award as to which the Restrictions have not lapsed as of the date of such termination of the Recipient’s employment shall be forfeited as of the date the Recipient’s employment is so terminated. 

6. Lapse of Restrictions Upon a Change in Control.  As provided for by Article 9 of the Plan, upon the occurrence of a Change in Control, the Restrictions applicable to any of the Restricted Units granted to the Recipient pursuant to this Instrument that have not lapsed as of the date a Change in Control occurs shall lapse on the date the Change in Control occurs if: (a) the Recipient’s employment with the Company or any subsidiary of the Company by whom the Recipient is employed is terminated on the date the Change in Control occurs; or (b) in connection with the Change in Control, the Acquiror does not agree to assume the obligations of the Company under this Award and does not issue an Alternative Award. 

7.Form of Payment.  Except as otherwise provided by Article 9 of the Plan, upon the lapse of the Restrictions on Restricted Units contained in this Award, the Company shall issue to the Recipient a stock certificate representing the number of Shares of Common Stock represented by the Restricted Units (and related Dividend Equivalent Units) with respect to which the Restrictions have lapsed, together with cash equal to the Fair Market Value, determined as of the date the Restrictions have lapsed, of any fractional Restricted Units as to which the Restrictions have lapsed.

8.Applicability of the Plan.  Except as otherwise provided by this Instrument, the terms of the Plan shall apply to the Award described in this Instrument and the rights of the Recipient with respect to such Award.  This Instrument, together with the Plan, contains all the terms and conditions of the Award described herein and the rights of the Recipient with respect to such Award.

9.Notices.  Any notices or other communications given in connection with this Agreement shall be mailed, and shall be sent by registered or certified mail, return receipt requested, to the indicated address as follows:

If to the Company:

Gibraltar Industries, Inc.
3556 Lake Shore Road
P.O. Box 2028
Buffalo, New York 14219
Attn: Corporate Secretary

If to the Recipient:

William T. Bosway
___________________ 
___________________

or to such changed address as to which either party has given notice to the other party in accordance with this Section 9.  All notices shall be deemed given when so mailed, except that a notice of a change of address shall be deemed given when received.

10.Defined Terms.  Capitalized terms used but not otherwise defined herein shall have the meaning provided to such terms by the Plan.

IN WITNESS WHEREOF, the parties hereto have executed this Agreement on and as of the day and year first set forth above.

GIBRALTAR INDUSTRIES, INC.

By: _/s/ Cherri L. Syvrud___________________
Senior Vice President Human Resources
and Organizational DevelopmentExhibit 10.2

 

EXCLUSIVE LICENSE AGREEMENT

 

THIS AMENDED AND RESTATED
EXCLUSIVE LICENSE AGREEMENT (the “Agreement”) is made in Jerusalem as of this _ day of November 14, 2005
(the “Effective Date”).

 

BETWEEN: 

 

YISSUM RESEARCH DEVELOPMENT COMPANY OF
THE

HEBREW UNIVERSITY OF JERUSALEM

 

(hereinafter referred to as “Yissum”)

 

AND

 

BIOCANCELL THERAPEUTICS INC.

A company incorporated under the laws of
the State of Delaware

(formerly known as DBT Biopharmaceuticals Inc.)

(hereinafter referred to as “DBTI”)

 

AND

 

BIOCANCELL THERAPEUTICS LTD. 

a company established under the laws of the State of Israel

formerly known as DBT Biopharmaceuticals Ltd.)

(hereinafter referred to as “DBTL”)

 

(DBTI and DBTL collectively hereinafter
referred to as the “Company”)

 

WHEREAS Yissum
is the owner of certain rights, title and interest in and to the Licensed Technology (defined below); and

 

WHEREAS Yissum
and the Company entered into that certain Exclusive License Agreement dated November 17, 2004 pursuant to which Yissum granted
to Company an exclusive worldwide license with rights to grant sublicenses and sub-sublicenses under the Licensed Technology (the
“Original Agreement”); and

 

WHEREAS Yissum
and the Company wish to amend and restated in full the Original Agreement entered into that certain Exclusive License, in the form
set forth herein.

 

NOW, THEREFORE,
for and in consideration of the premises and other good and valuable consideration, the receipt and sufficiency of which are
hereby acknowledged, Yissum and Company (hereinafter individually as a “Party”; and collectively as the “Parties”)
expressly agree as follows.

 

    	 

    	 

    

 

SECTION 1

Recitals and Definitions

 

In this Agreement the following expressions
shall have the corresponding meanings, unless the context otherwise requires:

 

“Affiliate”
shall mean any corporation, partnership, or other entity that at any time during the term of this Agreement directly through
one or more intermediaries Controls or is Controlled by or is under common Control with a party to this Agreement, but only for
so long as the relationship exists. A corporation or other entity shall no longer be an Affiliate when through loss, divestment,
dilution or other reduction of ownership, the requisite Control no longer exists.

 

“Control”
or “Controls” or “Controlled” shall mean: (i) in the case of a corporation, ownership
or control, directly or indirectly, of more than fifty percent (50%) of the shares of stock entitled to vote for the election of
directors; or (ii) in the case of an entity other than a corporation, ownership or control, directly or indirectly, of more than
fifty percent (50%) of the assets of such entity.

 

“First Commercial
Sale” means in each country, the date the Licensed Product is first sold, marketed, or otherwise made publicly
available for sale. Licensed Products that are distributed or used solely for pre-clinical studies, clinical trials, treatment
IND purposes or any other similar use prior to receiving regulatory approval by the relevant regulatory authority shall not be
considered sold, marketed or made publicly available for sale and shall not constitute First Commercial Sale hereunder.

 

“Licensed
Product” shall mean any product the manufacture, use, sale or importation of which is covered by a Valid Claim.

 

“Licensed
Technology” shall mean the Patents, and any technology, trade secrets, methods, processes, know-how, show-how,
formulas, data, information, inventions, improvements, discoveries or results relating t the Patents, whether patentable or otherwise.
Any future patents, technology, trade secrets, methods, processes, know-how, show-how, formulas, data, information, inventions,
improvements, discoveries or results, relating to the Patents whether or not patentable, will also be considered as Licensed Technology.

 

“Net Sales”
shall mean the gross amount invoiced by Company or Affiliates to third parties, which are not Sublicensee(s), from sales of
Licensed Products in an arm’s length transaction, less (i) discounts allowed in amounts customary in the trade for quantity
purchases, cash payments, or prompt payments, to wholesalers and distributors; (ii) sales, tariff duties and/or use taxes directly
imposed and with reference to particular sales, including VAT; (iii) outbound transportation prepaid or allowed, amounts allowed
or credited on returns, export licenses, import duties, and prepaid freight; (iv) amounts not actually collected by reason of
rejection, return of goods, and retroactive price reductions; and (iv) Third Party Royalties. No deductions shall be made for
commissions paid to individuals whether they are with independent sales agencies or regularly employed by Company and on its payroll
or for cost of collections. In the event of sales not made at “arm’s length”, Net Sales shall be calculated in
accordance with arm’s length prices determined by current market conditions. Yissum will have to establish that sales are
not made at arm’s length on the basis of adequate documentary evidence. Net Sales occur when a Licensed Product is invoiced.
Notwithstanding the immediately preceding sentence, distribution or sales of Licensed Products by Company to its Affiliates shall
not be deemed to be Net Sales unless such Affiliate is the final end user of such Licensed Products.

 

    	 

    	 

    

 

“Patents”
shall mean the patents set forth on Appendix 1 attached hereto, together with any and all registered patents covering Licensed
Technology granted whether in the United States of America or any other country, including any and all substitutions for and divisions,
continuations, continuations-in-part, provisionals, and non-provisionals, renewals, reissues, any foreign patent applications
and divisionals or national phase applications which claim priority of any application which issued into one of the patent applications
set forth in Appendix 1.

 

“Research”
shall mean the continued research regarding the Licensed Technology to be conducted pursuant to the Research Plan.

 

“Research
Plan” shall mean the description of the conduct of the Research as attached to this Agreement as Appendix II.

 

“Research
Results” shall mean the Research, including any patents, patent applications, information, material, results,
devices and know-how arising therefrom.

 

“Sublicensee(s)”
shall mean any third party to whom Company has granted a sublicense under the Licensed Technology to manufacture, develop,
distribute and market Licensed Products consistent with the provisions of this Agreement.

 

“Sublicensing
Revenue” shall mean all cash, sublicensing fees, running royalties and other consideration paid to Company by
Sublicensee(s) in consideration for the granting of rights to the Licensed Product and/or Licensed Technology and in connection
therewith. Sales of Licensed Products from Company to Sublicensee(s) shall not be deemed to be Sublicensing Revenue provided that
such Sublicensee(s) is/are not the final end user of the Licensed Products. Notwithstanding the above, Sublicensing Revenues shall
exclude (a) payments used or reimbursed for research, (b) payments used or reimbursed for parent costs, and (c) payments received
from the issuance of debt or equity securities of the Company.

 

“Third Party
Royalties” royalties calculated on any amount invoiced by the Company in connection with the sale of a Licensed
Product and actually paid by the Company to a third party for the right to use patents or other intellectual property rights of
such third party, without which right of use the Company would not be entitled to develop, manufacture and sell such Licensed Product;
provided that the duty to pay royalties to such third party has been established at arm’slength and in good faith and is
set out in a written agreement; and

 

“Valid Claim”
shall mean (i) a claim of an issued Patents which has not expired and which has not been held revoked, invalid or unenforceable
by decision of a court or other governmental agency of competent jurisdiction, unappealable or unappealed with the time allowed
for appeal having expired, and which has not been admitted to be invalid through reissue or disclaimer or otherwise; or (ii) any
claim of a pending patent application covering the Licensed Technology, which was filed in good faith and which has been prosecuted
with due diligence.

 

    	 

    	 

    

 

SECTION 2

Grant of License

 

2.1         Subject
to the terms of this Agreement, Yissum hereby grants to Company an exclusive, worldwide right and license under the Licensed Technology
to develop, have developed, make, have made, use, manufacture, market, sell, have sold, offer to sell, commercialize, import, export,
sublicense, sub-sublicense and distribute Licensed Products and/or provide services relating thereto (the “License”).

 

2.2         Company
shall have the exclusive right to enter into sublicense agreements with respect to the Licensed Technology. All sublicenses granted
by Company hereunder shall be subject to this Agreement in all respects. Each such sublicense agreement shall include a requirement
that the Sublicensee use its commercially reasonable efforts to bring the subject matter of the sublicense into commercial use.
No sublicense shall relieve Company of any of its obligations under this Agreement. Company shall forward to Yissum a complete
copy of each sublicense agreement (including, without limitation, all amendments and addenda thereto) granted hereunder within
thirty (30) days after execution of such agreement by the parties thereto. In the event that Company has granted more than one
sublicense, any breach by one Sublicensee will not effect any other non-breaching Sublicensee(s), such way that the License and
the sublicense in respect of any non-breaching Sublicensee(s) is not effected.

 

2.3         Notwithstanding
Section 2.1, not later than December 31, 2005 Company shall determine (the “Determination”): (i) to which
of either DBTI or DBTL the License shall be granted (the “DBT Licensee”), or (ii) which indications or
components of the Licensed Technology shall be granted on an exclusive basis to DBTI and which shall be granted on an exclusive
basis to DBTL. Within ten (10) days of the Determination, Company shall provide written notice to Yissum of its determination as
aforesaid. Upon the provision of such notice, the License shall be automatically modified to reflect the Determination and the
terms of this Agreement shall be modified mutatis mutandis to give effect thereto.

 

SECTION 3

Royalties and Reporting

 

3.1         In
consideration of the License granted hereunder, Company shall pay royalties to Yissum in the manner hereinafter provided (the “Royalties”).
Company shall pay to Yissum:

 

(i)            Five
percent (5%) of Net Sales; and

 

(ii)           For
Sublicensing Revenues of up to $30,000,000 per year – Ten Percent (10%); and

 

(iii)          For
Sublicensing Revenues above $30,000,000 per year – Six and One Half Percent (6.5%).

 

3.2         Sixty
(60) days after the end of each 6 month period commencing from the date of the First Commercial Sale, Company shall furnish Yissum
with a bi-annual report (herein the “Periodic Report”) detailing the total sales effected during the
reporting period and the total Royalties and Sub-license Revenues due to Yissum in respect of that period.

 

    	 

    	 

    

 

3.3         The
Periodic Reports shall state details of Net Sales and Sublicensing Revenues, including the country in which the sale was made,
the number of Licensed Products, the aggregate Net Sales and Sublicensing Revenues during the period covered by the report and
resulting Royalties due to Yissum for such completed year.

 

3.4         On
the date prescribed for the submission of each Periodic Report, Company shall pay the Royalties and amounts due to Yissum in accordance
with the Periodic Report.

