Document:

Exhibit

Exhibit 10.37
 
FOURTH AMENDMENT TO THE LOAN AND SECURITY AGREEMENT 
THIS FOURTH AMENDMENT TO THE LOAN AND SECURITY AGREEMENT (this “Amendment”) is made effective as of November 5, 2018 (the “Fourth Amendment Date”) by and among OXFORD FINANCE LLC, a Delaware limited liability company with an office located at 133 North Fairfax Street, Alexandria, Virginia 22314 (in its individual capacity, “Oxford”; and in its capacity as Collateral Agent, “Collateral Agent”), the Lenders listed on Schedule 1.1 of the Loan Agreement (as defined below) from time to time including Oxford in its capacity as a Lender (each a “Lender” and collectively, the “Lenders”) and REGULUS THERAPEUTICS INC., a Delaware corporation with offices located at 10614 Science Center Dr., San Diego, California 92121 (“Borrower”).
WHEREAS, Collateral Agent, Borrower and Lenders party thereto from time to time have entered into that certain Loan and Security Agreement, dated as of June 17, 2016 (as amended, supplemented or otherwise modified from time to time, the “Loan Agreement”), pursuant to which Lenders have provided to Borrower certain loans in accordance with the terms and conditions thereof;
WHEREAS, Borrower anticipates entering into a certain First Amendment to Second Amended and Restated Collaboration and License Agreement between Sanofi S.A. (“Licensee”) and Borrower, on or about November 5, 2018, the form of which is attached hereto as Exhibit A (the “License Amendment”), which will amend that certain Second Amended and Restated Collaboration and License Agreement between Licensee and Borrower, dated February 4, 2014 (the “Sanofi License Agreement”);
WHEREAS, Borrower has requested that Collateral Agent and Lenders consent to certain licenses and Transfers by Borrower to Licensee, in each case pursuant to the Sanofi License Agreement as amended by the License Amendment, as described in Section 2 hereof, to the extent that such consent may be required pursuant to Section 7.1 and Section 7.5 of the Loan Agreement; 
WHEREAS, Collateral Agent and Lenders have agreed to grant such consent as set forth in that certain Consent and Non-Disturbance Agreement, dated as of the date hereof, made by Borrower and Collateral Agent (the “Consent and Non-Disturbance Agreement”); and
WHEREAS, Borrower, Lenders and Collateral Agent desire to amend certain provisions of the Loan Agreement as provided herein and subject to the terms and conditions set forth herein.
NOW, THEREFORE, in consideration of the promises, covenants and agreements contained herein, and other good and valuable consideration, including, without limitation, the granting of the Consent by Collateral Agent and Lenders, the receipt and adequacy of which are hereby acknowledged, Borrower, Lenders and Collateral Agent hereby agree as follows:
		
	1.
	Capitalized terms used herein but not otherwise defined shall have the respective meanings given to them in the Loan Agreement.

		
	2.
	Upon this Amendment becoming effective, Collateral Agent hereby automatically releases it Liens in the Mir-21 Assigned Assets and shall cooperate with Borrower, solely at the expense of Borrower, to file and prepare all necessary UCC amendments, Intellectual Property Security Agreement amendments. terminations and Intellectual Property releases to be filed.

		
	3.
	Section 2.2(d)(ii) of the Loan Agreement is hereby amended and restated in its entirety as follows:

(ii) Notwithstanding anything herein to the contrary, Borrower shall also have the option to prepay part of Term Loans advanced by the Lenders under this Agreement provided Borrower (A) provides written notice to Collateral Agent of its election to prepay the Term Loans at least ten (10) days prior to such prepayment, and (B) pays to the Lenders on the date of such prepayment, payable to each Lender in accordance with its respective Pro Rata Share, an amount equal to the sum of (1) the portion of outstanding principal of such Term Loans plus all accrued and unpaid interest thereon through the prepayment date, (2) the applicable Final Payment, (3) all other Obligations that are then due and payable, including Lenders’ Expenses and interest at the Default Rate with respect to any past due amounts and (4) the applicable Prepayment Fee with respect to the portion of such Term Loans being prepaid. For the purposes of clarity, any partial prepayment 

shall be applied pro-rata to all outstanding amounts under each Term Loan, and shall be applied pro-rata within each Term Loan tranche to reduce amortization payments under Section 2.2(b) on a pro-rata basis. 

