Exhibit 4.16





Execution version


 





THE SYMBOL "[****]" DENOTES PLACES WHERE
PORTIONS OF THIS DOCUMENT HAVE

 BEEN OMIITTED PURSUANT TO A REQUEST FOR CONFIDENTIAL TREATMENT. SUCH 

MATERIAL HAS BEEN FILED SEPARATELY
WITH THE SECURITIES AND EXCHANGE COMMISSION


 


SECOND
AMENDMENT TO LICENSE AGREEMENT


 


This
Second Amendment to License Agreement (“Second Amendment”) is effective as of 16 March 2017 (the “Effective
Date”), 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 one part; and





TYRNOVO LTD.,
of One Azrieli Center, Round Tower, 23rd Floor, 132 Menachem Begin Road, Tel Aviv, 6701101, Israel, (the “Company”),
of the second part;





(each
a “Party” and jointly, the “Parties”).


 


WHEREAS,
Yissum and the Company are parties to a License Agreement dated 15 August 2013, as amended by the First Amendment to License Agreement
effective as of 8 April 2014, (the License Agreement, as amended, the “License Agreement”); and


 


WHEREAS,
the Company entered into a Services Agreement with Bar Ilan Research and Development Company Ltd. (“BIRAD”)
dated 12 February 2014 and, following the execution of this Second Amendment, the Company intends to enter into an Amended and
Restated Service Agreement with BIRAD which shall amend, supersede and replace the said Services Agreement (such Amended and Restated
Service Agreement, the “BIRAD Services Agreement”); and


 


WHEREAS,
the Parties wish to amend the License Agreement as set out below,


 


NOW
THEREFORE, the Parties hereby agree as follows:


  


		1.	Capitalized
                                         terms in this Second Amendment shall bear the meaning ascribed to such terms in the License
                                         Agreement unless the context otherwise requires. The Preamble hereto shall constitute
                                         an integral part hereof.



 


		2.	The
                                         definition of Development Results (Section 1.4.3 of the License Agreement) is hereby
                                         deleted in its entirety and replaced by the following:



 


“1.4.3.
“Development Results” shall mean the results of activities carried out by the Company or by third parties (other
than the Researcher and his team) at the direction of the Company pursuant to the Development Plan or otherwise in fulfillment
of the Company’s obligations hereunder (including its development obligations under Section 5 below), including, any invention,
patent or patent application, product, material, method, discovery, composition, process, technique, know-how, data, information
or other result which do not form part of the Licensed Technology, and further including any governmental or regulatory filing
submitted, or approval, license, registration, or authorization obtained, by the Company, an Affiliate or Sublicensee in respect
of the Products, as well as any other information, data, material, results, devices and know-how arising from the performance
of the Development Plan, and shall be deemed to include all Materials Results (as defined below), but excluding any invention,
know-how or other results that are not related, or connected to the Licensed Technology and/or the Products in any manner whatsoever.


 






    	 	1	 



     


    

 


The
term “Materials Results” shall mean any and all compositions, materials, data and other results with respect
to (i) NT219, NT157, NT701 and NT700 as more fully described in the Licensed Patents or any progeny or derivatives thereof (the
“Materials”) and/or chemical analogs of Materials, including with respect to new applications or uses thereof
(whether alone or in combination with other compounds); and/or (ii) biomarkers and/or target proteins identified through the use
of the Materials, in each case that are obtained or arrived at by Prof. Izhak Haviv, Prof. Salamon Stemmer of Rabin Medical Center
and/or students, researchers, and technicians working under the direction of either of them at Bar Ilan University and/or Rabin
Medical Center, as applicable, in the performance of the services under the BIRAD Services Agreement.”


 


		3.	Section
                                         1.4.5 of the License Agreement is hereby deleted in its entirety and replaced by the
                                         following:



 


“1.4.5.
“Existing Patent Applications” shall mean the patent applications listed in Appendix A2 hereto.”


 


Appendix
A2 is attached hereto as Exhibit 1A.


 


		4.	Appendix
                                         B (The Development Plan) of the License Agreement is hereby deleted in its entirety and
                                         replaced by a new Appendix B which is attached hereto as Exhibit 1B.



 


		5.	The
                                         definition of “Licensed Technology” in Section 1.4.13 of the License Agreement
                                         is hereby deleted in its entirety and replaced by the following:



 


“1.4.13.
“Licensed Technology” – shall mean the Know-How, the Licensed Patents and the NovoTyr Results.”


 


		6.	The
                                         definition of “NovoTyr Shareholders Approval” in Section 1.4.15 of the License
                                         Agreement is hereby deleted in its entirety and the following new definition is hereby
                                         added in place thereof:



 


“1.4.15.
“NovoTyr Results” – shall mean any proprietary, non-public know-how, data, information or other results
which were transferred and assigned by NovoTyr to Yissum and belonging to Yissum, as set forth in Appendix A3(a).”