 

3.5         The
value of each sale shall be computed on the date of sale in US Dollars based on the rates published in the Wall Street Journal.
The Royalties shall be computed and paid in US dollars. Payment of Value Added Tax (if applicable) shall be added to each payment
in accordance with the statutory rate in force at such time. In event that Company is prohibited under applicable foreign currency
laws to transact in US Dollars, payment shall be made in New Israeli Shekels according to the representative rate of exchange prevailing
on the date of payment. Subject to applicable law, Company shall be entitled to withhold and deduct from any payment made herein
to Yissum any and all taxes as required by law, and such withheld or deducted amount shall be treated as paid over to Yissum for
purposes of this Agreement, unless Yissum provides Company with an appropriate withholding exemption certificate. Any sum of money
due to Yissum hereunder which is not duly paid shall bear interest from the due date of payment until the actual date of payment
at the maximum rate of default interest prevailing at Bank Leumi in respect of US dollar lines of credit.

 

3.6         Company
shall keep full and correct books of accounts in accordance with General Accepted Accounting Procedures as required by U.S. Accounting
Standards enabling the Royalties to be calculated. Company shall procure that Sublicensee(s), if any, also keep such books of accounts
as aforesaid. Company shall submit to Yissum a report containing all the particulars mentioned in Section 3.3 above in respect
of each Periodic Report detailing the Royalties and Sublicensing Revenues due to it in respect of the period covered by the Periodic
Report. An annual report, authorized by a certified public accountant, shall be submitted not later than sixty (60) days following
the end of each calendar year.

 

3.7         For
five years following the end of the calendar year to which a Periodic Report pertain, Yissum may appoint an independent public
accountant to examine Company’s and Sublicensee(s)’ books of accounts and any report or information relating to the
manufacture, marketing, distribution and sale of the Licensed Products in order to verify the calculation of the Royalties and
Sublicensing Revenue and the accuracy of the information given to Yissum in the aforegoing reports. Such examination shall be made
at Company’s place of business during ordinary business hours with at least fifteen (15) days prior written notice. If an
error greater than five percent (5%) in the reports of Company will be found, Company will bear the full cost of the examination.
Company shall reasonably ensure that Yissum is able to exercise its rights pursuant to this section regarding Sublicensee(s).

 

    	 

    	 

    

 

SECTION 4

Development; Commercialization and Research

 

4.1         Company
undertakes, at its own expense, to use its commercially reasonable efforts to carry out the development work necessary to develop
and commercialize the Licensed Technology.

 

4.2         Company
shall provide Yissum with annual reports which shall detail the development results and other related work effected by Company
during the twelve (12) months prior to the report.

 

4.3         Company
shall give Yissum written notice of the First Commercial Sale within thirty (30) days thereof.

 

4.4         (i)            Yissum
shall procure the conduct of the Research at the Laboratory of Prof. Abraham Hochberg and under his supervision and in accordance
with the Research Plan. Company undertakes to finance the performance of the Research in accordance with the budget forming part
of the Research Plan.

 

(ii)           Yissum
shall procure that Company be provided with quarterly reports detailing the results and conclusions of the Research. Yissum shall
procure that appropriate records of the Research are kept in sufficient detail and in good scientific manner.

 

(iii)          The
initial period of the Research shall be for two years and the parties may agree to extend this period. Company may cease the financing
of the Research upon a written notice to Yissum of at least 90 days prior to the cessation of financing. In the event of cessation
of financing of the Research, Company shall reimburse Yissum for: (a) all expenses incurred in relation to the Research prior to
the notice of cessation of the financing of the Research; and (b) all committed outstanding expenses and obligations payable subsequent
to the notice of cessation of the financing, provided such outstanding expenses and obligations were incurred prior to the notice
of cessation.

 

SECTION 5

Ownership

 

All rights in and to
the Licensed Technology shall be owned by Yissum, and Company shall hold the rights granted pursuant to the License hereunder and
make use of them exclusively in accordance with the terms of this Agreement. The Research Results resulting from Research conducted
in accordance with Section 4.4 shall be exclusively owned by Yissum, shall form part of the Licensed Technology and shall be licensed
to the Company under the same terms and conditions of this Agreement.

 

    	 

    	 

    

 

SECTION 6

Patents

 

6.1         Company
shall assume full responsibility for and conduct patent prosecution and maintenance of the Patents and will be responsible for
preparing, filing, prosecuting and maintaining all Patents and shall use patent counsel of its own choice, subject to the approval
of Yissum (such approval not to be unreasonably withheld), at Company’s own expense. In the time period until the first round
of financing by Company, the decisions regarding preparing, filing, prosecuting and maintaining all patents will be accepted mutually
by Company and Yissum, after this time period, these decisions will borne only by Company. Company agrees to pay all costs, incident
to the United States and foreign applications, patents and like protection, including all costs incurred for filing, prosecution,
issuance and maintenance fees as well as any costs incurred in filing continuations, continuations-in-part, divisional or related
applications and any reexamination or re-issue proceedings. Company shall file and maintain patent applications corresponding to
the Licensed Technology in such countries as Company in its sole discretion shall select but shall notify and consult with Yissum
as to those countries where it shall not file and maintain patent applications. Upon the completion of Company’s first round
of financing of an amount of at least $2,500,000 (the “Financing”), Company hereby undertakes to reimburse
Yissum for previous documented expenses and costs incurred by Yissum up to 2005 relating to the filing, maintenance and prosecution
of the Patents not to exceed $50,000. Company shall pay such reimbursement in eight (8) equal quarterly installments commencing
ninety (90) days from the date of the Financing.

 

6.2         Company
agrees to keep Yissum informed of filing and prosecutions pursuant to this Section 6 including submitting to Yissum copies of all
official actions, all relevant correspondence with the patent attorneys, applications, continuations, re-examinations, re-issues,
divisionals or like proceedings and responses thereto. Company shall consult with Yissum regarding any abandonment of the prosecution
of patents application within the Patents.

 

6.3         Each
and every patent application as aforesaid in relation to the Licensed Technology shall be registered exclusively in the name of
Yissum at Company’s sole expense, and shall be included automatically within the scope of the License granted pursuant to
the terms of this Agreement.

 

6.4         In
the event that Company decides not to continue prosecution of a Patent application to issuance or maintain any patent application
or patent on technology within the Patents in a certain jurisdiction, Company shall timely notify Yissum in writing in order that
Yissum may continue said prosecution or maintenance of such applications at its option and at its own expense in such jurisdiction.
In the event that (i) Company elects not to file or not to prosecute or to discontinue or to abandon the filing, prosecution and/or
maintenance of the Patents in certain countries (the “Abandoned Countries”) and (ii) Yissum decides to do so at its
expense, then (iii) Yissum shall notify Company in writing of its intention to file, prosecute and/or maintain a patent and Company
shall have a ninety (90) day period to decide whether it wishes to bear the expenses of such actions. In the event the Company
shall notify Yissum that it does not wish to bear the costs of such filing, maintenance and/or prosecution or in absence of a reply
from the Company within the ninety (90) day period, the License shall no longer be applicable in the Abandoned Countries.

 

It is hereby clarified,
if Company fails to notify Yissum in a timely manner as required hereunder, which, for the purpose of this section, shall be the
time, considered reasonably, that would enable Yissum to effectively carry out such filing, prosecution or maintenance of the Patents,
Company shall be considered in default of this Agreement.

 

    	 

    	 

    

 

6.5         Company
and its Sublicensee(s) shall mark all products covered by Patents with patent numbers in accordance with the statutory requirements
in the country(ies) of manufacture, use, and sale, and pending the issue of any patents. Company shall ensure that its Sublicensee(s)
comply with the provisions of this section.

 

6.6         Company
undertakes to use commercially reasonable efforts at its own expense to protect against a third party’s infringement of the
Patents and forthwith to advise Yissum upon learning of the infringement. Company shall give Yissum immediate notice of any approach
made to it by a patent examiner and/or attorney in connection with the subject matter of this Agreement. Company shall reply to
such approaches after consultation with Yissum.

 

6.7         Company
shall use its commercially reasonable efforts at its own expense to defend any action, claim or demand made by any entity in connection
with rights in the Patents and/or patents and shall give notice to Yissum immediately upon learning of any such action, claim or
demand as aforesaid. Any assistance that will be requested by Company from Yissum for the purpose of defending any action, claim
or demand made by any entity in connection with rights in the Patents and/or patents, will be provided by Yissum without any additional
charge to Company.

 

6.8         Any
settlement, consent judgment or other voluntary final disposition of any action pursuant to the provisions of this section, shall
not be entered into without consultation with Yissum and the prior written consent of Yissum which shall not be reasonably withheld
or delayed.

 

6.9         Subject
to reimbursement of documented reasonable out-of-pocket expenses incurred by Company in relation to any legal action contemplated
under the provisions of this section, any award in favor of Yissum and/or Company resulting from such legal action shall be divided
by Yissum and the Company pursuant to Section 3.1 as if such award was Sublicensing Revenues. Any recovery of damages by Company
for each such suit shall be applied first in satisfaction of any unreimbursed documented reasonable expenses and legal fees of
Company relating to such suit.

 

SECTION 7

Confidentiality

 

7.1         Licensor
Confidential Information. Company agrees that, without the prior written consent of Yissum, in each case, during the term of
this Agreement, and for three (3) years thereafter, it will keep confidential, and not disclose or use Yissum Confidential Information
(as defined below) other than for the purposes of this Agreement or as detailed below. Company shall treat such Yissum Confidential
Information with the same degree of confidentiality as it keeps its own confidential information, but in all events no less than
a reasonable degree of confidentiality. Company may disclose the Yissum Confidential Information only to employees, consultants
or researchers of Company or of its affiliates who have a “need to know” such information in order to enable Company
to exercise its rights or fulfill its obligations under this Agreement and provided such parties are legally bound by agreements
which impose confidentiality and non-use obligations comparable to those set forth in this Agreement. For purposes of this Agreement.
“Yissum Confidential Information” means any scientific, technical, trade or business information relating to the subject
matter of this Agreement designated as confidential or which otherwise should reasonably be construed under the circumstances as
being confidential disclosed by or on behalf of Yissum, or any of its employees, consultants or researchers to Company, whether
in oral, written, graphic or machine-readable form, except to the extent such information: (i) was known to Company
at the time it was disclosed, other than by previous disclosure by or on behalf of Yissum or any of its employees, consultants
or researchers, as evidenced by Company’s written records at the time of disclosure; (ii) is at the time of disclosure or
later becomes publicly known under circumstances involving no breach of this Agreement; (iii) is lawfully and in good faith made
available to Company by a third party who is not subject to obligations of confidentiality to Yissum with respect to such information;
(iv) is independently developed by Company without the use of or reference to Yissum Confidential Information, as demonstrated
by documentary evidence, or (v) is disclosed pursuant to a court or administrative order, provided however that Company will first
notify Yissum of any such order and afford Yissum the opportunity to seek a protective order relating to such disclosure.

 

    	 

    	 

    

 

Notwithstanding anything
to the contrary in this Section 7.1, Company may disclose Yissum Confidential Information to actual and potential business partners,
collaborators, investors, contractors, service providers and consultants, provided, in each case, that such recipient of Confidential
Information first enters into a legally binding agreement with Company which imposes confidentiality and non-use obligations with
respect to Confidential Information comparable to those set forth in this Agreement for a period of at least five (5) years from
the date of disclosure of Yissum Confidential Information to such recipient.

 

7.2         Company
Confidential Information. Yissum agrees that, without the prior written consent of Company, in each case, during the
term of this Agreement, and for three (3) years thereafter, it will keep confidential, and not disclose or use Company Confidential
Information (as defined below) other than for the purposes of this Agreement. Yissum shall treat such Company Confidential Information
with the same degree of confidentiality as it keeps its own confidential information, but in all events no less than a reasonable
degree of confidentiality. Yissum may disclose the Company Confidential Information only to employees, consultants or researchers
of Yissum or its affiliates who have a “need to know” such information in order to enable Yissum to exercise its rights
or fulfill its obligations under this Agreement and provided such parties are legally bound by agreements which impose confidentiality
and non-use obligations comparable to those set forth in this Agreement. For purposes of this Agreement. “Company Confidential
Information” means any scientific, technical, trade or business information relating to the subject mailer of this Agreement
designated as confidential or which otherwise should reasonably be construed under the circumstances as being confidential disclosed
by or on behalf of Company whether in oral, written, graphic or machine-readable form, except to the extent such information: (i)
was known to Yissum at the time it was disclosed, other than by previous disclosure by or on behalf of Company as evidenced by
Yissum’s written records at the time of disclosure; (ii) is at the time of disclosure or later becomes publicly known under
circumstances involving no breach of this Agreement; (iii) is lawfully and in good faith made available to Yissum by a third party
who is not subject to obligations of confidentiality to Company with respect to such information; (iv) is independently developed
by Yissum without the use of or reference to the Company Confidential Information, as demonstrated by documentary evidence; or
(v) is disclosed pursuant to a court or administrative order, provided however that Yissum will first notify Company of any such
order and afford Company the opportunity to seek a protective order relating to such disclosure.