		
	4.
	A new Section 2.2(d)(iii) of the Loan Agreement is hereby added as follows:

Furthermore, notwithstanding anything herein to the contrary commencing upon the execution of the License Amendment, Borrower shall (1) prepay part of Term Loans advanced by the Lenders under this Agreement with twenty five percent (25.00%) of the License Amendment Payments received by Borrower (the “Sanofi License Prepayments”) within five (5) Business Days after receipt of such License Amendment Payment (or installment thereof), (2) pay the applicable Prepayment Fee with respect to such Sanofi License Prepayments (or installment thereof) and (3) pay the applicable Final Payment that relates to such Sanofi License Prepayments (or installment thereof).  “License Amendment Payments” shall mean all cash net proceeds received by Borrower pursuant to (i) Paragraph 6.1 of the License Amendment consisting of an upfront payment payable in two installments, (ii) Section 6.2 of the License Amendment consisting of a milestone payment in the amount of $10,000,000 payable upon achievement of the First Milestone Event (as defined in the License Amendment), and (iii) Section 5.5 of the License Amendment relating to the transfer of the Mir-21 Fibrosis POC Program-specific materials identified in Schedule 5.5 to the License Amendment.  For the purposes of clarity, any partial prepayment shall be applied pro-rata to all outstanding amounts under each Term Loan, and shall be applied pro-rata within each Term Loan tranche to reduce amortization payments under Section 2.2(b) on a pro-rata basis.

		
	5.
	The following new Section 7.12 is hereby added to the Loan Agreement:

7.12    Cash Covenant.  Fail to maintain at all times cash in a Collateral Account subject to a Control Agreement in favor of Collateral Agent, an amount equal to at least the Minimum Cash Balance.

		
	6.
	Section 13.1 of the Loan Agreement is hereby amended by adding the following definitions thereto in alphabetical order:

“Capital Event” means the receipt by Borrower on or after the Fourth Amendment Date of unrestricted net cash proceeds of not less than Fifteen Million Dollars ($15,000,000.00) from (i) the issuance and sale by Borrower of its unsecured subordinated convertible debt and/or equity securities and/or (ii) “up front” or milestone payments in connection with a joint venture, collaboration or other partnering transaction other than pursuant to the Sanofi License Agreement.

“Consent and Non-Disturbance Agreement” is that certain Consent and Non-Disturbance Agreement, dated as of the date hereof, made by Borrower and Collateral Agent.

“Collateral Assignment Agreement” is that certain Collateral Assignment Agreement, between Collateral Agent and Borrower, dated as of the Fourth Amendment Date, regarding the collateral assignment of Borrower’s interest in the Sanofi License Agreement.

“Fourth Amendment Date” means November 5, 2018.

“License Amendment” is that certain First Amendment to Second Amended and Restated Collaboration and License Agreement, dated November 5, 2018, entered into by and between Borrower and Sanofi S.A.

“Minimum Cash Balance” is (i) Ten Million Dollars ($10,000,000.00) if the Capital Event has not occurred, and (ii) Five Million Dollars ($5,000,000.00) if the Capital Event has occurred.

“MIR-21 Assigned Assets” is defined in the Consent and Non-Disturbance Agreement, including without limitation all property required to be delivered to Sanofi under Article 5 of the License Amendment, such as the Mir-21 Product Specific Patents, the RG-012 Regulatory Materials, the Max-Planck Agreement and Wurzburg Agreement, the Mir-21 Fibrosis POC Program-specific materials identified in Schedule 5.5 to the License Amendment, the Domain name alportstudy.com, and the Assigned Mir-21 Contracts (each as defined in the License Amendment).

“Sanofi License Agreement” is that certain Second Amended and Restated Collaboration and License Agreement between Sanofi S.A. and Borrower, dated February 4, 2014, as amended from time to in accordance with the terms of this Agreement.

“Sanofi License Prepayments” is defined in Section 2.2(d)(iii).

		
	7.
	Section 13.1 of the Loan Agreement is hereby further amended by deleting therefrom the definitions of “Cash Out Date,” “Cash Out Principal Loan Balance,” “Operative Monthly Cash Burn,” “Past Actual Monthly Cash Burn,” “Projected Monthly Cash Burn” and “Projected Trailing Monthly Cash Burn.”

		
	8.
	Section 13.1 of the Loan Agreement is hereby further amended by amending and restating the following definition therein as follows:

“Final Payment” is a payment (in addition to and not a substitution for the regular monthly payments of principal plus accrued interest) due on the earliest to occur of (a) the Maturity Date, or (b) the acceleration of any Term Loan, or (c) the prepayment of a Term Loan pursuant to Section 2.2(c) or Section 2.2(d), equal to the original principal amount of such Term Loan multiplied by the Final Payment Percentage, payable to Lenders in accordance with their respective Pro Rata Shares.  For the avoidance of doubt, the calculation of any Final Payment due on the maturity date or upon acceleration shall not include the principal amount prepaid in accordance with Section 2.2(d)(ii) or Section 2.2(d)(iii) if a Final Payment based on such principal amount prepaid was made at the time of such prepayment.