 


The
NovoTyr Results are described in Exhibit 2 hereto which shall be attached to the License Agreement as Appendix
A3(a).


 


		7.	The
                                         following provision is hereby added at the end of the definition of Net Sales (Section
                                         1.4.14 of the License Agreement):



 


“It
is agreed that the sales price invoiced or received for the sale of Products by the Company to its Affiliate(s), or by the Company
to its Sublicensee(s) shall not constitute Net Sales.”


 






    	 	2	 



     


    

 


		8.	The
                                         definition of Products (Section 1.4.19 of the License Agreement) is hereby deleted in
                                         its entirety and replaced by the following:



 


“1.4.19.
“Product” shall mean any product, process, or service that (a) uses the Licensed Technology and/or the Development
Results (or any part of the foregoing); or (b) the sale of which, in the absence of the license granted to the Company in this
Agreement, would infringe one or more of the Licensed Patents.”


 


		9.	The
                                         definition of Sublicense Consideration (Section 1.4.23 of the License Agreement) is hereby
                                         deleted in its entirety and replaced by the following:



 


“1.4.23.
“Sublicense Consideration” shall mean any proceeds or consideration or benefit of any kind whatsoever, whether
monetary or otherwise, including securities and options to buy securities, that the Company or an Affiliate may receive from a
Sublicensee, as a direct or indirect result of the grant of a Sublicense to a Sublicensee and/or pursuant thereto or an option
to obtain such Sublicense, except: (i) amounts received by the Company which constitute royalties based on Net Sales by
Sublicensees, in respect of which the Company is required to pay Royalties to Yissum; and (ii) amounts expressly dedicated to,
and actually expended upon the research and development of Products to be performed by the Company for the relevant Sublicensee,
provided that: (a) any such amounts constitute research and/or development funding only and not payment for Products nor other
type of grant or benefit; (b) such research and/or development activities are performed pursuant to a defined research and development
program and budget agreed with such Sublicensee, a copy of which is provided to Yissum; and (c) the Company submits to Yissum
a written expense report confirmed by the Company’s chief financial officer demonstrating that such amounts have actually
been expended and/or incurred by the Company in the conduct of such research and/or development activities in accordance with
such research and development program and budget, and that the expenses actually incurred as aforesaid include reasonable overhead
costs, it being agreed, that any amounts received by the Company as aforesaid, but not expended and/or incurred as set out above,
shall be deemed to be Sublicense Consideration. It is hereby further agreed that if the Sublicense Consideration comprises securities
or options to purchase securities, Yissum shall receive the portion of such Sublicense Consideration to which it is entitled under
this Agreement in the form of securities or options to purchase such securities (as the case may be), under the same terms as
the Company receives its Sublicense Consideration from the Sublicensee, it being understood and agreed, however, that any VAT
payable (if any in connection with the grant and/or exercise of such options and the sale and/or release of securities issued
upon exercise of these options and/or any other options-related event or act (of Yissum or the Company), shall be borne solely
by the Sublicensee issuing these options to Yissum, and such Sublicensee will be solely liable for the payment of such VAT.


 






    	 	3	 



     


    

 


		10.	Section
                                         5.5 of the License Agreement is hereby deleted in its entirety and replaced by the following:



 


“5.5.
In the event the Company does not use commercially reasonable efforts to commercialize any Product, unless such delay is due to
(i) the requirement of any regulatory or other governmental authority; (ii) force majeure in accordance with section 18.8 below;
or (iii) agreed revisions in the timelines in the amended Development Plan, Yissum shall notify the Company in writing of the
Company's failure to meet its obligation of diligence and shall allow the Company at least twelve (12) month to cure such failure
of diligence (the “Cure Period”). In the event that the Company fails to cure such failure of diligence to
Yissum’s reasonable satisfaction within the Cure Period, Yissum shall be entitled to terminate this Agreement, including
the License, by written notice to the Company (effective immediately), it being agreed, however, that such failure to cure as
aforesaid shall not be considered a material breach of this Agreement.”


 


		11.	Section
                                         7.1 of the License Agreement is hereby deleted in its entirety and replaced by the following:



 


“7.1.
Royalties at the rate of [****] percent ([****]%) of Net Sales (the “Royalties”).


 


In
the event that the Company pays BIRAD royalties pursuant to the BIRAD Services Agreement on Net Sales of Products which were developed
(in whole or in part) using Materials Results, or any part thereof, then the percentage set forth above shall be reduced from
[****] percent ([****]%) to [****]percent ([****]%).”


 


		12.	Section
                                         10.1 of the License Agreement is hereby deleted in its entirety and replaced by the following:



 


“10.1.
The Company shall reimburse Yissum for all previous documented expenses and costs relating to the registration and maintenance
of the Licensed Patents (listed in Appendix A2), which are detailed in Appendix C hereto (the “Historical Patent
Costs”) by no later than 31 December 2018.”