 

    	 

    	 

    

 

7.3         Each
party may disclose the terms of this Agreement to the extent required, in the reasonable opinion of such party’s legal counsel,
to comply with applicable laws, as well as to sublicensees and prospective and current investors, pursuant to appropriate non-disclosure
arrangements. If a party discloses this Agreement or any of the terms hereof in accordance with this Section7.3, such party agrees,
at its own expense, to seek confidential treatment of portions of this Agreement or such terms, as may be reasonably requested
by the other party.

 

7.4         Without
prejudice to the aforegoing. Yissum agrees that Company shall have the right to mention or reference the Hebrew University of Jerusalem’s
and/or Yissum’s names without obtaining Yissum’s prior consent to the extent the use of such names is reasonably consistent
with Company’s obligations pursuant to Section 4.1 hereof.

 

7.5         The
breach of this section, by any person or entity other than Yissum or Company shall not be deemed a breach of the Agreement, if
Yissum or Company establish that they took all reasonable steps to avoid such breach.

 

7.6         The
expiration or termination of this Agreement shall not release the Parties from their obligations pursuant to this section.

 

7.7         The
provisions of this section shall be subject to permitted publications pursuant to Section 8 herein.

 

SECTION 8

Publications

 

8.1         Yissum
shall ensure that no publications in writing, in scientific journals or orally at scientific conventions relating to the Licensed
Technology are published by it or its Researchers. For the purposes of this Agreement, the term “Researchers” means
Pro. Avraham Hochberg and his scientific research group or other scientific research group whose work is related to the Licensed
Technology.

 

8.2         Notwithstanding
Section 8.1 above, Yissum may allow the Researchers to publish any research, research results or know-how relating to the Licensed
Technology provided that it obtains Company’s prior written consent. Company undertakes to reply to any request by Yissum
for Company’s consent within forty-five (45) days of receiving such request. Company may only decline such request upon reasonable
grounds which shall be fully detailed in writing. In the event that Company does not reply to such request within the forty-five
(45) day period, then Company shall be deemed to have consented to Yissum’s request to allow the Researchers to publish in
the manner contemplated herein.

 

8.3         Should
Company decide not to allow publication as provided in Section 8.2 for reasons which in Yissum’s opinion are unreasonable,
acting reasonably, publication shall be postponed for a period of three (3) months to enable Company to file patent applications.

 

    	 

    	 

    

 

8.4         The
provisions of this Section 8 shall not prejudice any other right that Yissum has pursuant to this Agreement and at law.

 

8.5         For
the avoidance of doubt, the provisions of this Section 8 in connection with the prohibition against publication shall not apply
to internal publication by Yissum made in the Hebrew University of Jerusalem for the Researchers and employees subject to Section
7.

 

SECTION 9

Liability and Indemnity

 

9.1         Except
as set forth herein, Yissum expressly disclaims any and all implied or express warranties and makes no express or implied warranties
of merchantability or fitness for any particular purpose of the Licensed Technology contemplated by this Agreement.

 

9.2         Company
shall be solely liable for any loss, injury and/or damage whatsoever caused to its employees and/or any person acting on its behalf
by reason of Company’s acts and/or omissions pursuant to this Agreement and/or by reason of any use made of the Licensed
Technology by Company.

 

9.3         Company
undertakes to indemnify, defend and hold harmless (i) Yissum and any person acting on its behalf and any of its directors, officers,
employees and representatives, and (ii) the Hebrew University of Jerusalem and any person acting on its behalf and any of its directors,
officers, employees and representatives (herein referred to as “Indemnitees”) from and against any liability including
without limitation product liability, damages, losses or expenses including reasonable legal fees and litigation expenses incurred
by or imposed upon the Indemnitees (collectively, “Losses”) only by reason of Company’s acts and/or omissions
and/or which derive from Company’s use, development, manufacture, marketing, sale and/or sublicensing of the Licensed Technology
except to the extent such Losses are determined to have resulted from the gross negligence or willful misconduct of Indemnitees.

 

9.4         Company
shall obtain prior to the commencement of clinical trials by Company and prior to the First Commercial Sale, comprehensive general
liability insurance which shall provide:

 

(i)            product
liability coverage,

 

(ii)           contractual
liability coverage for Company’s indemnification under this Agreement and in particular as stated in Section 9.3, and

 

(iii)          Yissum
as an additional named insured.

 

Upon the commencement of any clinical trial, Company shall procure and maintain comprehensive clinical
trial liability insurance in amounts commensurate with accepted commercial practice. All required insurance will be at Company’s
sole cost and expense.

 

9.5         Company
shall provide Yissum with written evidence of such insurance upon request of Yissum. Company shall ensure that it maintains on
a continuous basis only during the relevant term of this Agreement the foregoing insurance coverage, and shall not cancel or terminate
such insurance with any insurance provider unless it has in place alternative coverage consistent with the foregoing. Company shall
provide Yissum with written notice of any material change in such insurance not later than fifteen (15) days of such change taking
effect.

 

    	 

    	 

    

 

9.6         Company
shall maintain comprehensive general liability insurance beyond the expiration or termination of this Agreement during the period
that a Licensed Product is being commercialized, distributed or sold by Company and/or any Sublicensee. In the event of early termination
by Yissum, the cost of such general liability insurance for a period of three (3) months following the date of termination will
he borne by Company and thereafter will be borne by Yissum.

 

9.7         Yissum
represents and warrants that to the best of its actual knowledge: (i) the Patents which have been issued and are listed in Appendix
1 are valid and enforceable: (ii) it has the full power to enter into this Agreement, to carry out its obligations under this Agreement,
and to grant the rights granted to Company herein; (iii) it has not previously granted and shall not grant to any third party any
rights which are inconsistent with the rights granted to Company herein, (iv) it has the rights, title, and interest in and to
the Patents, and (v) the Licensed Technology constitutes all of the intellectual property rights developed by Prof. Abraham Hochberg
laboratory in the Hebrew University in the field of H19 and IGF2 gene.

 

9.8         Company represents
that: (i) it has full corporate power and authority to enter into this Agreement and carry out all the provisions of this Agreement;
(ii) it is authorized to execute this Agreement on its behalf; (iii) the person executing this Agreement is duly authorized to
do so; and (iv) no consent, approval or authorization of any other party is required in connection with entering into this Agreement.

 

SECTION 10

Term and Termination

 

10.1       Unless
earlier terminated, as hereinafter provided, the term of this Agreement shall expire on a country-by-country basis at such time
when no Valid Claim exists, or if no Patent was issued in a country, on the eleventh anniversary of the First Commercial Sale in
such country, thereafter the License in such country shall expire, provided in each case that Company may extend the term of the
Agreement on a country-by-country basis for additional period of one year each by continuing to pay the consideration set forth
in section 3. In countires where a Patent was registered, after the expiration of Patent, Company shall have a perpetual, worldwide,
royalty-free, fully paid-up and sublicenseable License in relation to that Patent.

 

10.2       In
the event of a material default or failure by Company to perform any of the terms, covenants or provisions of this Agreement, Company
shall have ninety (90) days after the giving of written notice of such default by Yissum to correct such default, provided, however,
that if the breach is not capable of being cured within ninety (90) days of such written notice, the Agreement may not be terminated
so long as Company commences and is taking commercially reasonable actions to cure such breach as promptly as practicable. In any
event, if a curable breach has not been cured within ninety (90) days after notice requesting cure, Yissum shall have the right,
at its option, to terminate this Agreement.

 

    	 

    	 

    

 

10.3       Yissum
shall have the right, at its option, to terminate this Agreement in the event that Company shall become involved in insolvency,
bankruptcy, liquidation, winding-up or receivership proceedings. Company shall immediately notify Yissum upon commencement of any
bankruptcy, insolvency, liquidation, winding-up or receivership proceedings or the placing of an attachment on its assets.

 

10.4       In
the event of termination of this Agreement for any reason whatsoever, the License shall terminate and all rights to the Licensed
Technology (including Research Results) shall revert to Yissum and Company may make no further use thereof. Notwithstanding the
aforesaid, the expiration or termination of this Agreement shall not release Company from its obligation to carry out any financial
or other obligation which it was liable to perform prior to the Agreement’s expiration or termination, including the payment
of Royalties and Sub-License Revenues.

 

10.5       Upon
termination of this Agreement for any reason, nothing herein shall be construed to release either Party from any obligation that
matured prior to the effective date of such termination; and Articles 1, 5, 7, 8, 9, 10, 11, 12 and 13 shall survive any such termination.

 

10.6       No
termination of this Agreement shall constitute a termination or a waiver of any rights of either Party against the other Party
accruing at or prior to the time of such termination.

 

10.7       Company
shall have the right to terminate this Agreement at any time on three (3) months advance notice to Yissum, and upon payment of
all amounts due to Yissum through the effective date of termination.

 

SECTION 11

Law

 

11.1       The
provisions of this Agreement and everything concerning the relationship between the parties in accordance with this Agreement shall
be governed by the law of the State of Israel and, subject to Section 12 below, jurisdiction shall be granted only to the appropriate
court in Jerusalem. Any and all proceedings, documents and other communications or correspondences between the parties shall be
in the English language.

 

11.2       Notwithstanding
the above, Company hereby agrees that, in the event that no treaty exists upholding the enforceability of temporary orders and/or
judgments issued by Israeli courts in the foreign jurisdiction in which Yissum may require such an order and/or judgment to be
upheld, Yissum may, at its own discretion, elect the place of jurisdiction for the obtaining of orders and/or judgments against
Company. Company undertakes not to object to the enforcement against it of orders and/or judgments issued by any aforesaid jurisdiction
under such circumstances.

 

SECTION 12

Arbitration

 

12.1       All
differences and disputes arising between the parties in connection with this Agreement and/or its interpretation and/or its performance
and/or breach, shall be referred for the decision of a single arbitrator, who shall be appointed by Agreement between the parties.

 

    	 

    	 

    

 

12.2       Should
the parties not reach agreement as to the arbitrator’s identity, the arbitrator shall be appointed by the Chairman of the
Israeli Bar Association on the application of either of the parties.

 

12.3       The arbitration shall be held in Israel. The arbitrator
shall not be bound by the civil procedure regulations and laws of evidence, but shall be bound by the substantive law of Israel
and be liable to give grounds for his decision.

 

12.4        The arbitrator’s decision shall be final and shall bind the parties.

 

SECTION 13

Miscellaneous

 

13.1       This
Agreement shall be binding upon and shall inure to the benefit of Yissum and its assigns and successors in interest, and shall
be binding upon and shall inure to the benefit of Company and its assigns and successors to all or substantially all of its assets
or business to which this Agreement relates, but shall not otherwise be assignable or assigned by Company without prior written
approval by Yissum being first obtained, which approval shall not be unreasonably withheld.

 

13.2       If
any provision of this Agreement shall be declared by a court of competent jurisdiction to be invalid, illegal or incapable of being
enforced in whole or in part, the remaining conditions and provisions or portions thereof shall nevertheless remain in full force
and effect and enforceable to the extent they are valid, legal and enforceably, and no provision shall be deemed dependent upon
any other covenant or provision unless so expressed herein.

 

13.3       Each
Party hereby agrees that it does not intend to violate any public policy, statutory or common law, rule, regulation, treaty or
decision of any government agency or executive body thereof of any country or community or association of countries; that if any
word, sentence, paragraph or clause or combination thereof of this Agreement is found, by a court or executive body with judicial
powers having jurisdiction over this Agreement or any of its Parties hereto, in a final unappealed order to be in violation of
any such provision in any country or community or association of countries, such words, sentences, paragraphs or clauses or combination
shall be inoperative in such country or community or association of countries, and the remainder of this Agreement shall remain
binding upon the Parties hereto.

 

13.4       The
Parties covenant and agree that if a Party fails or neglects for any reason to take advantage of any of the terms provided for
the termination of this Agreement or if a Party, having the right to declare this Agreement terminated, shall fail to do so, any
such failure or neglect by such Party shall not be a waiver or be deemed or be construed to be a waiver of any cause for the termination
of this Agreement subsequently arising, or as a waiver of any of the terms, covenants or conditions of this Agreement or of the
performance thereof. None of the terms, covenants and conditions of this Agreement may be waived by a Party except by its written
consent. A waiver by Yissum of any breach by Company of any provision or condition of this Agreement to be performed by Company
shall not be deemed a waiver of similar or dissimilar provisions or conditions at the same or any prior or subsequent time.

 

    	 

    	 

    

 

13.5       This
Agreement contains the entire agreement and understanding of the Parties with respect to the subject matter hereof, supersedes
any prior agreements and understandings with respect thereto and cannot be modified, amended or waived, in whole or in part, except
in writing signed by the Parties.

 

13.6       Each
Party shall bear its own legal expenses involved in the making of this Agreement.

 

13.7       The
headings to the sections in this agreement are for the sake of convenience only and shall not serve in the Agreement’s interpretation.

 

13.8       Company
shall disclose to Yissum any existing agreement and/or arrangement or relationship of any kind between it and employees of Yissum
and/or the Hebrew University of Jerusalem with respect to the Licensed Technology and in connection therewith and shall not enter
into any agreement or arrangement with any employees of Yissum and/or the Hebrew University of Jerusalem, as aforesaid, without
the prior written consent of Yissum.