		
	9.
	Section 13.1 of the Loan Agreement is hereby amended by amending and restating the following definition

therein as follows:

“Loan Documents” are, collectively, this Agreement, the Perfection Certificates, each Compliance
Certificate, the Consent and Non-Disturbance Agreement, each Disbursement Letter, the Collateral Assignment Agreement, the IP Agreement, any subordination agreements, any note, or notes or guaranties executed by Borrower or any other Person, and any other present or future agreement entered into by Borrower, any Guarantor or any other Person for the benefit of the Lenders and Collateral Agent in connection with this Agreement; all as amended, restated, or otherwise modified.

		
	10.
	The form of Exhibit A to the Loan Agreement is hereby amended and restated as set forth on Exhibit B attached hereto.

		
	11.
	The form of the Compliance Certificate (Exhibit C to the Loan Agreement) is hereby amended and restated as set forth on Exhibit C attached hereto.

		
	12.
	Limitation of Amendment.

		
	a.
	The amendments and consents set forth above are effective for the purposes set forth herein and shall be limited precisely as written and shall not be deemed to (a) be a consent to any amendment, waiver or modification of any other term or condition of any Loan Document, or (b) otherwise prejudice any right, remedy or obligation which Lenders or Borrower may now have or may have in the future under or in connection with any Loan Document, as amended hereby.

		
	b.
	This Amendment shall be construed in connection with and as part of the Loan Documents and all terms, conditions, representations, warranties, covenants and agreements set forth in the Loan Documents, except as herein amended, are hereby ratified and confirmed and shall remain in full force and effect.

		
	13.
	To induce Collateral Agent and Lenders to enter into this Amendment, Borrower hereby represents and warrants to Collateral Agent and Lenders as follows: 

		
	a.
	Immediately after giving effect to this Amendment (a) the representations and warranties contained in the Loan Documents are true, accurate and complete in all material respects as of the date hereof (except to the extent such representations and warranties relate to an earlier date, in which case they are true and correct as of such date), and (b) no Event of Default has occurred and is continuing;

		
	b.
	Borrower has the power and due authority to execute and deliver this Amendment and to perform its obligations under the Loan Agreement, as amended by this Amendment; 

		
	c.
	The organizational documents of Borrower delivered to Collateral Agent on the Effective Date, and updated pursuant to subsequent deliveries by the Borrower to the Collateral Agent, remain true, accurate and complete and have not been amended, supplemented or restated and are and continue to be in full force and effect; 

		
	d.
	The execution and delivery by Borrower of this Amendment and the performance by Borrower of its obligations under the Loan Agreement, as amended by this Amendment, do not and will not contravene (i) any law or 

regulation binding on or affecting Borrower, (ii) any contractual restriction with a Person binding on Borrower, (iii) any order, judgment or decree of any court or other governmental or public body or authority, or subdivision thereof, binding on Borrower, or (iv) the organizational documents of Borrower; 

		
	e.
	The execution and delivery by Borrower of this Amendment and the performance by Borrower of its obligations under the Loan Agreement, as amended by this Amendment, do not require any order, consent, approval, license, authorization or validation of, or filing, recording or registration with, or exemption by any governmental or public body or authority, or subdivision thereof, binding on Borrower, except as already has been obtained or made; 

		
	f.
	This Amendment has been duly executed and delivered by Borrower and is the binding obligation of Borrower, enforceable against Borrower in accordance with its terms, except as such enforceability may be limited by bankruptcy, insolvency, reorganization, liquidation, moratorium or other similar laws of general application and equitable principles relating to or affecting creditors’ rights; 

		
	g.
	Without limiting any provision of the Loan Agreement, Borrower hereby acknowledges that Collateral includes the Sanofi License Agreement; and

		
	h.
	The Borrower hereby remises, releases, acquits, satisfies and forever discharges the Lenders and Collateral Agent, their agents, employees, officers, directors, predecessors, attorneys and all others acting or purporting to act on behalf of or at the direction of the Lenders and Collateral Agent (“Releasees”), of and from any and all manner of actions, causes of action, suit, debts, accounts, covenants, contracts, controversies, agreements, variances, damages, judgments, claims and demands whatsoever, in law or in equity, which any of such parties ever had, now has or, to the extent arising from or in connection with any act, omission or state of facts taken or existing on or prior to the date hereof, may have after the date hereof against the Releasees, for, upon or by reason of any matter, cause or thing whatsoever relating to or arising out of the Loan Agreement or the other Loan Documents on or prior to the date hereof through the date hereof.  Without limiting the generality of the foregoing, the Borrower waives and affirmatively agrees not to allege or otherwise pursue any defenses, affirmative defenses, counterclaims, claims, causes of action, setoffs or other rights they do, shall or may have as of the date hereof, including the rights to contest: (a) the right of Collateral Agent and each Lender to exercise its rights and remedies described in the Loan Documents; (b) any provision of this Amendment or the Loan Documents; or (c) any conduct of the Lenders or other Releasees relating to or arising out of the Loan Agreement or the other Loan Documents on or prior to the date hereof.