 


		13.	Section
                                         12.6 of the License Agreement is hereby deleted in its entirety and replaced by the following:



 


“12.6.
Without prejudice to the foregoing, the Company shall not mention the name of the University, Yissum or the Researcher, in any
manner or for any purpose in connection with this Agreement, or any matter relating to the Licensed Technology, without obtaining
the prior written consent of Yissum, except that the Company may make routine disclosures to government agencies, any disclosures
by the Company, or an affiliate thereof, to the extent required in the fulfillment of any reporting requirements to competent
authorities under applicable security laws and/or by any applicable securities exchange or other disclosures as required by law,
or disclosures in response to any due diligence enquiry relating to the Company, subject to the execution of a customary non-disclosure
agreement. Notwithstanding the foregoing, the Company shall be entitled to identify the Licensed Technology as having been developed
by the Researcher and the other Inventors and licensed from Yissum.”


 


 


		14.	Section
                                         12.7 of the License Agreement is hereby deleted in its entirety and replaced by the following:



 


“12.7.
Neither Party shall issue any press release or other media statement regarding the execution, existence or terms of this Agreement
or in connection with the Licensed Technologywithout the prior written approval of the other Party, which shall not be withheld
unreasonably; provided that such approval shall not be required where disclosure is required in the fulfillment of any reporting
requirements by the Company, or an affiliate thereof, to competent authorities under applicable security laws and/or by any applicable
securities exchange or as otherwise required by law.”


 



    	 	4	 



     


    

 


		15.	The
                                         following new limitation of liability provision shall be added at the end of Section
                                         14.1 of the License Agreement:



 


“EXCEPT
FOR ANY LIABILITY UNDER SECTION 12 (CONFIDENTIALITY), SECTIONS 14.2 AND 14.3 ABOVE (LIABILITY AND INDEMNITY) AND/OR ANY LIABILITY
ARISING FROM THE MISAPPROPRIATION OF ANY INTELLECTUAL PROPERTY OF YISSUM AND/OR THE UNIVERSITY, NEITHER THE COMPANY NOR ANY OF
ITS AFFILIATES SHALL BE LIABLE TO YISSUM, THE RESEARCHER, THE UNIVERSITY, OR THE REPRESENTATIVES OF YISSUM AND/OR THE UNIVERSITY
OR TO ANY THIRD PARTY FOR ANY CONSEQUENTIAL, INCIDENTAL, INDIRECT, SPECIAL, PUNITIVE OR EXEMPLARY DAMAGES (INCLUDING, LOST PROFITS,
BUSINESS OR GOODWILL) SUFFERED OR INCURRED BY ANY OF THE FOREGOING OR THIRD PARTY, WHETHER BASED UPON A CLAIM OR ACTION OF CONTRACT,
WARRANTY, NEGLIGENCE OR TORT, OR OTHERWISE, ARISING OUT OF THIS AGREEMENT.”


 


		16.	Sections
                                         14.4, 14.5 and 14.6 of the License Agreement shall be deleted in their entirety and replaced
                                         by the following:



 


“14.4.
The Company or its Affiliate shall procure and maintain, or require that its Sublicensee procure and maintain, at no cost to Yissum,
the following policies of insurance: (i) comprehensive clinical trials liability insurance in amounts commensurate with accepted
commercial practice and the minimum coverage requirements prescribed by applicable laws and regulations and/or the relevant regulatory
authority in the country in which such clinical trials are conducted and/or the relevant clinical trial site, during the period
that any Product is being tested in clinical trials prior to commercial sale; and (ii) comprehensive general liability insurance
in reasonable amounts and on reasonable terms in the circumstances, having regard, in particular, to the nature of the relevant
Product(s) and accepted practice in the relevant industry, during the period that such Product(s) is/are being commercially distributed
or sold by the Company, an Affiliate or a Sublicensee, and thereafter as required by applicable law. Such comprehensive general
liability insurance shall provide contractual liability coverage for the Company’s indemnification under this Agreement
and in particular as stated above in Section 14.3 above.


  


14.5.
Without derogating from the foregoing, beginning at the time any Product shall be commercially distributed or sold by the Company,
an Affiliate or a Sublicensee, but in any event no later than the First Commercial Sale, the Company, its Affiliates or Sublicensee
(if applicable) shall procure and maintain at their own cost and expense, in addition to the above general liability insurance,
product liability insurance, in amounts that are standard in the industry for similar products.


 



    	 	5	 



     


    

 


14.6.
The named insured under any insurance policy for clinical trials shall be the Company, the Researcher, Yissum and the University
and the beneficiaries thereof shall include also the respective employees, officers and directors of Yissum and the University.
The named insured under any insurance policy for product liability shall be the Company, Yissum and the University. The policy
or policies so issued shall include a “cross-liability” provision pursuant to which the insurance is deemed to be
separate insurance for each named insured (without right of subrogation as against any of the insured under the policy, or any
of their representatives, employees, officers, directors).