 

13.9       The
appendixes annexed hereto constitute an integral part hereof and shall be read jointly with its terms and provisions.

 

13.10     The
recitals hereto constitute an integral part hereof. In this Agreement, unless otherwise required or indicated by the context, the
singular shall include the plural and vice-versa, and the masculine gender shall include all other genders.

 

SECTION 14

Notices

 

All notices and communications
pursuant to this Agreement shall be made in writing and sent by registered mail to or served in person at the following addresses:

 

		(i)	If to Yissum:

 

YISSUM RESEARCH DEVELOPMENT COMPANY

OF THE HEBREW UNIVERSITY OF JERUSALEM

Hi-Tech Park, Edmond J. Safra Campus

Givat Ram, P.O.Box 39135, Jerusalem 91390, Israel

 

		(ii)	If to Company:

 

BIOCANCELL PHARMACEUTICALS INC.

2711 Centerville Road, Suite 400

Wilmington, New Castle County, Delaware, 19808

and

 

BIOCANCELL PHARMACEUTICALS LTD.

Hi-Tech Park, Edmond J. Safra Campus

Givat Ram, P.O.Box 39135, Jerusalem, 91390, Israel

 

    	 

    	 

    

 

or such other address furnished in writing
by one Party to the other. Any notice sent as aforesaid shall be deemed to have been received five (5) days after being posted
by registered mail, or one (1) day following the date of personal service.

 

[REMAINDER OF PAGE INTENTIONALLY LEFT BLANK)

 

    	 

    	 

    

 

IN WITNESS WHEREOF,
the Parties hereto have executed and delivered this Agreement in multiple originals by their duly authorized officers and representatives
on the respective dates shown below, but effective as of the Effective Date.

	 	 	 	 	 
	YISSUM RESEARCH DEVELOPMENT COMPANY 

OF THE HEBREW UNIVERSITY OF JERUSALEM
	 	 	 	 	 
	By:	/s/ Herve Bercovier	 	By:	/s/ Reuven Ron
	 	 	 	 	 
	Name:	Prof. Herve Bercovier	 	Name:	Reuven Ron
	 	 	 	 	 
	Title:	Director	 	Title:	VP Marketing
	 	 	 	 	 
	Date:	November 14, 2005	 	Date:	November 14, 2005
	 	 	 	 	 
	BIOCANCELL PHARMACEUTICALS INC.
	 	 	 	 	 
	By:	/s/ Avi Barak	 	By:	/s/ Uri Danon
	 	 	 	 	 
	Name:	Avi Barak	 	Name:	Uri Danon
	 	 	 	 	 
	Title:	Chairman	 	Title:	President
	 	 	 	 	 
	Date:	Nov 14, 2005	 	Date:	November 14, 2005
	 	 	 	 	 
	BIOCANCELL PHARMACEUTICALS LTD.
	 	 	 	 	 
	By:	/s/ Avi Barak	 	By:	/s/ Uri Danon
	 	 	 	 	 
	Name:	Avi Barak	 	Name:	Uri Danon
	 	 	 	 	 
	Title:	Chairman	 	Title:	President
	 	 	 	 	 
	Date:	Nov 14, 2005	 	Date:	November 14, 2005

 

    	 

    	 

    

 

APPENDIX 1 - PATENTS

 

		2148	DIAGNOSTIC ASSAY FOR MALIGNANCIES USING H-19 GENE, KIT 

		Inventors:	ARIEL ILANA, HOCHBERG ABRAHAM

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	File	 	Country	 	Status	 	Appl Date	 	Appl No	 	Reg Date	 	Reg No	 	Pub Date	 	Pub No
	2148-00	 	Israel	 	Granted	 	7/Mar/94	 	108879	 	3/Dec/00	 	108879	 	 	 	 
	2148-01	 	PCT	 	Published	 	6/Mar/95	 	PCT/EP95/00823	 	 	 	 	 	14/Sep/95	 	WO95/24503
	2148-03	 	US	 	Granted	 	6/Sep/96	 	08/704,786	 	21/Sep/99	 	5,955,273	 	 	 	 
	2148-04	 	Europe	 	Granted	 	6/Mar/95	 	95927570.2	 	29/May/02	 	0759092	 	 	 	 

 

		2324	METHODS AND COMPOSITIONS FOR INDUCING TUMOR-SPECIFIC CYTOTOXICITY 

		Inventors:	AYESH SUHAIL, HOCHBERG ABRAHAM

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	File	 	Country	 	Status	 	Appl Date	 	Appl No	 	Reg Date	 	Reg No	 	Pub Date	 	Pub No
	2324-00	 	US	 	Abandoned	 	3/Oct/97	 	08/943,608	 	 	 	 	 	 	 	 
	2324-01	 	PCT	 	Published	 	4/Oct/98	 	PCT/IL98/00486	 	 	 	 	 	15/Apr/99	 	WO 99/18195
	2324-02	 	PCT	 	Published	 	22/Oct/02	 	PCT/IL02/00843	 	 	 	 	 	1/May/03	 	WO 03/035883
	2324-03	 	Brazil	 	Filed	 	4/Oct/98	 	PI9812717-9	 	 	 	 	 	 	 	 
	2324-03	 	US	 	Granted	 	l/Oct/98	 	09/165,240	 	11/Jul/00	 	6,087,164	 	 	 	 
	2324-04	 	China	 	Exam	 	4/Oct/98	 	98811833.5	 	 	 	 	 	 	 	 
	2324-05	 	Europe	 	Published	 	4/Oct/98	 	98947759.1	 	 	 	 	 	 	 	1019499
	2324-06	 	Hungary	 	Filed	 	4/Oct/98	 	P0003745	 	 	 	 	 	 	 	 
	2324-07	 	Israel	 	Filed	 	4/Oct/98	 	135430	 	 	 	 	 	 	 	 
	2324-08	 	Korea	 	Exam	 	4/Oct/98	 	2000-7003609	 	 	 	 	 	 	 	 
	 	 	Mexico	 	Filed	 	4/Oct/98	 	2000003251	 	 	 	 	 	 	 	 
	2324-09	 	Mexico	 	Filed	 	4/Oct/98	 	2000-003843	 	 	 	 	 	 	 	 
	2324-10	 	New Zealand	 	Filed	 	4/Oct/98	 	503843	 	 	 	 	 	 	 	 
	2324-11	 	Norway	 	Filed	 	4/Oct/98	 	20001684	 	 	 	 	 	 	 	 
	2324-12	 	Poland	 	Filed	 	4/Oct/98	 	P339949	 	 	 	 	 	 	 	 
	2324-13	 	Russia	 	Granted	 	4/Oct/98	 	2000111553	 	22/Oct/03	 	2214280	 	 	 	 
	2324-14	 	US	 	Granted	 	10/May/00	 	09/568,059	 	23/Oct/01	 	6,306,833	 	 	 	 
	2324-15	 	US	 	Exam	 	22/Oct/01	 	10/012,131	 	 	 	 	 	 	 	US-2004-0082529

 

    	 

    	 

    

 

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	2324-16	 	Australia	 	Granted	 	4/Oct/98	 	94571/98	 	19/Dec/02	 	755774	 	 	 	 
	2324-17	 	Japan	 	Exam	 	4/Oct/98	 	2000-514993	 	 	 	 	 	 	 	 
	2324-18	 	Canada	 	Exam	 	4/Oct/98	 	2,308,124	 	 	 	 	 	 	 	 
	2324-19	 	Singapore	 	Granted	 	4/Oct/98	 	200001824-2	 	4/Jun/02	 	72207	 	 	 	 
	2324-20	 	Czech Republic	 	Exam	 	4/Oct/98	 	PV2000-1201	 	 	 	 	 	 	 	 
	2324-21	 	Europe	 	Published	 	22/Oct/02	 	02779859.4	 	 	 	 	 	 	 	1438412
	2324-22	 	China	 	Filed	 	22/Oct/02	 	02825940.8	 	 	 	 	 	 	 	 
	2324-23	 	Japan	 	Filed	 	22/Oct/02	 	2003-538383	 	 	 	 	 	 	 	 
	2324-24	 	Israel	 	Filed	 	22/Oct/02	 	161553	 	 	 	 	 	 	 	 
	2324-25	 	Canada	 	Filed	 	22/Oct/02	 	2,464,394	 	 	 	 	 	 	 	 
	2324-26	 	Australia	 	Filed	 	22/Oct/02	 	2002343189	 	 	 	 	 	 	 	 
	2324-27	 	Mexico	 	Filed	 	22/Oct/02	 	PAa2004/003732	 	 	 	 	 	 	 	 
	2324-28	 	Czech Republic	 	Filed	 	18/Jun/04	 	PV 2004-741	 	 	 	 	 	 	 	 

 

		2617	TRACKING GENE EXPRESSION 

		Inventors:	HOCHBERG ABRAHAM, HONIGMAN ALIK, ZEIRA EVELYN, AXELROD JONATHAN, GOMORI MOSHE, TAVOR EINAT, GILADI HILA, GALUN EITAN

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	File	 	Country	 	Status	 	Appl Date	 	Appl No	 	Reg Date	 	Reg No	 	Pub Date	 	Pub No
	2617-00	 	US	 	Provisional	 	31/Jan/00	 	60/179,139	 	 	 	 	 	 	 	 
	2617-01	 	US	 	Provisional	 	27/Dec/00	 	60/758,038	 	 	 	 	 	 	 	 

 

		2807	METHOD FOR DETECTION OF MICRO-METASTASIS 

		Inventors:	HOCHBERG ABRAHAM

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	File	 	Country	 	Status	 	Appl Date	 	Appl No	 	Reg Date	 	Reg No	 	Pub Date	 	Pub No
	2807-00	 	US	 	Exhausted	 	12/Sep/02	 	60/409,975	 	 	 	 	 	 	 	 
	2807-01	 	PCT	 	Published	 	12/Sep/03	 	PCT/US03/28 807	 	 	 	 	 	 	 	WO 2004/02 4957

 

		2808	METHOD FOR REGULATING EXPRESSION GENES 

		Inventor:	HOCHBERG ABRAHAM, AYESH SUHAIL, PORADOSU ENRIQUE

	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	File	 	Country	 	Status	 	Appl Date	 	Appl No	 	Reg Date	 	Reg No	 	Pub Date	 	Pub No
	2808-00	 	US	 	Provisional	 	3/Oct/02	 	60/415,528	 	 	 	 	 	 	 	 
	2808-01	 	PCT	 	Published	 	3/Oct/03	 	PCT/US2003/ 031306	 	 	 	 	 	 	 	WO 2004/03 1359

 

    	 

    	 

    

 

ADDENDUM

This
Addendum is made in Jerusalem as of this 22 day of November, 2005 (the “Effective Date”) and is entered in
to by and among Yissum the Research Development Company of the Hebrew University of Jerusalem (hereinafter: “Yissum”)
and Biocancell Therapeutic Inc., a company incorporated under the laws of the State of Delaware (hereinafter: “DBTI”)
and Biocancell Therapeutics Ltd., a company established under the laws of the State of Israel (hereinafter: “DBTL”)
(DBTI and DBTL shall collectively be referred to as the “Company”), for the purposes of amending certain provisions
in the Exclusive License Agreement executed by Yissum, DBTI and DBTL on November 14, 2005 (hereinafter: the “License
Agreement”), all as set forth hereunder.

 

	1.	Capitalized
                                         terms used in this Addendum shall have the meaning ascribed to them in the License Agreement.

 

	2.	This
                                         Addendum shall form an integral part of the License Agreement.

 

	3.	Yissum
                                         and the Company agree that as of the Effective Date, the provisions set forth below in
                                         the License Agreement will be amended as follows:

 

(a)          section
3.2 of the License Agreement shall be replaced in its entirety with the following provision:

 

Sixty
(60) days after the end of each calendar year commencing from the date of the First Commercial Sale, Company shall furnish Yissum
with an annual report (herein the “Periodic Report”) detailing the total sales effected during the reporting period
and the total Royalties and Sub-license Revenues due to Yissum in respect of that period.

 

(b)          section
10.1 of the License Agreement shall be replaced in its entirety with the following provision:

 

Unless
earlier terminated, as hereinafter provided, the term of this Agreement shall expire on a country-by-country basis at such time
when no Valid Claim exists, or if no Patent was issued in a country, on the ninth anniversary of the First Commercial Sale in
such country, thereafter the License in such country shall expire, provided in each case that Company may extend the term of the
Agreement on a country-by-country basis for an additional period of one year each by continuing to pay the consideration set forth
in section 3. Upon the expiration of the License in a given country (as set forth above), the Company shall have a perpetual,
worldwide, royalty-free, fully paid-up License in that country.

 

(c)          All
sections of the License Agreement not amended by the terms of this Addendum shall remain unchanged and of full force and effect.

 

	4.	Yissum
                                         and Company agree that the Research Plan and budget attached hereto shall also be attached
                                         to the License Agreement and shall form Appendix 2 of the License Agreement.