		
	14.
	Except as expressly set forth herein, the Loan Agreement shall continue in full force and effect without alteration or amendment.  This Amendment and the Loan Documents represent the entire agreement about this subject matter and supersede prior negotiations or agreements.

		
	15.
	Borrower agrees to promptly pay (but in no event in less than 5 Business Days of invoice date) all unpaid Lenders’ Expenses incurred through the date hereof, which may be debited (or ACH’d) from any of Borrower’s accounts.

		
	16.
	This Amendment shall be deemed effective as of the Fourth Amendment Date upon (a) the due execution and delivery to Collateral Agent of this Amendment by each party hereto, (b) the delivery by Borrower to Collateral Agent of a fully executed copy of the License Amendment and (c) the due execution and delivery to Collateral Agent of the Collateral Assignment Agreement by each party thereto.

		
	17.
	This Amendment may be executed in any number of counterparts, each of which shall be deemed an original, and all of which, taken together, shall constitute one and the same instrument.

		
	18.
	This Amendment and the rights and obligations of the parties hereto shall be governed by and construed in accordance with the laws of the State of California.

[Balance of Page Intentionally Left Blank - Signature Pages to Follow]

IN WITNESS WHEREOF, the parties hereto have caused this Fourth Amendment to Loan and Security Agreement to be executed as of the date first set forth above.
	
			
	BORROWER:
	 
	 

	REGULUS THERAPEUTICS INC.
	 
	 

	 
	 
	 

	By  /s/ Joseph P. Hagan
	 
	 

	Name: Joseph P. Hagan
	 
	 

	Title:   President & CEO
	 
	 

	 
	 
	 

	COLLATERAL AGENT AND LENDER:
	 
	 

	OXFORD FINANCE LLC
	 
	 

	 
	 
	 

	By /s/ Colette H. Featherly
	 
	 

	Name: Colette H. Featherly
	 
	 

	Title: Senior Vice President
	 
	 

EXHIBIT A

License Amendment

License Amendment (incorporated by reference to Exhibit 10.38 to the Borrower’s Annual Report on Form 10-K, filed with the Securities and Exchange Commission on March 18, 2019).

EXHIBIT B

Amendment and Restatement of Exhibit A to Loan Agreement

Description of Collateral
The Collateral consists of all of Borrower’s right, title and interest in and to the following personal property:
All goods, Accounts (including health‐care receivables), Equipment, Inventory, contract rights or rights to payment of money, leases, license agreements, franchise agreements, General Intangibles (including all Intellectual Property), commercial tort claims, documents, instruments (including any promissory notes), chattel paper (whether tangible or electronic), cash, deposit accounts and other Collateral Accounts, all certificates of deposit, fixtures, letters of credit rights (whether or not the letter of credit is evidenced by a writing), securities, and all other investment property, supporting obligations, and financial assets, whether now owned or hereafter acquired, wherever located; and
All Borrower’s Books relating to the foregoing, and any and all claims, rights and interests in any of the above and all substitutions for, additions, attachments, accessories, accessions and improvements to and replacements, products, proceeds and insurance proceeds of any or all of the foregoing.
Notwithstanding the foregoing, the Collateral does not include (i) more than 65% of the total combined voting power of all classes of stock entitled to vote the shares of capital stock (the “Shares”) of any Foreign Subsidiary, if Borrower demonstrates to Collateral Agent’s reasonable satisfaction that a pledge of more than sixty five percent (65%) of the Shares of such Subsidiary creates a present and existing adverse tax consequence to Borrower under the U.S. Internal Revenue Code; (ii) any intent to use trademarks, (iii) the Mir-21 Assigned Assets, and (iv) any license or contract, in each case if the granting of a Lien in such license or contract is prohibited by or would constitute a default under the agreement governing such license or contract (but (A) only to the extent such prohibition is enforceable under applicable law and (B) other than to the extent that any such term would be rendered ineffective pursuant to Sections 9-406, 9-408 or 9-409 (or any other Section) of Division 9 of the Code); provided that upon the termination, lapsing or expiration of any such prohibition, such license or contract, as applicable, shall automatically be subject to the security interest granted in favor of Collateral Agent hereunder and become part of the “Collateral.”