 


14.7.
The Company hereby undertakes to comply punctually with all obligations imposed upon it under such policies, including, the obligation
to pay in full and punctually all premiums and other payments due under such policies. The Company will provide Yissum upon request
with written evidence of such insurance. The Company shall provide the Yissum with at least thirty (30) days’ written notice
prior to the cancellation, non-renewal or material change in such insurance.


 


14.8.
The insurance requirements above shall not be construed to create a limit of the Company’s liability with respect to its
indemnification obligations under this Section 14.”


 


		17.	Section
                                         15.3 of the License Agreement is hereby deleted in its entirety and replaced by the following:



 


“15.3.In
addition to the above, and without prejudice to Yissum’s rights pursuant to this Agreement or at law, Yissum shall be entitled
to terminate this Agreement immediately upon written notice to the Company in the following circumstances:


 


15.3.1.       pursuant
to Section 5.5;


 


15.3.2.       if
an attachment is made over the majority of the Company’s assets or if execution proceedings are taken against the Company
and the same are not set aside within ninety (90) days of the date the attachment is made or the execution proceedings are taken;
or


 


15.3.3.       a
claim by the Company, made in any forum, claiming that one or more of the Licensed Patents are invalid or unenforceable.”


 


		18.	The
                                         following new Section is hereby added after Section 15.6 of the License Agreement and
                                         the current Section 15.7 shall be renumbered Section 15.8:



 





“15.7.
In the event that any or all of the Development Results assigned to Yissum as set forth in above shall be licensed or otherwise
transferred to a third party and shall generate any income to Yissum, then subject to the Company having complied and continuing
to comply with the obligations under this Agreement which remain in existence following termination of the License as aforesaid,
Yissum shall pay to the Company [****]  percent
([****] %) of the Net Proceeds actually received
by Yissum in respect of such license, until such time as the Company shall have received, in aggregate, an amount equal to the
amount of the documented expenses of any kind (internal (e.g. salaries) and out-of-pocket) actually incurred by the Company in
order to generate and/or develop the Development Results, less any amounts actually received or receivable by the Company from
third parties in connection with the Development Results prior to the transfer and assignment of the Development Results to Yissum,
as reflected in the Company's audited financial statements (the “Development Reimbursement”).







 






    	 	6	 



     


    

 


The
Company will allow Yissum a credit against Development Reimbursements to be paid in the future, of any Development Reimbursements
previously paid on account of Net Proceeds that were reported as bad debts in Yissum's annual audited financial statements or,
if there are no future Development Reimbursements to be made by Yissum and to the extent possible, return the amount of Development
Reimbursements paid to the Company on account of Net Proceeds that were reported as bad debts in Yissum's annual audited financial
statements. Yissum shall pay to the Company amounts, if any, payable under this Section 15.7, within ninety (90) days of receipt
of the relevant Net Proceeds.


 


For
the purpose of this Section, “Net Proceeds” means royalties, license fees any other monetary proceeds or consideration
of any kind, actually received by Yissum in respect of such license (or an option to obtain such license) with a third party (excluding
funds for research or development at the University or payments for the supply of services) after the deduction of all costs,
fees, and expenses incurred by Yissum in connection with such license (including, patent costs, and all attorneys fees and expenses
and other costs and expenses in connection with the negotiation and conclusion of such license). ”


 


		19.	In
                                         the event of termination of the License (in whole or in part, such as termination with
                                         respect to a particular country), any existing agreements that contain a Sublicense of,
                                         or other grant of right with respect to, the Licensed Technology shall terminate to the
                                         extent of such Sublicense or other grant of right; provided, however, that, for
                                         each Sublicensee, upon termination of the Sublicense agreement with such Sublicensee,
                                         if the Sublicensee is not then in breach of such Sublicense agreement with the Company
                                         such that the Company would have the right to terminate such Sublicense or Yissum would
                                         have the right to terminate this Agreement as a consequence thereof pursuant to the terms
                                         of this Agreement, Yissum shall be obligated, at the request of such Sublicensee, to
                                         enter into a new agreement with such Sublicensee on substantially the same terms as those
                                         contained in such Sublicense agreement, and provided further that such terms shall
                                         be amended, if necessary, to the extent required to ensure that such Sublicense agreement
                                         does not impose any obligations or liabilities on Yissum which are not included in this
                                         Agreement.



 


		20.	Upon
                                         the execution of this Second Amendment, the Company shall execute the letter of assignment
                                         attached hereto as Exhibit 3 concerning its interest in any Joint Patents
                                         and Development Results that will provide that such interest will be irrevocably assigned
                                         to Yissum in the event that the License Agreement is terminated for any reason whatsoever
                                         other than the expiration of its term or due to an uncontested uncured breach by Yissum.