 

    	 

    	 

    

 

IN
WITNESS WHEREOF, the Parties hereto have executed and delivered this Agreement in multiple originals by their duly authorized
officers and representatives on the respective dates shown below, but effective as of the Effective Date. 

	 	 	 	 	 
	YISSUM RESEARCH DEVELOPMENT COMPANY
	OF THE HEBREW UNIVERSITY OF JERUSALEM
	 
	By:	 /s/ Reuven Ron	 	By:	 /s/ Herve Bercovier
	 	 	 	 	 
	Name:	 REUVEN RON	 	Name:	 PROF. HERVE BERCOVIER
	 	 	 	 	 
	Title:	 VICE PRESIDENT	 	Title:	 Chairman
	 	 	 	 	 Authority for Research and Development
	 	 	 	 	 Hebrew University
    of Jerusalem
	 	 	 	 	 
	Date:	 NOV 22 2005	 	Date:	 
	 	 	 	 	 
	BIOCANCELL PHARMACEUTICALS INC.
	 
	By:	 /s/ Avi Barak	 	By:	 /s/ Uri Danon
	 	 	 	 	 
	Name:	 	 	Name:	 URI DANON
	 	 	 	 	 
	Title:	 	 	Title:	 PRESIDENT
	 	 	 	 	 
	Date:	 	 	Date:	 NOV 22, 2005
	 	 	 	 	 
	BIOCANCELL PHARMACEUTICALS LTD.
	 
	By:	 /s/ Avi Barak	 	By:	 /s/ Uri Danon
	 	 	 	 	 
	Name:	 	 	Name:	 URI DANON
	 	 	 	 	 
	Title:	 	 	Title:	 PRESIDENT
	 	 	 	 	 
	Date:	 	 	Date:	 NOV 22, 2005

 

Research
Plan

 

General
Aims:

 

		1)	To
                                         develop additional novel DNA based therapy strategies for bladder cancer. The goals of
                                         the present project are accordingly the development of molecular markers for TCC prognosis
                                         and of a DNA-based gene therapy tailored to the properties of each tumor, by implementing
                                         new molecular diagnostic methods. A novel therapy approach based on patient-specific
                                         gene expression profiles in each cancer tailored to individual patients by using selected
                                         transcriptional regulatory sequences for DNA-based therapy will be developed. It should enable us to identify likely non-responders in advance, thereby avoiding treatment failures with unnecessary suffering
and costs.

 

    	 

    	 

    

 

		2)	Evaluation
                                         of the therapeutic effect of new toxin vectors now carrying kanamycin driven by the H19
                                         regulatory sequences.

 

		3)	To
                                         continue testing the therapeutic potential of our toxin vector in compassionates patients
                                         (case study), to base the safety and efficacy of the treatment for a long term..

 

		4)	In
                                         order to perform the clinical trials a large amount of plasmid will be required that
                                         can no longer be generated using bench protocols, thus scaling-up nuclei acid purification
                                         protocol will be developed.

 

		5)	To
                                         use the regulatory sequences of the imprinted genes H19 and Insulin growth factor 2 (IGF-2)
                                         for preclinical development of DNA based therapy of human colorectal cancer liver metastasis.
                                         The therapeutic potential of the toxin vector will be tested in compassionate patients
                                         suffering of liver colon metastases, preparing a platform for a Phase I clinical study.

 

		6)	To
                                         further validate the role of H19 acting as an oncogene, to determine the potential dowstream
                                         targets of H19, and to substantiate the potential therapeutic value of knocking down
                                         H19 in human tumors.

 

Research
Program

 

1. Since
our results so far are based on limited study populations, quantitative expression profiles for H19 and IGF2 (P3 and
P4 transcripts) will be determined in a large number of bladder carcinoma specimens using a computerized in situ RNA
hybridization analysis technology and quantified by “TMP” (telemolecular pathology) software that permits high
resolution quantitative analysis of in situ hybridization photomicrographs and real-time transmission of the resulting
images. The goal is to correlate both the numbers of cells expressing H19 and other genes with different stages of
bladder cancer and their co-expression in human bladder tumors. This study will be extended to each gene identified as highly
expressed in TCC but not expressed in normal tissue. From published data sets on gene expression in TCC and from our own
Micro array-based gene expression profiling in bladder cancer, we will extract genes that are not expressed in normal bladder
tissue but become induced in invasive or papillary TCC. This expression pattern will be confirmed by RT-PCR on a set of RNAs
from TCC and normal bladder tissues from different stages available in the lab and on TCC cell lines. For the following
investigation, genes will be selected that are not significantly expressed in other adult tissues (except in testes), i.e.
oncofetal markers (like H19) or cancer-testis antigens (like the MAGE-A genes). In parallel to the ongoing
investigation of tissue specimens, collection of follow-up data for the patients will be continued to determine whether
expression of transcripts of H19, IGF2 or other genes identified using expression profiling with DNA Microarrays, differs not
only between different stages and grades of bladder cancer, but has also prognostic value. Genes yielding significant
prognostic results in univariate analysis will be tested further in multivariate analysis together with
established prognostic parameters (TNM stage, tumor grade, multifocality etc.). Further, selected regulatory sequences
confirmed as differentially expressed in normal tissue/cells and cancer tissues/cells will be tested for promoter activity in
transfection experiments.

 

    	 

    	 

    

  

Subsequently to the studies on tumor tissues, we aim to evaluate at least one urine-based DNA TCC
marker each or a combination of markers that supersedes the diagnostic accuracy and reproducibility, and preferably also the
economy, of presently known markers.

 

2. The experiments in this part of the work program aim at expanding the repertoire of transcriptional activating sequences that
are differentially expressed in bladder cancer to become capable of treating a broader range of TCC beyond those that express
H19. The research plan calls for invoking tumor specific-dependent regulatory sequences to selectively express cytotoxic
effectors in tumor cells. Currently, the arsenal of our therapeutic vectors comprises constructs carrying regulatory sequences
of H19 and of IGF2. H19-DT-A constructs have been developed to the point of using them in patients. The selected
regulatory elements will be incorporated into plasmid vectors (“naked DNA”) containing reporter (β-galactosidase,
luciferase or GFP) or toxin genes. The plasmid vector to be used as backbone for the regulatory sequence analyses will be pGL3
(Promega). Delivery via plasmid vector (“naked DNA”), has been found to be surprisingly efficient in vivo according
to our Preliminary Studies. Activity of the plasmid constructs will be assessed ex vivo in human and murine tumor cell lines selected
by their pattern of expression and in normal urothelial cells for comparison. By the end of these ex vivo analyses, we expect
to assemble a variety of optimized vectors, with both reporter and toxin genes, to be entered into animal in vivo efficacy studies
as described below. The therapeutic potential of toxin expression constructs driven by the selected tumor specific regulatory
sequences will be studied in distinct animal models of bladder cancers which are complementary and permit the study of tumors
with distinctive histopathologies. All animal models and techniques for investigation of the animal tumors are established and
have been used in previous work. (A) Since BBN-induced rat bladder tumors share histological features with human papillary bladder
TCC, we will employ this animal model. Once rumors have been BBN induced, our therapeutic vectors will be evaluated by intravesical
gene delivery. Naked DNA expression constructs complexed with a DNA/PEI (polyethylenimine) will be delivered intravesically via
catheter, after removing the urine. Intravesical delivery enables local administration and efficient delivery of therapeutic genes
to cancer cells with minimal systemic exposure. We will start with marker experiments, using reporter expression constructs (β-gal,
GFP and Luc) to monitor delivery efficiency and check the selective activity of tumor-specific promoters. Then the DT-A toxin
and the CD expression vectors will be evaluated. (2) The second animal model will consist of human bladder carcinoma cell
lines implanted into nude mice. We will study the therapeutic potential of our toxin vectors on orthotopically implanted cell
lines (UMUC-3, RT-112) in female CD-1 nude mice. DNA will be administered transurethrally 4 and 7 d after cells implantation.
We will use these human bladder cancer cells engineered to stably express the GFP protein in vivo to visualize the tumor burden
over time by intravital imaging using a Macro-illumination imaging system, allowing us to reduce the number of animals used in
these experiments.

 

    	 

    	 

    

 

3. An
expression vector expressing the human gene TNF-α under the control of the H19 promoter will be generated and
its function will be assessed ex-vivo in various bladder carcinoma cell lines selected by their pattern of expression of H19.
The anti-proliferation and in vitro killing effect of TNF-α will be verified by cell counting and MTT assay. The
TNF-α expression level following transfection will be assayed by ELISA in the supernatant. Effects of the
H19-TNF-α vector will be compared to those of DTA-H19 and the combined effect of both vectors. These experiments will
serve to test the potential synergisim between DT-A and TNF-α in TCC. In particular, the combined effect of the two
plasmids expressing the DT-A or the TNF-α will be tested in cell lines that are resistant to the cytotoxic effect of
either DT-A or TNF-α. The therapeutic potential of the expression vectors for TNF-α and their potential
synergistic antitumor effect with DT-A vectors will then be explored in two animal models: (A) immunocompromised CD-1 mice
implanted with human bladder carcinoma cell lines. Two weeks after tumor cell inoculation the tumor size will be measured.
One group of mice will then be treated with the toxin vector DTA-H19, a second group with the vector expressing the
TNF-α under the control of the H19 promoter, a third group will be treated with the combination of both toxin
vectors. A fourth control group will be treated with luciferase reporter vector, containing H19 transcriptional
regulatory sequences. The mice will receive three intratumoral injection of the vectors every 2 days. The animals will be
sacrificed 3 days after the last injection, the tumors will be excised and their ex-vivo weight and volume will be measured.
Samples of the tumors will be processed for histological examination for evidence of necrosis and persistent tumor. To
monitor the in vivo TNF-α expression at the mRNA level, RNA from the tumors will be isolated and RT-PCR will he
performed. (B) bladder tumors induced by subcutaneous injection of syngenic mouse bladder carcinoma cells into the back of
female C3H/He mice. Two weeks after tumor development the mice will be randomized into four groups and treated as described
in (A).

 

4. We have previously reported the construction of expression vectors carrying the gene for diphtheria toxin A (DT-A under the
control of a 814 bp 5’-flanking region of the H19 gene). The cell killing activity of these constructs corresponded to the
activity of the H19 regulatory sequence in the transfected cells. The therapeutic potential of toxin expression constructs driven
by H19 regulatory sequences was evaluated in distinct animal models of bladder cancers. The Food and Drug Administration (FDA)
advises strongly against the use of β-lactam resistance markers in plasmids that will be used as therapeutics. Thus, the
β-lactam resistance marker cassette in the plasmid expressing either the DT-A gene or the reporter gene will be replaced
by kanamycin resistance gene. Governmental regulatory issues and plasmid efficacy should be taken into account when designing
the plasmid vector intended for use in clinical trials. In order to validate the biological activity of the vectors now carrying
the kanamicyn resistance gene, in vitro and in vivo experiments will be performed. The biologic or pharmacologic activity of the
constructs carrying the kanamycin resistance gene will be tested by in vitro bridging experiments, and compared to that obtained
using the plasmids carrying the Amp resistance gene. The therapeutic potential and the safety of the kanamycin carrying toxin
expression constructs driven by H19 regulatory sequences will be evaluated in two distinct animal models of bladder cancers which
are complementary and permit the study of tumors with distinctive histopathologies: I) a rat carcinogen-induced bladder tumor
model (with a prominent papillary component) that parallels superficial papillary TCC in humans at varying stages of tumor progression,
and II) immunocompromised SCID mice implanted with human bladder carcinoma cell lines.

 

    	 

    	 

    

 

5.
The therapeutic potential of the kanamycin carrying toxin expression constructs driven by H19 regulatory sequences will be
tested in compassionate patients (including the patients that were already treated with the toxin vector carrying the Amp resistance
gene) that underwent several transurethral resection of superficial low-grade tumor, while no adjuvant intravesical treatments
succeeded to stop the recurrences. Patients will receive DTA-H19 intravesically on day 1. Treatment will continue once a week
for a total of 6 weeks in the absence of unacceptable toxicity. The patient will receive escalating doses of DTA-H19. In the absence
of grade III toxicity or worse in the first cohort treated, subsequent cohorts of patients each will receive escalating doses
of DTA-H19 on the same schedule. If no toxicity will be observed dose escalation will continue. If the patient experiences grade
IV toxicity, dose escalation will cease and the MTD (maximal tolerated dose) will be defined as the previous dose level. One week
after completion of treatment the patient will be evaluated by video-cytoscopy, urinary cytology and bladder biopsy, monitoring
of residual H19-DTA in body fluids including urine, blood and nose smear will be performed by PCR. Patients will be tested for
electrolytes, kidney and liver function. Six weeks after treatment completion patients will undergo video-cytoscopy, urinary cytology
and biopsy, monitoring of residual DTA-H19 in body fluids including urine, blood and nose smear by PCR, and testing for electrolytes,
kidney and liver function. Follow-up will continue every three months by video-cytoscopy during the first year after treatment
and by routine clinical monitoring after that.