EXHIBIT C

Amendment and Restatement of Exhibit C to Loan Agreement

Compliance Certificate

	
		
	TO:
	OXFORD FINANCE LLC, as Collateral Agent and Lender

	FROM:
	REGULUS THERAPEUTICS INC.

The undersigned authorized officer (“Officer”) of REGULUS THERAPEUTICS INC. (“Borrower”), hereby certifies that in accordance with the terms and conditions of the Loan and Security Agreement by and among Borrower, Collateral Agent, and the Lenders from time to time party thereto (the “Loan Agreement;” capitalized terms used but not otherwise defined herein shall have the meanings given them in the Loan Agreement),
(a)    Borrower is in complete compliance for the period ending _______________ with all required covenants in the Loan Agreement except as noted below;
(b)    There are no Events of Default, except as noted below;
(c)    Except as noted below, all representations and warranties of Borrower stated in the Loan Documents are true and correct in all material respects on this date and for the period described in (a), above; provided, however, that such materiality qualifier shall not be applicable to any representations and warranties that already are qualified or modified by materiality in the text thereof; and provided, further that those representations and warranties expressly referring to a specific date shall be true, accurate and complete in all material respects as of such date.
(d)    Borrower, and each of Borrower’s Subsidiaries, has timely filed all required tax returns and reports or extensions therefor, Borrower, and each of Borrower’s Subsidiaries, has timely paid all foreign, federal, state, and local taxes, assessments, deposits and contributions owed by Borrower, or Subsidiary, except as otherwise permitted pursuant to the terms of Section 5.8 of the Loan Agreement;
(e)    No Liens have been levied or claims made against Borrower or any of its Subsidiaries relating to unpaid employee payroll or benefits of which Borrower has not previously provided written notification to Collateral Agent and the Lenders.
Attached are the required documents, if any, supporting our certification(s).  The Officer, on behalf of Borrower, further certifies that the attached financial statements are prepared in accordance with Generally Accepted Accounting Principles (GAAP) and are consistently applied from one period to the next except as explained in an accompanying letter or footnotes and except, in the case of unaudited financial statements, for the absence of footnotes and subject to year‐end audit adjustments as to the interim financial statements.  
Please indicate compliance status since the last Compliance Certificate by circling Yes, No, or N/A under “Complies” column.

	
							
	 
	Reporting Covenant
	Requirement
	Actual
	Complies

	1)
	Financial statements - balance sheet and income statement
	Monthly within 30 days
	 
	Yes
	No
	N/A

	2)
	Financial statements - cash flow statement
	Quarterly within 45 days
	 
	Yes
	No
	N/A

	3)
	Annual (CPA Audited) statements
	Within 120 days after FYE
	 
	Yes
	No
	N/A

	4)
	Annual Financial Projections/Budget (prepared on a monthly basis)
	Annually (within 45 days of FYE), and when revised
	 
	Yes
	No
	N/A

	5)
	8‐K, 10‐K and 10‐Q Filings
	If applicable, within 5 days of filing
	 
	Yes
	No
	N/A

	6)
	Compliance Certificate
	Monthly within 30 days
	 
	Yes
	No
	N/A

	7)
	IP Report
	When required
	 
	Yes
	No
	N/A

	8)
	Total amount of Borrower’s cash and cash equivalents at the last day of the measurement period
	 
	$______
	Yes
	No
	N/A

	9)
	Total amount of Borrower’s Subsidiaries’ cash and cash equivalents at the last day of the measurement period
	 
	$______
	Yes
	No
	N/A

	10)
	Updated Exhibit A to Landlord Waiver
	Quarterly within 30 days, and in any month in which new Collateral in excess of $100,000 was delivered to 10614 Science Center Dr., San Diego, California 92121 
	 
	Yes    
	No
	N/A

	15)
	Minimum Cash Balance
	 
	$________
	Yes    
	No
	N/A

Deposit and Securities Accounts
(Please list all accounts; attach separate sheet if additional space needed)

	
								
	 
	Institution Name
	Account Number
	Account Balance as of the date hereof
	New Account?
	Account Control Agreement in place?