 


		21.	This
                                         Second Amendment shall be read together with the License Agreement, and save for the
                                         changes contained herein, all the terms and conditions contained in the License Agreement
                                         remain unchanged, and in full force and effect.



 


		22.	This
                                         Second Amendment together with the License Agreement (as amended hereby) constitute the
                                         entire agreement between the Parties in respect of the subject matter hereof, and supersede
                                         all prior agreements or understandings between the Parties relating to the subject matter
                                         hereof, and this Second Amendment may be amended only by a written document signed by
                                         the authorized representatives of both Parties. Following the execution of this Second
                                         Amendment, the Parties undertake and commit to work together in good faith in order to
                                         prepare an Amended and Restated License Agreement which shall incorporate the License
                                         Agreement as amended hereby in one agreement.



 


[signature
page follows]





 






    	 	7	 



     


    

 


IN
WITNESS WHEREOF, the Parties have caused this Second Amendment to be executed effective as of the date first above written.


 


	YISSUM
    RESEARCH  DEVELOPMENT COMPANY OF  THE HEBREW UNIVERSITY OF  JERUSALEM LTD.	 	TYRNOVO
    LTD.
	 	 	 	 	 
	Signature:	/s/
    Itzik Goldwaser, PhD	 	Signature:	/s/
    Hadas Reuveni
	Name:	Itzik
    Goldwaser	 	Name:
    	Hadas
    Reuveni
	Title:
    	VP,
    Head of Research Collaborations	 	Title:	Founder
    & CTO
	Collaborations	 	 	 
	Signature:
    	/s/
    Ariela Markel	 	Signature:
    	/s/
    Simcha Rock
	Name:
    	Ariela
    Markel	 	Name:
    	Simcha
    Rock
	Title:	VP
    Licensing, Biotechnology	 	Title:
    	Director
	Date:	March
    16, 2017	 	Date:
    	April
    20, 2017




 


I
the undersigned, Prof. Alexander Levitzki, 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/
    Alex Levitzki	 	April
    20, 2017
	Prof.
    Alexander Levitzki	 	Date
    signed




 


Exhibit
1A - Appendix A2 to License Agreement – Existing Patent Applications


Exhibit
1B – Appendix B to License Agreement – Development Plan


Exhibit
2 -Appendix A3(a) to License Agreement – NovoTyr Results


Exhibit
3 -TyrNovo Assignment Letter


 



    	 	8	 



     


    




 


Exhibit
1A

Existing Patent Applications


 





	Family:	3711
    	Title:	NOVEL
    PROTEIN KINASE MODULATORS AND THERAPEUTIC USES THEREOF (NT-157) 







 





	Inventor
    	 	University
    	 	Faculty
    	 	Department
    
	Ben-David
    Iris	 	 	 	 	 	 
	Levitzki
    Alexander	 	HUJI	 	Faculty
    of Science	 	The
    Alexander Silberman Institute for Life Sciences
	SASSON
    Revital	 	 	 	 	 	 
	STEINER
    Lilach	 	 	 	 	 	 
	WEISSBERG
    Avi	 	 	 	 	 	 
	Reuveni
    Hadas	 	 	 	 	 	 




 





	 	 	Application	 	 	Publication	 	 	Patent	 
	Patent ID	 	Status	 	 	Country	 	Date	 	 	Number	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3711-00	 	 	Expired	 	 	US	 	 	04/12/2006	 	 	 	60/872,511		 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3711-01	 	 	Exhausted	 	 	PCT	 	 	04/12/2007	 	 	 	PCT/IL2007/0014	 	 	 	12/06/2008	 	 	 	WO2008/068751	 	 	 	 	 	 	 	 	 
	3711-02	 	 	Granted	 	 	US	 	 	04/12/2007	 	 	 	12/517,278		 	 	04/03/2010	 	 	 	US2010/0056635	 	 	 	15/11/2011	 	 	 	8,058,309	 
	3711-03	 	 	Granted	 	 	Europe	 	 	04/12/2007	 	 	 	07827467.7	 	 	 	02/12/2009	 	 	 	2125712	 	 	 	 	 	 	 	2125712	 
	3711-04	 	 	Abandoned	 	 	Australia (Oceania)	 	 	04/12/2007	 	 	 	2007330333	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3711-05	 	 	Abandoned	 	 	Canada	 	 	04/12/2007	 	 	 	2,671,632	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3711-06	 	 	Abandoned	 	 	China	 	 	04/12/2007	 	 	 	200780050587.5	 	 	 	15/02/2010	 	 	 	CN101652345	 	 	 	 	 	 	 	 	 
	3711-07	 	 	Abandoned	 	 	India	 	 	04/12/2007	 	 	 	3739/DELNP/2009		 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3711-08	 	 	Abandoned	 	 	Israel	 	 	04/12/2007	 	 	 	199097	 	 	 	31/10/2012	 	 	 	 	 	 	 	 	 	 	 	 	 
	3711-09	 	 	Abandoned	 	 	Japan (Asia)	 	 	04/12/2007	 	 	 	2009-539869	 	 	 	15/04/2010	 	 	 	P2010-511694A	 	 	 	 	 	 	 	 	 
	3711-10	 	 	Abandoned	 	 	US	 	 	11/10/2011	 	 	 	13/293,546		 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 