 

6. After testing the selected regulatory sequences in animal models, optimization of therapy strategies in human will be performed.
In order to perform a clinical trial using one of the validated therapeutic vectors a large amount of plasmid will be required
that can no longer be generated using bench protocols, thus scaling-up nuclei acid purification protocol will be developed. Following
the scale-up procedure, lot-to-lot release tests will be established, monitoring consistency and lot reproducibility. Govermental
regulatory issues and plasmid efficacy will he taken into account when designing the plasmid vetor intended for use in clinical
trials. In accordance with regulatory requirements, a master cell bank will be generated for small-scale GMP production. A pilot
batch of the plasmid will be produced and evaluated in pre-clinical studies. A process for the production of 65 liter will be
developed, in comparison to the current lab procedure, that produces only 0.5 liter. GMP manufacture of plasmid for use in human
clinical studies will include the performance and documentation of Quality Control (QC) tests. The production process will be
free of RNase for the generation of media lysates to avoid potential contamination of the final product with any animal derived
component, and hence putative human pathogens (e.g. bovine spongiform encephalopathy), which is in compliance with FDA regulations
and deals with the challenges related to the large-scale production of E. Coli, which includes optimization of the biologicals
system (vector/host/fermentation media). Essentially the process involves fermentation, cell lysis and purification through a
series of centrifugation and wash steps, endotoxin removal and plasmid purification on a DEAE anion exchange chormatography column,
and plasmid concentration by isopropanol. The plasmid product will be tested for specifications and lot-to-lot release. The DNA
contenst in the plasmid and the presence of other cell-derived contaminants, such as RNA and proteins, will be evaluated by measuring
the A260/280 ratio of absorbance. The homogeneity of size and structure, supercoiled vs. linear, will be tested by gel electrophoresis.

 

The identity of the DNA plasmid will be determined by restriction enzyme digestion with multiple enzymes. A test for sterility
to detect aerobic and anaerobic bacteria and Mycoplasm testing will be performed.

 

    	 

    	 

    

 

7.
We have previously showed that the human H19 and IGF2-P3 regulatory sequences were able to drive the DT-A expression in the
rat colon carcinoma CC531 cells (Ohana et al 2005). The cell killing activity of these constructs corresponded to the activity
of the H19 regulatory sequence in the transfected cells. Therefore, these cells proved to be suitable for the generation of the
orthotopic animal model used in this study to examine the anti-tumor effect of DTA-H19 and DTA-P3 expression vectors in vivo.
This therapy was shown recently to successfully reduce subcapsular induced liver tumors in a metastatic model of rat CC531 colon
carcinoma (Ohana et al. 2005). Although a connection between IGF II expression and the development of liver metastases from colorectal
cancers has been shown thus far H19 expression in liver metastases in humans, has not been studied. We investigated the expression
of the imprinted oncofetal H19 gene in hepatic metastases derived from a range of human carcinomas, and assessment of its prognostic
value in order to establish the basis for developing a DNA based therapy for such metastases. The positive results using the toxin
vector DTA-H19, prompted us to test during the next year the antitumoral effect of the toxin vector DTA-P3 and DTA-P4 injected
intraperitoneally in combination with the transfection enhancer PEI, into the rat orthotopic model for colon metastases in the
liver. Preliminary experiments support the concept that regional arterial delivery of the expression vectors might be an effective
treatment for colorectal liver metastases. The therapeutic potential of the toxin constructs DTA-H19, DTA-P3 and DTA-P4, will
be evaluated in the established liver metastases animal model following repeated regional delivering of the toxin vectors using
intrahepatic injection. In this approach we combine the use of the regulatory sequences of the H19 and IGF2-P3 genes that drive
the expression of the cytotoxic gene in the tumors only and regional arterial delivery of these toxin vectors. Like in clinical
practice, implantable ports will be used to allow repeat administration of the vector.

 

The replacement of the Amp resistance gene
by the Kan resistance gene in the expression vectors DTA-P3 and DTA-P4 will also be performed.

 

These experiments may serve as
a platform for the design of a clinical study on compassionate patients.

 

8. Preliminary
in vitro experiments using Hep3B hepatocarcinoma cells showed that H19 RNA was knockdown as determined by RT-PCR analysis.
Recent results showed that HCC tumors fromed from Hep3B in vitro transfected with H19 siRNA encountered a
significant retardation of tumor growth, and in some cases tumor did not form at all. These preliminary observations
encourages us to assess H19 as a therapeutic target for HCC and possibly for other tumors in which H19 is significantly
increased. Our initial experiments will be to explore the hypothesis that H19 act as an oncogene both in vitro and in vivo
based in our preliminary results. Our next step will be to explore the molecular mechanism of this effect. Our initial
observations are suggestive of a therapeutic potential for siRNA against H19 inhibiting tumor growth. We will assess the anti
tumor growth effect in vitro in a panel of H19 positive cell lines. The experiments will be performed both in normal and
serum starvation conditions. For controls we would apply H19 negative cell lines, from the same lineages and also
non-relevant siRNAs with potential low off target effects. The effect of the siRNA against H19 will be assessed by cell
proliferation studies and metabolic read-outs. We will investigate and employ different siRNA delivery methods for in vitro
and in vivo delivery. To check the therapeutic potential of siRNA duplexes targeting the human H19 RNA, CD-1 nude mice will
be implanted with H19 expressing Hep3B cells or other tumor cell lines. For the assessment to the anti-tumor effect in vivo,
all tested cell lines will be stably transduced with the luciferse (luc) expression vector; then, luc expression will be
assessed with the sensitive CCCD system to monitor and quantify the levels of luc. This will enable us to measure the
efficiency of siRNA delivery and also will serve to assess the effect of anti H19 siRNA on tumor growth. We would also
determine the anti tumor effect through tumor volume measurements, and by survival studies. The mechanism of the
anti-tumor effects will also be investigated in vivo as described above for the in vitro studies.

 

    	 

    	 

    

 

	Research Budget	 
	 	 
	Hochberg’ lab costs	 
	All figures are in US $K	Updated: October 31, 2005
	Lab
    costs (for year #1 only)	 

 

	Study group	 	Cost item	 	Total   	 
	Bladder studies	 	Bridging studies	 	10	 
	 	 	Immunology studies, cell necrosis caused
    by DTA-H19 treatment might induce an immune reaction	 	5	 
	 	 	Compassionate use	 	4	 
	 	 	IGF2, siRNA and TNF studies	 	12	 
	Liver studies	 	Intra arterial administration studies	 	14	 
	 	 	IGF2, siRNA and TNF studies	 	12	 
	Annual personnel costs(detailed below)	 	 	 	219	 
	Total costs	 	 	 	276	 
	University overhead of 35%	 	 	 	97	 
	Total Research Cost	 	 	 	373	 

 

The
Total Research Cost as set forth in this Research Budget shall be paid to Yissum in advance, in four (4) equal installments. 

 

The
first installment shall be on July 1, 2006 and the remaining installments shall be paid thereafter at the beginning of each 3
month period. 

 

Lab
wages breakdown: 

 

	Name	 	Role	  Annual wage	 	Effort
                                         (%)	 
	Prof. Avraham Hochberg	 	 	0	 	 	 
	Dr. Patricia Chana	 	Laboratory Manager	60	 	100	%
	Prof. Suhail Ayash	 	Diagnostics and immunology	50	 	100	%
	Dr. Birman Tatiana	 	Pathology and Animal studies	45	 	100	%
	Aya Mizrahi, PhD student	 	Liver studies	10	 	50	%
	Blumberg Yair, Msc	 	Bladder studies	10	 	100	%
	Tamar Snieder	 	Lab Technichian	18	 	100	%
	Doron Amit PhD student	 	IGF2-P4 studies	20	 	100	%
	Colel Turgemam	 	 	6	 	25	%
	 	 	 	 	 	 	 
	Total of annual wages	 	 	219	 	 	 

 

	Lab R&D costs	Confidential	Page 1

 

    	 

    	 

    

 

AMENDMENT
TO LICENSE AGREEMENT

 

Made
in Jerusalem this 11 day of September 2007, by and between:

 

YISSUM
RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM,
of Hi Tech Park, Edmond J. Safra Campus, Givat Ram, Jerusalem 91390 Israel, Fax: +972-2-658 6689; ( “Yissum”);
and

 

BIOCANCELL
THERAPUEUTICS LTD., of Beit Beck, Har Hotzvim, Jerusalem (the
“Company”)

 

		WHEREAS: 	the
                                         Company and Yissum executed an amended and restated license agreement on November 14,
                                         2005 (the “License Agreement”), pursuant to which the Company obtained
                                         an exclusive license to certain patents owned by Yissum based upon the inventions of
                                         Professor Abraham Hochberg (the “Researcher”); and

 

		WHEREAS: 	The
                                         Parties wish to amend certain aspects of the License Agreement.

 

NOW
THEREFORE THE PARTIES DO HEREBY AGREE AS FOLLOWS: 

 

	1.	Interpretation
                                         and Definitions

 

		1.1.	The
                                         preamble constitutes an integral part this Amendment and shall be read jointly with its
                                         terms and conditions.

 

		1.2.	Capitalized
                                         terms set forth in this Amendment and which are not defined, shall have the meaning ascribed
                                         thereto in the License Agreement.

 

		1.3.	Unless
                                         otherwise indicated herein, the terms and conditions of the License Agreement shall apply
                                         to this Amendment.

 

		1.4.	The
                                         headings of the sections in this Amendment are for the sake of convenience only and shall
                                         not serve in the interpretation of the Amendment.

 

	2.	Ownership

 

		2.1.	Section
                                         5 shall be amended to read as follows:
	 	 	 
	 	 	5.1          All
rights in and to the Licensed Technology shall be owned by Yissum, and the Company shall hold the rights granted pursuant to the
License hereunder and make use of them exclusively in accordance with the terms of this Agreement. The Research Results resulting
from the Research conducted in Section 4.4 shall be exclusively owned by Yissum, shall form part of the Licensed Technology and
shall be licensed to the Company under the same terms and conditions of this Agreement.

 

    	 

    	 

    

 

	 	 	5.2
          Notwithstanding the foregoing, in light of the current requirements
of the Office of the Chief Scientist of the Israel Ministry of Industry, Trade and Labor (the “OCS”), the Parties
agree that all intellectual property rights developed pursuant to this Agreement using OCS funding, including, but not limited
to, intellectual property rights arising from the conduct of clinical trials funded by the OCS, (“OCS IP”)
will be fully and absolutely owned by the Company. In the event that the Company receives such OCS funding, it will provide Yissum
with sufficient written documentation to enable the Parties to define what intellectual property will be subject to provisions
of this section. Nevertheless, (i) should there be a change in OCS requirements concerning ownership of intellectual property
that are applicable to the OCS IP; or (ii) should the Company be voluntarily or involuntarily dissolved, all rights in OCS IP
shall revert, as far as legally possible and appropriate, to Yissum, subject, if required, to the approval of the OCS. The Company
agrees to take all reasonable steps necessary to assign or have assigned ownership of such OCS IP to Yissum.

 

REST
OF PAGE LEFT DELIBERATELY BLANK

 

    	 

    	 

    

 

IN
WITNESS THE HANDS OF THE PARTIES

 

	YISSUM	 	 	THE COMPANY	 
	 	 	 	 	 
	By:	/s/ Nava Swerky	 	By:	/s/ Avi Barak
	 	 	 	 	 
	Name:	Nava Swerky	 	Name:	Avi Barak
	 	 	 	 	 
	Title:	Pres & CEO	 	Title:	Chief Executive Officer
	 	 	 	 	 
	Date:	16.9.07	 	Date:	Sep 11, 2007
	 	 	 	 	 
	By:	/s/ Bob Frantenberg	 	By:	/s/ Ira Weinstein
	 	 	 	 	 
	Name:	Bob Frantenberg	 	Name:	Ira Weinstein
	 	 	 	 	 
	Title:	General Counsel	 	Title:	CFO
	 	 	 	 	 
	Date:	16.9.07	 	Date:	Sept. 10, 2007

 

I
the undersigned, Prof. Abraham Hochberg, have reviewed, am familiar with and agree to all of the above terms and conditions. I
hereby undertake to cooperate fully with Yissum in order to ensure its ability to fulfill its obligations hereunder, as set forth
herein.

 

	  /s/
    Abraham Hochberg	 	  16/9/07
	  Prof. Abraham Hochberg	 	Date signed

    	 

    	 

    

 

AMENDMENT

 

This
Amendment is made as of this 24th day of January 2011, by and between YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY
OF JERUSALEM LTD., of Hi Tech Park, Edmond J. Safra Campus, Givat Ram, Jerusalem 91390, Israel (“Yissum”); and

 

BIOCANCELL
THERAPEUTICS ISRAEL LTD. of Beit Beck, Har Hotzvim, Jerusalem,
Israel (the “Company”), of the second part;

 

WHEREAS, the Company and Yissum executed an amended and
restated license agreement on November 14, 2005, as supplemented and amended (the “License Agreement”), pursuant
to which the Company obtained an exclusive license to certain patents owned by Yissum; and

 

WHEREAS
the Parties wish to amend the License Agreement to add new
patents and patent applications to the list of Patents exclusively licensed to the Company as part of the Licensed Technology.