	1)
	 
	 
	 
	Yes
	No
	Yes
	No

	2)
	 
	 
	 
	Yes
	No
	Yes
	No

	3)
	 
	 
	 
	Yes
	No
	Yes
	No

	4)
	 
	 
	 
	Yes
	No
	Yes
	No

Other Matters

	
				
	1)
	Have there been any changes in management since the last Compliance Certificate?
	Yes
	No

	 
	 
	 
	 

	2)
	Have there been any transfers/sales/disposals/retirement of Collateral or IP prohibited by the Loan Agreement?
	Yes
	No

	 
	 
	 
	 

	3)
	Have there been any new or pending claims or causes of action against Borrower that involve more than Two Hundred Fifty Thousand Dollars ($250,000.00)?
	Yes
	No

	4)
	Have there been any amendments of or other changes to the Borrower’s Operating Documents or any of its Subsidiaries’ Operating Documents?  If the Borrower is no longer subject to Securities Exchange Act of 1934, as amended, have there been any material changes to the capitalization of Borrower? If yes, please provide copies of any such amendments or changes to the Operating Documents and capitalization table, as applicable, with this Compliance Certificate.
	Yes
	No

	 
	 
	 
	 

Exceptions

Please explain any exceptions with respect to the certification above: (If no exceptions exist, state “No exceptions.”  Attach separate sheet if additional space needed.)

REGULUS THERAPEUTICS INC.

By __________________                 
Name: _______________                 
Title: ________________                 

Date:

	
		
	LENDER USE ONLY

	 
	 

	Received by: _______________________
	Date:  ___________

	 
	 

	Verified by: ________________________ 
	Date:  ___________

	 
	 

	Compliance Status:YesNoa201810k1038firstamendme

                                                                     Exhibit 10.38                                                                                                                                      ***Text Omitted and Filed Separately                                               with the Securities and Exchange Commission.                                                        Confidential Treatment Requested                                        Under 17 C.F.R. Sections 200.80(c) and Rule 24b-2 of the                                                 Securities Exchange Act of 1934, as amended.                                                                     Execution Copy                              FIRST AMENDMENT TO                        SECOND AMENDED AND RESTATED                    COLLABORATION AND LICENSE AGREEMENT          THIS FIRST AMENDMENT TO SECOND AMENDED AND RESTATED  COLLABORATION AND   LICENSE AGREEMENT (“First Amendment”) is made and entered into as of November 5, 2018 (the   “First Amendment Date”), by and between SANOFI, a company organized under the laws of France  (“Sanofi”) having a place of business at 54, rue la Boétie, 75008, Paris, France, registered in the  Paris Trade and Company Register under no. 395 030 844, and REGULUS THERAPEUTICS INC., a   corporation organized under the laws of the State of Delaware, USA (“Regulus”) having a place of   business at 10614 Science Center Drive, San Diego, California 92121, USA.  Sanofi and Regulus   each may be referred to herein individually as a “Party,” or collectively as the “Parties.”           WHEREAS, Sanofi and Regulus entered into that certain Second Amended and Restated   Collaboration and License Agreement effective February 4, 2014 (as in effect prior to the First   Amendment Date, the “Agreement”), pursuant to which, among other things, Regulus is responsible  for all activities under each POC Program Plan (other than Sanofi Program Activities) through the  Achievement of Proof of Concept (as such term is defined in the Agreement); and            WHEREAS, Regulus has suspended the Mir-21 Fibrosis POC Program and has requested that   Sanofi restructure the Agreement and take responsibility for obligations of Regulus under the   Agreement, including the administration and expense of clinical trials related to the Mir-21 Fibrosis   POC Program; and          WHEREAS, Sanofi is willing to restructure the Agreement as it pertains to the Mir-21 POC  Programs, Mir-21 Compounds, and Mir-21 Products, as requested by Regulus and on the terms and  subject to the conditions set forth in this First Amendment.  Unless stated otherwise in this First  Amendment, this Amendment affects only the Mir-21 POC Programs, Mir-21 Compounds, and  Mir-21 Products.         NOW,  THEREFORE, in consideration of the foregoing and the mutual covenants herein   contained, the Parties do hereby agree as follows:    1.    DEFINED TERMS.            Capitalized terms used but not otherwise defined in this First Amendment shall have the   meanings ascribed to them in the Agreement.    2.    ADDITIONAL DEFINITIONS.           2.1   “Amended Agreement” shall mean the Agreement, as amended by this First   Amendment.          2.2   “Biopsy Study” shall mean that certain study of the Mir-21 Product RG-012 having  the ClinicalTrials.gov identifier NCT03373786 in subjects with Alport syndrome.                                          1     

 