 


	Family:	3712
    	Title:	NOVEL
    MODULATORS OF PROTEIN KINASE SIGNALING 




 






    	 	9	 



     


    

 


	Inventor
    	 	University
    	 	Faculty
    	 	Department
    
	 	 	 	 	 	 	 
	Levitzki
    Alexander	 	HUJI	 	Faculty
    of Science	 	The
    Alexander Silberman Institute for Life Sciences
	LUCASSEN
    Andre C. B	 	 	 	 	 	 
	SASSON
    Revital	 	 	 	 	 	 
	Reuveni
    Hadas	 	 	 	 	 	 







 





	 	 	Application	 	 	Publication	 	 	Patent	 
	Patent ID	 	Status	 	 	Country	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3712-00	 	 	Expired	 	 	 	US	 	 	 	05/06/2008	 	 	 	61/058,943		 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3712-01	 	 	Exhausted	 	 	 	PCT	 	 	 	07/06/2009	 	 	 	PCT/IL2009/000568	 	 	 	10/12/2009	 	 	 	WO
                                         2009/147682	 	 	 	 	 	 	 	 	 
	3712-02	 	 	Granted	 	 	 	US	 	 	 	07/06/2009	 	 	 	12/995,669		 	 	05/05/2011	 	 	 	US
                                         2011/0105618 A1	 	 	 	28/01/2014	 	 	 	8,637,575	 
	3712-03	 	 	Granted	 	 	 	Europe	 	 	 	07/06/2009	 	 	 	09758026.0	 	 	 	23/02/2011	 	 	 	2285774	 	 	 	25/02/2015	 	 	 	2285774	 
	3712-04	 	 	Granted	 	 	 	Israel	 	 	 	07/06/2009	 	 	 	209638	 	 	 	 	 	 	 	 	 	 	 	01/10/2016	 	 	 	209638	 
	3712-05	 	 	Abandoned	 	 	 	Canada	 	 	 	07/06/2009	 	 	 	2,758,016	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 








 





	Family:	[****] 	Title:	[****][****][****][****][****][****][****][****]







 





	Inventor
    	 	University
    	 	Faculty
    	 	Department
    
	 	 	 	 	 	 	 
	[****]	 	[****]	 	[****][****]	 	[****][****][****]

        [****][****][****]

        [****]

	[****]	 	 	 	 	 	 




 





	 	 	 	Application	 	 	Publication	 	 	Patent	 
	Patent ID	 	 	Status	 	 	Country	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	[****]		 	 	[****]		 	 	[****]		 	 	[****]		 	 	[****]	 	 	 		 	 	 		 	 	 		 	 	 	     	 
	 	[****]	 	 	 	[****]	 	 	 	[****]	 	 	 	[****]	 	 	 	[****]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	[****]	 	 	 	[****]	 	 	 	[****]	 	 	 	[****]	 	 	 	[****]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	 	[****]	 	 	 	[****]	 	 	 	[****]	 	 	 	[****]	 	 	 	[****]	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 





 





	Family:	3745
    	Title:	COMPOUNDS
    WHICH MODULATE PROTEIN KINASE SIGNALING 







 





	Inventor
    	 	University
    	 	Faculty
    	 	Department
    
	 	 	 	 	 	 	 
	Levitzki
    Alexander	 	HUJI	 	Faculty
    of Science	 	The
    Alexander Silberman Institute for Life Sciences
	Reuveni
    Hadas	 	 	 	 	 	 







 






    	 	10	 



     


    

 





	 	 	Application	 	 	Publication		 	Patent	 
	Patent ID	 	Status	 	 	Country	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 	Date	 	 	Number	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3745-00	 	 	Expired	 	 	 	US	 	 	 	27/12/2010	 	 	 	61/427,220		 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3745-01	 	 	Expired	 	 	 	US	 	 	 	06/07/2011	 	 	 	61/504,722		 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3745-02	 	 	Exhausted	 	 	 	PCT	 	 	 	27/12/2011	 	 	 	PCT/IL2011/050078	 	 	 	05/07/2012	 	 	WO 2012/090204 A1	 	 	 	 	 	 	 	 
	3745-03	 	 	Granted	 	 	 	US	 	 	 	27/12/2011	 	 	 	13/976,876		 	 	17/10/2013	 	 	US 2013/0274251 A1.	 	 	07/07/2015	 	 	 	9,073,880	 
	3745-04	 	 	Granted	 	 	 	Europe	 	 	 	27/12/2011	 	 	 	11813909.6	 	 	 	 	 	 	 	 	 	23/12/2015	 	 	 	2658847	 