 

NOW
THEREFORE, in consideration of the mutual promises and covenants
set forth herein, the parties hereby agree, as follows:

 

	1.	All
                                         capitalized terms not defined herein shall have the meaning ascribed to them in the License
                                         Agreement.

	 	 

	2.	Appendix
                                         1 of the License Agreement shall be amended to add the following patents and patent applications:

 

		•	NUCLEIC
                                         ACID CONSTRUCTS, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USING SAME FOR TREATING CANCER
                                         (H19 + Tnf Alpha), Yissum Ref# 2989

 

		•	NUCLEIC
                                         ACID AGENTS FOR DOWNREGULATING H19, AND METHODS OF USING SAME, Yissum Ref# 3025

 

		•	NUCLEIC
                                         ACID CONSTRUCTS AND METHODS FOR SPECIFIC SILENCING OF H19 (siRNA H19 - cancer + stem
                                         cells) Yissum Ref# 3309

 

		•	H19
                                         SILENCING NUCLEIC ACID AGENTS FOR TREATING RHEUMATOID ARTHRITIS (siRNA - RA), Yissum
                                         Ref# 3310

 

		•	CONSTRUCTS
                                         CONTAINING MULTIPLE EXPRESSION CASSETTES FOR CANCER THERAPY, Yissum Ref# 3423

 

A
new Appendix 1 to the License Agreement, including Yissum Reference Numbers, is annexed to this Amendment.

 

	3.	All
                                         other provisions of the License Agreement, including, without limitation, all terms of
                                         the Amendment to License Agreement dated September 11, 2007 which shall apply to the
                                         terms hereof, shall continue to have the same force and effect as they had prior to this
                                         Addendum.

 

    	 

    	 

    

 

IN
WITNESS WHEREOF, the parties have executed this Agreement
as a deed and delivered on the date first above written.

  

	YISSUM RESEARCH DEVELOPMENT	 	BIOCANCELL THERAPEUTICS
	COMPANY OF THE HEBREW	 	ISRAEL, LTD.
	UNIVERSITY OF JERUSALEM LTD	 	 

  

	By: /s/ Shoshi Keynan	/s/ Yaakov Michlin	 	By: /s/ Uri Danon	/s/ Ira Weinstein
	Shoshi Keynan	Yaakov Michlin	 	Uri Danon	Ira Weinstein
	Title: VP Licensing,	President & CEO	 	Title: CEO	CFO
	Pharmaceuticals	 	 	 	 
	Date: 30/1/2011	30/1/2011	 	Date: 24/1/11	24/1/11

 

    	 

    	 

    

 

APPENDIX
1 – THE PATENTS

 

	 	 	 	Sensitive Cancer
	Family:	2148	Title:	Assay

 

	Inventor	Faculty/Department	 
	Ariel Ilana	Hadassah	 
	 	HUJI Faculty of	 
	 	Science The	 
	 	Alexander Silberman	 
	Hochberg	Institute for Life	 
	Avraham	Sciences	 

	 	 	 	 	 	 	 	 	 
	 	 	 	Application	Publication	Patent
	Patent ID	Status	Country	Date	Number	Date	Number	Date	Number
	2148-00	Granted	Israel	7/3/1994	108879	 	 	31/08/2000	108879
	2148-01	Published	PCT	6/3/1995	PCT/EP95/00823	4/9/1995	WO95/24503	 	 
	2148-03	Granted	US	6/9/1996	08/704,786	 	 	21/09/1999	5,955,273
	2148-04	Granted	Europe	6/3/1995	95927570	 	 	29/05/2002	759092

 

	 	 	 	Methods and
	 	 	 	Compositions for
	 	 	 	Inducing Tumor-
	Family:	2324	Title:	Specific Cytotoxicity

	 	 	 
	Inventor	Faculty/Department	 
	 	HUJI Faculty of	 
	 	Science The	 
	 	Alexander Silberman	 
	Ayesh	Institute for Life	 
	Suhail	Sciences	 
	Hochberg	HUJI Faculty of	 
	Avraham	Science The	 
	 	Alexander Silberman	 
	 	Institute for Life	 
	 	Sciences	 

 

    	 

    	 

    

	 	 	 	 	 	 	 	 	 
	 	 	 	Application	Publication	Patent
	Patent ID	Status	Country	Date	Number	Date	Number	Date	Number
	2324-00	Abandoned	US	3/10/1997	08/943,608	 	 	 	 
	2324-01	Exhausted	PCT	4/10/1998	PCT/IL98/00486	8/12/1999	WO 99/18195	 	 
	2324-02	Exhausted	PCT	22/10/2002	PCT/IL02/00843	1/5/2003	WO 03/035883	 	 
	2324-03	Granted	US	1/10/1998	09/165,240	 	 	11/7/2000	6,087,164
	2324-04	Granted	China	4/10/1998	98811834	 	 	30/11/2005	ZL 

    98811833.5
	2324-05	Granted	Europe	4/10/1998	98947759	 	1019499	10/9/2008	1019499
	2324-06	Filed	Hungary	4/10/1998	P0003745	 	 	 	 
	2324-07	Granted	Israel	4/10/1998	135430	19/08/2007	Pat & Designs J.

    6/2007	20/11/2007	135430
	2324-08	Granted	Korea	4/10/1998	2000-7003609	 	 	20/10/2005	524262
	2324-09	Filed	Mexico	4/10/1998	2000-003843	 	 	 	 
	2324-10	Abandoned	New 

    Zealand	4/10/1998	503843	 	 	 	 
	2324-11	Allowed	Norway	4/10/1998	20001684	 	 	 	 
	2324-12	Abandoned	Poland	4/10/1998	P339949	 	 	 	 
	 	 	Russian	 	 	 	 	 	 
	2324-13	Granted	Federation	4/10/1998	2E+09	 	2214280	20/10/2003	2214280
	2324-14	Granted	US	10/5/2000	09/568,059			23/10/2001	6,306,833
	2324-15	Granted	US	22/10/2001	10/012,131	29/04/2004	US-2004-

    0082529	9/5/2006	7,041,654
	2324-16	Granted	Australia	4/10/1998	94571/98	 	 	19/12/2002	755774
	2324-17	Examination	Japan	4/10/1998	2000-514993	 	 	 	 
	2324-18	Granted	Canada	4/10/1998	2,308,124	 	 	8/7/2008	2,308,124
	2324-19	Granted	Singapore	4/10/1998	200001824-2	 	 	4/6/2002	72207
	2324-20	

    Granted	Czech

    Republic	4/10/1998	PV2000-1201	 	 	16/02/2005	294694
	2324-21	Abandoned	Europe	22/10/2002	2779859.4	21/07/2004	1438412	 	 
	2324-22	Abandoned	China	22/10/2002	2825940.8	 	 	 	 
	2324-23	Abandoned	Japan	22/10/2002	2003-538383	 	 	 	 
	2324-24	Abandoned	Israel	22/10/2002	161553	 	 	 	 
	2324-25	Abandoned	Canada	22/10/2002	2,464,394	 	 	 	 
	2324-26	Abandoned	Australia	22/10/2002	2.002E+09	 	 	 	 
	2324-27	Abandoned	Mexico	22/10/2002	PAa2004/003732	 	 	 	 
	2324-28	Granted	Czech Republic	18/06/2004	PV 2004-741	 	 	14/02/2005	294941
	2324-29	Allowed	Brazil	4/10/1998	PI9812717-9	 	 	 	 
	2324-30	Examination	Japan	24/05/2006	2006-144648	9/11/2006	2006-304801	 	 
	2324-31	Granted	Mexico	4/10/1998	PA/a/2000/03251	 	 	10/4/2007	244867
	2324-32	Examination	Japan	24/05/2006	2007-270777	19/06/2008	2008-136480	 	 
	2324-33	Filed	Norway	 	20093194	 	 	 	 

 

    	 

    	 

    

 

	 	 	 	Nucleic Acid
	 	 	 	Constructs,
	 	 	 	Pharmaceutical
	 	 	 	Compositions and
	 	 	 	Methods of Using
	 	 	 	Same for Treating
	 	 	 	Cancer (H19 + Tnf
	Family:	2989	Title:	Alpha)

	 	 	 
	Inventor	Faculty/Department	 
	 	HUJI Faculty of	 
	 	Science The	 
	 	Alexander Silberman	 
	Hochberg	Institute for Life	 
	Avraham	Sciences	 

	 	 	 	 	 	 	 	 	 
	 	 	 	Application	Publication	Patent
	Patent ID	Status	Country	Date	Number	Date	Number	Date	Number
	 	 	 	 	 	 	 	 	 
	2989-00	Expired	US	22/09/2005	60/719,178	 	 	 	 
	2989-01	Exhausted	PCT	21/09/2006	PCT/IL2006/001110  	29/03/2007	WO 

    2007/034487	 	 
	2989-02	Examination	US	21/09/2006	12/067,410	 	 	 	 
	2989-03	Examination	Israel	21/09/2006	190311	 	 	 	 
	2989-04	Published	Japan	21/09/2006	2008-531883	5/3/2009	2009-508516	 	 
	2989-05	Granted	Europe	21/09/2006	6780498.9	4/6/2008	1926814	28/04/2010 	1926814

 

    	 

    	 

    

	 	 	 	 
	 	 	 	NUCLEIC ACID
	 	 	 	AGENTS FOR
	 	 	 	DOWNREGULATING
	 	 	 	H19, AND METHODS
	Family:	3025	Title:	OF USING SAME

	 	 	 
	Inventor	Faculty/Department	 
	 	HUJI Faculty of	 
	 	Science The	 
	 	Alexander Silberman	 
	Matouk	Institute for Life	 
	Imad	Sciences	 
	 	HUJI Faculty of	 
	 	Science The	 
	 	Alexander Silberman	 
	Hochberg	Institute for Life	 
	Avraham	Sciences	 
	 	 	 

	 			Application	Publication	Patent
	Patent ID	Status	Country	Date	Number	Date	Number	Date	Number
	3025-00	Expired	US	7/7/2005	60/696,795	 	 	 	 
	3025-01	Exhausted	PCT	6/7/2006	PCT/IL2006/000785  	18/01/2007	WO 

    2007/007317	 	 
	3025-02	Examination	US	16/01/2008	12/015,325	 	 	 	 
	3025-03	Published	Japan	6/7/2006	2008-520061	11/12/2008	2008-545011	 	 
	3025-04	Examination	US	6/7/2006	11/994,810	4/6/2009	US-	 	 
	 	 	 	 	 	 	2009/0143321

    A1	 	 
	3025-05	Filed	Canada	6/7/2006	2,614,531	 	 	 	 
	3025-06	Exhausted	Australia	6/7/2006	2.006E+09	 	 	 	 
	3025-07	Examination	Europe	6/7/2006	6766118.1	30/04/2008	1915448	 	 
	3025-08	Filed	India	6/7/2006	2008/DELNP/758	 	 	 	 
	3025-09	Examination	China	21/05/2006	2.007E+11	 	 	 	 
	3025-10	Examination	Israel	 	188501	 	 	 	 

 

    	 

    	 

    

	 	 	 	 
	 	 	 	NUCLEIC ACID
	 	 	 	CONSTRUCTS AND
	 	 	 	METHODS FOR
	 	 	 	SPECIFIC
	 	 	 	SILENCING OF H19
	 	 	 	(siRNA H19 - cancer +
	Family:	3309	Title:	stem cells)

	 	 	 
	Inventor	Faculty/Department	 
	 	HUJI Faculty of	 
	 	Science The	 
	 	Alexander Silberman	 
	Hochberg	Institute for Life	 
	Avraham	Sciences	 

 

	 	 	 	Application	Publication	Patent
	Patent ID	Status	Country	Date	Number	Date	Number	Date	Number
	3309-00	Expired	US	16/01/2007	60/880,425	 	 	 	 
	3309-01	Exhausted	PCT	16/01/2008	PCT/IL2008/000072  	24/07/2008	WO 

    2008/087642 A2	 	 
	3309-02	Examination	Europe	16/01/2008	8702653	28/10/2009	2111450	 	 
	3309-03	Filed	Israel	16/01/2008	199867	 	 	 	 
	3309-04	Filed	Canada	16/01/2008	2,675,967	 	 	 	 
	3309-05	Published	US	16/01/2008	12/523,298	8/4/2010	US-	 	 
	 	 	 	 	 	 	2010/0086526 

    A1.	 	 
	3309-06	Filed	India	16/01/2008	5257/DELNP/2009	 	 	 	 

 

    	 

    	 

    

 

	 	 	 	H19 SILENCING
	 	 	 	NUCLEIC ACID
	 	 	 	AGENTS FOR
	 	 	 	TREATING
	 	 	 	RHEUMATOID
	 	 	 	ARTHRITIS (siRNA -
	Family:	3310	Title:	RA)

	 	 	 
	Inventor	Faculty/Department	 
	 	HUJI Faculty of	 
	 	Science The	 
	 	Alexander Silberman	 
	Hochberg	Institute for Life	 
	Avraham	Sciences	 