           2.3   “Contract” means any contract, agreement, arrangement, or understanding,   whether written or oral and whether express or implied.          2.4   “HERA Study” shall mean that certain Phase 2 Trial of the Mir-21 Product   RG-012 having the ClinicalTrials.gov identifier NCT02855268 in subjects with Alport   syndrome.          2.5   “HERA Study Protocol” shall mean the protocol for the HERA Study, as the   same may be amended from time to time by Sanofi.          2.6   “Legal Proceedings” shall mean any action, suit, litigation, arbitration,  proceeding (including any civil, criminal, administrative, investigative or appellate proceeding),  hearing, inquiry, audit, examination or investigation commenced, brought, conducted or heard by  or before, or otherwise involving, any court or other government authority or any arbitrator or  arbitration panel.          2.7   “Max-Planck” shall mean Max-Planck-Innovation GmbH.         2.8   “Max-Planck Agreement” shall mean that certain Amended and Restated  License Agreement among Max-Planck, Regulus, Ionis Pharmaceuticals, Inc. (formerly known  as Isis Pharmaceuticals, Inc.) and Alnylam Pharmaceuticals, Inc., dated April 18, 2011.          2.9   “Mir-21 Product Specific Patents” shall mean all Product Specific Patents  directed to Mir-21 or to any Mir-21 Compound or Mir-21 Product, in each case, that are owned  solely by Regulus, or jointly with another Person,  as of the First Amendment Date (immediately  prior to giving effect to any assignment to Sanofi pursuant to this First Amendment).  The  Mir-21 Product Specific Patents are listed in Schedule 10.2(k) to this First Amendment.          2.10  “Other Fibrosis POC Study” shall have the meaning provided in Paragraph 4.1  of this First Amendment.           2.11  “Oxford Consent” shall mean the Consent and Non-Disturbance Agreement  entered into for the benefit of Sanofi in respect of the Oxford Credit Agreement on or before the  First Amendment Effective Date by and between Regulus and Oxford Finance LLC, in its  capacity as Collateral Agent and on behalf of the Lenders (each, as defined in the Oxford Credit  Agreement).         2.12  “Oxford Credit Agreement” shall mean that certain Loan and Security  Agreement by and between Regulus and Oxford Finance LLC, in its capacity as Collateral Agent  and on behalf of the Lenders (each, as defined in such Loan and Security Agreement), dated as  of June 17, 2016, collectively with the Loan Documents (as defined therein) and any exhibits,  addenda and supplements thereto, and as the same may be amended, supplemented or modified  from time to time.         2.13  “Sanofi Mir-21 Fibrosis POC Program” shall mean a program to develop the  Mir-21 Product RG-012 in Alport syndrome with the objective of demonstrating clinical proof of  concept with respect to such Mir-21 Product in Alport syndrome.                                         2     

 

           2.14  “Sanofi Mir-21 Fibrosis POC Program Term” shall mean, with respect to the   Sanofi Mir-21 Fibrosis POC Program, the period beginning on the First Amendment Date and,   subject to earlier termination of the Sanofi Mir-21 Fibrosis POC Program pursuant to   Paragraph 4.3 of this First Amendment or earlier termination of the Amended Agreement pursuant   to ARTICLE 9 thereof, ending upon Sanofi’s delivery to Regulus of top-line results of the HERA  Study or Other Fibrosis POC Study (whichever study is completed first).          2.15  “Technology Transfer and Stand-by Letter Date” shall mean the date of  occurrence of the last to occur of the following: (a) the IND Transfer Date (as defined in  Paragraph 5.2 of this First Amendment); (b) confirmation by Sanofi that all items listed in  Schedule 5.3 hereto have been delivered to Sanofi in a format reasonably acceptable to Sanofi and  otherwise in accordance with Paragraph 5.3 of this First Amendment (the “Paragraph 5.3  Confirmation Date”); (c) confirmation by Sanofi that all materials specified in Schedule 5.5  hereto have been transferred to and reasonably accepted by Sanofi in accordance with  Paragraph 5.5 of this First Amendment (the “Paragraph 5.5 Confirmation Date”); (d) [...***...]  ([...***...]) business days after Sanofi has received executed copies of a Stand-by License  Agreement with each Existing Third Party Licensor in accordance with Paragraph 6.4(b) of this  First Amendment; and (e) the Parties entering into an SDEA pursuant to Paragraph 5.11.    3.    MIR-21 LICENSE.            Section 2.1 (including Sections 2.1.1, 2.1.2, 2.1.3 and 2.1.4) of the Agreement is hereby   eliminated in its entirety.  For purposes of Sections 3.11 and 4.3 of the Agreement and Article 5 of   the Agreement (as amended by this First Amendment), from and after the First Amendment Date,   Sanofi shall be deemed to have exercised all of its Options with respect to the Mir-21 POC   Programs.  Accordingly, effective as of the First Amendment Date, Regulus hereby grants to   Sanofi a worldwide, royalty-free (but fee-bearing as expressly set forth in this First Amendment),  exclusive license under Regulus Know-How and Regulus Patents (to the extent that such Regulus  Know-How and Regulus Patents are not assigned to Sanofi pursuant to this First Amendment), to  Research, Develop, make, have made, use, gain Approval, Commercialize, sell, offer for sale, have  sold, export and import Mir-21 Compounds, Mir-21 Products and Companion Diagnostics for use  with Mir-21 Products; in each case, in the Product Field (the “Mir-21 License”).  Sanofi will have   the right to grant sublicenses under the Mir-21 License as set forth in Section 2.4 of the  Agreement; provided that Sanofi may freely grant sublicenses in the U.S. under such license,  notwithstanding the proviso set forth in such Section 2.4.  Regulus stipulates and agrees that,  notwithstanding anything in the Agreement, Regulus will not have any Co-Promote Options or Co- Promote Rights with respect to the Mir-21 Products, and Regulus hereby waives any and all such  Co-Promote Options and Co-Promote Rights with respect to Mir-21 Products.     4.    DEVELOPMENT OF MIR-21 PRODUCTS.            4.1   Responsibility for Development of Mir-21 Products.  Notwithstanding   Sections 3.1, 3.2, 3.6.2 and 3.9 of the Agreement to the contrary, from and after the First   Amendment Date, and except for Regulus’ obligations under Paragraph 5 of this First Amendment,   Sanofi shall solely control and be solely responsible for all further Development of Mir-21   Compounds, Mir-21 Products and Companion Diagnostics for use with Mir-21 Products,                                                   ***Confidential Treatment Requested                                          3     