 





	Family:	3787
    	Title:	COMBINATIONS
    FOR TREATING CANCER 




 





	Inventor
    	 	University
    	 	Faculty
    	 	Department
    
	 	 	 	 	 	 	 
	Reuveni
    Hadas	 	 	 	 	 	 
	Levitzki
    Alexander	 	HUJI	 	Faculty
    of Science	 	The
    Alexander Silberman Institute for Life Sciences







 





	 	 	Application	 	 	Publication	 	 	Patent	 
	Patent ID	 	Status	 	 	Country	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3787-00	 	 	Expired	 	 	 	US	 	 	 	01/03/2011	 	 	 	61/447,733		 	 	 	 	 	 	 	 	 	 		 	 	 		 
	3787-01	 	 	Abandoned	 	 	 	PCT	 	 	 	01/03/2012	 	 	 	PCT/IL2012/000098	 	 	 	07/09/2012	 	 	 	WO 2012/117396A1	 	 	 	 	 	 	 	 	 








 





	Family:	3946
    	Title:	IGF-1R
    SIGNALING PATHWAY INHIBITORS USEFUL IN THE TREATMENT OF NEURODEGENERATIVE DISEASES 




 





	Inventor
    	 	University
    	 	Faculty
    	 	Department
    
	 	 	 	 	 	 	 
	Ben-Sasson
    Shmuel	 	HUJI	 	Faculty
    of Medicine	 	Experimental
    medicine and cancer research
	Cohen
    Ehud	 	HUJI	 	Faculty
    of Medicine	 	Biochemistry
	Reuveni
    Hadas	 	 	 	 	 	 
	Levitzki
    Alexander	 	HUJI	 	Faculty
    of Science	 	The
    Alexander Silberman Institute for Life Sciences







 


	 	 	Application	 	Publication	 	 	Patent	 
	Patent ID	 	Status	 	Country	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 	 	Date	 	 	Number	 
	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3946-00	 	Expired	 	 	US	 	 	 	27/06/2012	 	 	 	61/664,786		 	 		 	 	 		 	 	 		 	 	 		 
	3946-01	 	Expired	 	 	US	 	 	 	14/07/2013	 	 	 	61/846,014		 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3946-02	 	NP-Entry	 	 	PCT	 	 	 	13/07/2014	 	 	 	PCT/IB2014/063071	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3946-03	 	Filed	 	 	Europe	 	 	 	13/07/2014	 	 	 	14825966.6	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3946-04	 	Filed	 	 	Israel	 	 	 	13/07/2014	 	 	 	243566	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 	 
	3946-05	 	Examination	 	 	US	 	 	 	13/07/2014	 	 	 	14/904,787		 	 	09/06/2016	 	 	 	US2016/0158243 A1	 	 	 	 	 	 	 	 	 





 






    	 	11	 



     


    




 


Exibit
1B


Development
Plan


 





[****]







 



    	 	12	 



     


    




 


Exhibit
2


Appendix
A3(a) to License Agreement – NovoTyr Results


 





		1.	The compounds developed are inhibitors of the IGF1R/IRS1-2 pathway as well as inhibitors of STAT-3 signaling. We have additional
data derived from large number of cancer cell lines in tissue culture and in a number of in vivo animal models targeting metastatic
melanoma, metastatic prostate cancer, colon cancer and multiple myeloma.



		2.	In vivo data on the NT compounds with Chemotherapy (Taxol)



		3.	[****].



		4.	[****].






		5.	Inhibition of the STAT-3 phosphorilation which is involved in anti-cancer immunomodulation, anti-metastatic, anti-angiogenic,
anti-proliferative.



		6.	[****].



		7.	Toxicity, safety,solubilty, pharmacodinamic and pharmacokinetic data related to the NT compounds.








 



    	 	13	 



     


    

 





EXHIBIT
3


 


ASSIGNMENT
LETTER


 


ASSIGNMENT
AGREEMENT


Made
as a Deed


 





This ASSIGNMENT AGREEMENT (the “Agreement”)
is made this 16 day of March, 2017, by and between Yissum Research Development Company of the Hebrew University of Jerusalem
Ltd., Hi-Tech Park, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel on the one hand (“Yissum”) and
TyrNovo Ltd. of One Azrieli Center, Round Tower, 23rd Floor, 132 Menachem Begin Road, Tel Aviv, 6701101, Israel,
on the other hand (the “Company”). Yissum and the Company shall be referred each as a “Party”,
and together as the “Parties”.