	 	 	 	 	 	 	 	 	 
	 	 	 	Application	Publication	Patent
	Patent ID	Status	Country	Date	Number	Date	Number	Date	Number
	3310-00	Expired	US	16/01/2007	60/880,430	 	 	 	 
	3310-01	Exhausted	PCT	16/01/2008	PCT/IL2008/000071  	24/07/2008 	WO 

    2008/087641 A2	 	 
	3310-02	Examination	Europe	16/01/2008	8702652	28/10/2009 	2111449	 	 
	3310-03	Filed	Canada	16/01/2008	2,675,964	 	 	 	 
	 	 	 	 	 	 	US-

    2010/0105759	 	 
	3310-04	Allowed	US	16/01/2008	12/523,288	29/04/2010 	A1	 	 
	3310-05	Filed	Israel	16/01/2008	199866	 	 	 	 
	3310-06	Filed	India	16/01/2008	5271/DELNP/2009	 	 	 	 

 

    	 

    	 

    

 

	 	 	 	 
	 	 	 	CONSTRUCTS
	 	 	 	CONTAINING
	 	 	 	MULTIPLE
	 	 	 	EXPRESSION
	 	 	 	CASSETTES FOR
	Family:	3423	Title:	CANCER THERAPY

	 	 	 
	Inventor	Faculty/Department	 
	 	HUJI Faculty of	 
	 	Science The	 
	 	Alexander Silberman	 
	 	Institute for Life	 
	Amit Doron 	Sciences	 
	 	HUJI Faculty of	 
	 	Science The	 
	 	Alexander Silberman	 
	Hochberg	Institute for Life	 
	Avraham	Sciences	 

	 	 	 	 	 	 	 	 	 
	 	 	 	Application	Publication	Patent
	Patent ID	Status	Country	Date	Number	Date	Number	Date	Number
	3423-00	Expired	US	25/10/2007	60/982,442	 	 	 	 
	3423-01	Exhausted	PCT	23/10/2008	PCT/IL2008/001405  	30/04/2009	WO 

    2009/053982	 	 
	3423-02	Filed	Russian 

    Federation	23/10/2008	2.01E+09	 	 	 	 
	3423-03	Published	US	23/10/2010	12/738,620	7/10/2010	US 

    2010/0256225

    A1	 	 
	3423-04	Filed	Canada	23/10/2008	2,703,774	 	 	 	 
	3423-05	Filed	Brazil	23/10/2008	PI 0818937-4	 	 	 	 
	3423-06	Filed	India	23/10/2008	2846/DELNP/2010	 	 	 	 
	3423-07	Pre-Filing	Korea	 	 	 	 	 	 
	3423-08	Filed	China	23/10/2008	2.009E+11	 	 	 	 
	3423-09	Examination	Europe	23/10/2008	8842129.2	7/7/2010	2203187	 	 
	3423-10	Filed	Israel	23/10/2008	205048	 	 	 	 
	3423-11	Filed	Australia	23/10/2008	2.008E+09	 	 	 	 
	3423-12	Filed	Japan	23/10/2008	2010-530628	 	 	 	 

 

    	 

    	 

    

 

FOURTH AMENDMENT

 

This Fourth Amendment is made as of this
6th day of November 2013, by and between YISSUM RESEARCH DEVELOPMENT COMPANY OF THE HEBREW UNIVERSITY OF JERUSALEM
LTD., of Hi Tech Park, Edmond J. Safra Campus, Givat Ram, Jerusalem 91390, Israel (“Yissum”), of the first
part; and

 

BIOCANCELL LTD. (“BioCancell”)
and BIOCANCELL THERAPEUTICS ISRAEL LTD. (“BT Israel”), both of Beit Beck, Har Hotzvim, Jerusalem, Israel
(the “Company”), of the second part;

 

WHEREAS, BioCancell Therapeutics
Inc. (“BioCancell USA”) and Yissum executed an Exclusive License Agreement on November 14, 2005, as supplemented
and amended on November 22, 2005, September 11, 2007 and January 24, 2011 (such Exclusive License Agreement, as supplements and
amended, the “License Agreement”), pursuant to which the BioCancell USA and BT Israel obtained an exclusive
license to certain patents owned by Yissum; and

 

WHEREAS, BioCancell USA has assigned
all of its rights and obligations under the License Agreement to BioCancell, and Yissum consents to such assignment; and

 

WHEREAS the parties hereto wish
to amend the License Agreement to alter certain terms of the License Agreement.

 

NOW THEREFORE, in consideration
of the mutual promises and covenants set forth herein, the parties hereto hereby agree, as follows:

 

All capitalized terms not defined
herein shall have the meaning ascribed to them in the License Agreement. For the avoidance of doubt, all references to the “Company”
shall be construed as meaning BioCancell and BT Israel, collectively.

 

In Section 1 of the License Agreement,
the following definitions shall be amended as follows:

 

“Licensed Product”
shall mean any product, process or service, the development, manufacture, use, sale or importation of which (a) is based on, or
involves, in whole or in part, the use of Licensed Technology or which is produced or manufactured in whole or in part, using a
process, method or system covered by, or falling within the Licensed Technology, or uses the Licensed Technology as a basis for
subsequent modifications that are standard in drug development including, without limitation, the construction of pro-drugs, and
modified compounds based on the Licensed Technology that work essentially in a physiologically analogous manner to the Licensed
Technology; or (b) but for the License granted in this Agreement, would infringe one or more Patents.

 

“Licensed Technology”
shall mean the Patents, the Know-How and the Research Results.

 

    	 

    	 

    

 

Add the following definitions
to Section 1 of the License Agreement:

 

“Generic Product” shall
mean a product having the same composition of matter as a Licensed Product or which has a marketing approval as a generic product
by the regulatory authorities and which could not have been sold or with respect to which a license would have been required to
be obtained from the Company, if patent or other exclusivity rights covering the Licensed Product would have been in full force
and effect in the relevant jurisdiction.

 

“Know-How” shall mean
any proprietary, non-public, tangible or intangible information, techniques, technology, practices, trade secrets, inventions (whether
patentable or not), methods, knowledge, ancillary materials, results, devices, or know-how developed by the Researcher directly
related to the Patents.

 

Section
3.1 of the License Agreement shall be amended as follows:

 

3.1 In consideration of the License granted
hereunder, Company shall pay royalties to Yissum in the manner hereinafter provided (the “Royalties”). Company shall
pay to Yissum:

 

Four percent (4%) of Net Sales; and

Ten percent (10%) of Sublicensing Revenues.

 

Section 10.1 of the License Agreement shall
be amended to read as follows:

 

10.1 Unless earlier terminated, as hereinafter provided, the term of the License and this Agreement
shall expire on a country-by-country basis as follows:

 

		(a)	Where a Patent has issued, on the later of: (i) the date in such country when no Valid Claim exists;
or (ii) the date of expiration of any exclusivity on the Licensed Product granted by a regulatory or government body in such country;
or (iii) the end of a period of nine (9) years from the date of the First Commercial Sale in such country; or

 

		(b)	Where no application for a Patent was filed or, if one was filed, a Patent did not issue, on the
later of: (i) the date of expiration of any exclusivity on the Licensed Product granted by a regulatory or government body in such
country; or (ii) the end of a period of nine (9) years from the date of the First Commercial Sale in such country. In the event
that a third party sells or markets a Generic Product in a country where no application for a Patent was filed or, if one was filed,
after the time when the application was finally rejected and the Patent did not issue (a “Third Party Product”),
the Royalties payable by the Company to Yissum pursuant to Section 3.1, above, on the Company’s Net Sales or Sublicensing
Revenues attributable to such country shall be reduced by fifty percent (50%). For the avoidance of doubt, however, the Company
will pay full Royalties on sales of Licensed Products in countries where a patent application has been filed during the period
such application is pending and has not been finally rejected.

 

    	 

    	 

    

 

Section 10.4 of the License Agreement shall
be amended to read as follows:

 

10.4 In the event of termination of
this Agreement in full, for any reason other than the passage of time, the License shall terminate and all rights to the
Licensed Technology (including the Research Results) shall revert to Yissum and Company may make no further use thereof. Upon
the expiration of the License and this Agreement in any particular country pursuant to Section 10.1, Company shall have a
perpetual, royalty-free, paid-up, sub-licensable License in that country. Notwithstanding the aforesaid, the expiration or
termination of this Agreement shall not release Company from its obligation to carry out any financial or other obligation
which accrued prior to the Agreement’s expiration or termination, including the payment of Royalties and Sub-License
Revenues.

 

For ease of reference, Appendix 1 to the
License Agreement, which was amended on January 24, 2011, updated as of May 19, 2013, is appended to this Fourth Amendment.

 

    	 

    	 

    

 

Section 14 of the Agreement (Notices) is
hereby amended to read as follows:

 

Any notice under this Agreement
shall be in writing and shall be deemed to have been duly given for all purposes (a) when received or three (3) days after it
is mailed by prepaid registered mail; (b) upon the transmittal thereof by facsimile or email; or (c) upon the manual delivery
thereof, to the respective addressee, fax numbers or email address set forth below or to such other address of which notice
as aforesaid is actually received:

 

	 	(i)	If to Yissum:
	 	 	 
	 	 	Yissum Research Development Company of the 

Hebrew University of Jerusalem, 

P.O. Box 39135, 

Jerusalem 91390 

Israel 

Attention: CEO 

Fax: 02-658-6689 

Email: Yaacov.Michlin@yissum.co.il
	 	 	 
	 	(ii)	If to the Company: 

Beit Beck 

Har Hotzvim 

Jerusalem, Israel 

Attention: CEO 

Fax: 02-5648550 

Email: jonathon.burgin@biocancell.com

 

	9.	All other provisions of the License Agreement, including, without limitation, all terms of the prior Amendments to the License Agreement, not inconsistent with the provisions of this Fourth Amendment, shall continue to have the same force and effect as they had prior to this Fourth Amendment.

 

IN WITNESS WHEREOF, the parties
hereto have executed this Fourth Amendment as of the date first above written.

 

	          /s/ Shoshi Keynan          /s/ Yaacov Michlin	 

	YISSUM RESEARCH DEVELOPMENT COMPANY OF THE 

HEBREW UNIVERSITY OF JERUSALEM LTD
	 
	By:
	 
	Title:
	 
	Date:          /s/ Jonathan Burgin          /s/
Or Dolev	 
	 	 

 

    	 

    	 

    

 

	BIOCANCELL LTD.
	 
	By:
	 
	Title:
	 
	Date:          /s/ Jonathan Burgin          /s/ Or Dolev
	 	 
	BIOCANCELL THERAPEUTICS ISRAEL LTD.
	 
	By:
	 
	Title:
	 
	Date:

 

    	 

    	 

    

 

APPENDIX 1
– THE PATENTS

<Omitted>

 

<Omitted>  <Omitted>  <Omitted>  <Omitted>

 

	<Omitted>	<Omitted>
	<Omitted>	<Omitted>
	<Omitted>	<Omitted>

 

	 	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>		
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			<Omitted>	<Omitted>

 

    	 

    	 

    

 

 

<Omitted>  <Omitted>  <Omitted>  <Omitted>

 

	<Omitted>	<Omitted>
	<Omitted>	<Omitted>
	<Omitted>	<Omitted>

 

	 	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>		
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 		<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 		

 

    	 

    	 

    

 

	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 		
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>		<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>		<Omitted>		
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 

 

    	 

    	 

    

 

	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>				
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>		
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>		
	<Omitted>	<Omitted>	<Omitted>	 	<Omitted>	 	 	 	 

 

<Omitted>  <Omitted>  <Omitted>  <Omitted>

 

	<Omitted>	<Omitted>
	<Omitted>	<Omitted>

 

    	 

    	 

    

 

 

 

	 	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>				
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>		
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>				
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>				
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>		
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>

 

<Omitted>  <Omitted>  <Omitted>  <Omitted>

 

	<Omitted>	<Omitted>
	<Omitted>	<Omitted>

 

    	 

    	 

    

 

	<Omitted>	<Omitted>

 

	 	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>		<Omitted>			 	 

 

    	 

    	 

    

 

<Omitted>  <Omitted>  <Omitted>  <Omitted>

 

	<Omitted>	<Omitted>
	<Omitted>	<Omitted>

 

	 	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 

 

    	 

    	 

    

 

 

 

<Omitted>  <Omitted>  <Omitted>  <Omitted>

 

	<Omitted>	<Omitted>
	<Omitted>	<Omitted>

 

	 	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 

 

    	 

    	 

    

 

	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 

 

<Omitted>  <Omitted>  <Omitted>  <Omitted>

 

	<Omitted>	<Omitted>
	<Omitted>	<Omitted>
	<Omitted>	<Omitted>

 

	 	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 

 

    	 

    	 

    

 

	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 	 	 
	<Omitted>	<Omitted>	<Omitted>			 	 	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>	 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>			 	 
	<Omitted>	<Omitted>	<Omitted>	<Omitted>	<Omitted>

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00290-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00290-of-00352.parquet"}]]