 


		WHEREAS,	Yissum
                                         and the Company are parties to a License Agreement dated 15 August 2013, as amended by
                                         the First Amendment to License Agreement effective as of 8 April 2014, and the Second
                                         Amendment to License Agreement effective as of __ February 2017 (the above License Agreement,
                                         as amended, the “License Agreement”); according to which the Company
                                         received, among other things, a License to the Licensed Patents;



 


		WHEREAS,	pursuant
                                         to the License Agreement, certain inventions have been or shall/may be registered jointly
                                         in the name of Yissum and the Company and shall be regarded as Joint Patents; and



 


		WHEREAS,	the
                                         Parties have agreed that, upon the occurrence of the Trigger Event (as defined below),
                                         the Company shall assign and transfer to Yissum its title and ownership in and to the
                                         Joint Patents and all Development Results and thereafter Yissum shall become the sole
                                         and exclusive owner of such Joint Patents and Development Results; all in accordance
                                         with the terms and conditions of this Agreement;



 







NOW THEREFORE THE PARTIES DO HEREBY AGREE AS FOLLOWS:



 


	1.	Preamble



 


	 	1.1	The recitals hereto constitute an integral part hereof.




 


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



 


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



 


		1.4	In this Agreement the following expressions shall have the meanings appearing alongside them, unless
the context otherwise requires:



 


“Intellectual
Property Rights” shall mean any and all rights relating to intellectual property, including without limitation, all inventions,
patents and patent applications, including all re-issuances, continuations, continuations-in-part, divisions, revisions, extensions
and re-examinations thereof.


 


“Effective
Date” shall mean the date of occurrence of the Trigger Event.


 


“Trigger
Event” shall mean the termination of the License Agreement for any reason whatsoever, other than the expiration of its
term or due to an uncontested breach by Yissum.


 



    	 	14	 



     


    

 


		2.	Assignment of Joint Patents and Development Results.



 


		2.1	Upon the Effective Date, the Company shall assign, convey and transfer to Yissum, its successors
and assigns, the entire right, title and interest in and to any Joint Patent(s) and Development Results, including all Intellectual
Property Rights therein, and all rights and benefits under any applicable law, treaty or convention.



 


		2.2	Subsequent to an assignment pursuant to this Agreement, the Company or its successors, legal representatives
or assigns shall notify Yissum, its successors, legal representatives and assigns, of any facts known to it regarding said Joint
Patents and Development Results, testify in any legal proceeding, sign all lawful papers, execute all divisional, continuing, reissue
and foreign applications, make all rightful oaths, and generally do everything possible to assist Yissum, its successors, legal
representatives and assigns, to obtain and enforce proper protection, full ownership and rights of use for said Joint Patents and
Development Results in all countries.



 


		2.3	In the event the Company, its successors, legal representatives or assigns fail to execute and
deliver such documents and instruments promptly upon Yissum’s request, Yissum is hereby authorized and appointed attorney-in-fact
of and for the Company to make, execute and deliver any and all such documents and instruments.



 


		3.	Governing Law and Jurisdiction. The provisions of this Agreement and everything concerning
the relationship between the Parties in accordance with this Agreement shall be governed by the laws of the State of Israel and
exclusive jurisdiction shall be granted to the appropriate courts in Jerusalem, Israel.



 


		4.	Miscellaneous. This Agreement supersedes any prior understanding, agreement, practice or
contract, oral or written, between the Parties with respect to the matters covered by this Agreement. This Agreement may not be
modified except by written instrument signed by all Parties hereto. This Agreement may be executed in counterparts, each of which
shall be deemed an original, but which together shall constitute one and the same instrument. This Agreement shall be binding upon
the Parties’ heirs, executors, administrators, successors, and assigns. The invalidity of any provision of this Agreement
shall not result in the invalidity of the entire Agreement.



 


AS WITNESS THE HANDS OF THE PARTIES:


 


	TyrNovo
    Ltd.	 	Yissum
    Research Development Company  
	One Azrieli Center, Round Tower, 23rd Floor,	 	of
    the Hebrew University of Jerusalem Ltd.
	132 Menachem Begin Road, Tel Aviv, 6701101,
Israel	 	Hi-Tech
    Park, Edmond J. Safra Campus,
	 	 	Givat
    Ram, P.O.B 39135, Jerusalem 91390, Israel
	 	 	 	 	 
	By:
    	/s/
    Hadas Reuveni	 	By:
    	/s/
    Ariela Markel
	Name:
    	Hadas
    Reuveni	 	Name:
    	Ariela
    Markel
	Title:
    	CEO	 	Title:
    	VP
    Lisencing, Biothecnology
	 	 	 	 	 
	By:
    	/s/
    Shimca Rock	 	By:
    	/s/
    Itzik Goldwaser 
	Name:
    	Shimca
    Rock	 	Name:
    	Itzik
    Goldwaser
	Title:
    	CEO	 	Title:
    	Head
    of Research Collaboration
	Date:
    	April
    23, 2017	 	Date:
    	March
    16, 2017



 


 


15