 

     at Sanofi’s sole expense.  Without limiting the generality of the foregoing, Sanofi shall be solely   responsible for conducting (a) the HERA Study in accordance with the HERA Study Protocol, or  (b) if for any reason Sanofi does not enroll, continue and conduct the HERA Study, another  Phase 2 Trial of the Mir-21 Product RG-012 designed to demonstrate clinical proof of concept in   subjects with Alport syndrome (an “Other Fibrosis POC Study”).  Regulus acknowledges that  Sanofi intends, and has the right, to amend the HERA Protocol in Sanofi’s sole discretion.   Notwithstanding Section 3.5 or any other provision of the Agreement to the contrary, the JSC  shall cease to have any decision-making authority with respect to the Mir-21 POC Programs or  any Mir-21 Compound or Mir-21 Product and shall not have any decision-making authority with  respect to the Sanofi Mir-21 Fibrosis POC Program.  For clarity, Regulus shall have no further  right or obligation to conduct the Mir-21 POC Programs except as necessary to fulfill its  transition obligations under Paragraph 5 of this First Amendment.          4.2   Exclusivity.  Solely with respect to Mir-21, all references to the “POC Program  Term” in Section 2.5.2 of the Agreement shall be deemed to refer to the Sanofi Mir-21 Fibrosis  POC Program Term and all references to the “POC Program Product” shall be deemed to refer to  the Mir-21 Product RG-012 in Alport syndrome.           4.3   Early Termination of Sanofi Mir-21 Fibrosis POC Program.  Sections 3.4.1,  3.4.2, 3.4.3 and 3.4.4 of the Agreement shall not apply to the Mir-21 POC Programs.  Sanofi will  have the right to terminate the Sanofi Mir-21 Fibrosis POC Program upon written notice to  Regulus if Sanofi determines in good faith that, further pursuit of the Sanofi Mir-21 Fibrosis  POC Program would be scientifically, clinically or commercially unwarranted (e.g., due to target  validation issues, delivery issues, potency issues or safety issues).  Any such notice by Sanofi to  Regulus shall include a brief explanation of Sanofi’s grounds for determining that further pursuit  of the Sanofi Mir-21 Fibrosis POC Program is scientifically, clinically or commercially  unwarranted.         4.4   Commercialization and Regulatory Responsibilities for Mir-21 Products.                 (a)   Section 5.1 of the Agreement shall not apply to Mir-21, Mir-21  Compounds or Mir-21 Products, and, in lieu thereof, the Parties agree as follows: Sanofi will  have sole responsibility, including without limitation sole responsibility for all funding,  resourcing and decision-making, for all Development and Commercialization with respect to  Mir-21 Compounds, Mir-21 Products and Companion Diagnostics for use with Mir-21 Products,  and, subject to Regulus’ compliance with its obligations under Paragraph 5.2 of this First  Amendment, Sanofi hereby assumes all regulatory responsibilities as of the Technology Transfer  and Stand-by Letter Date in connection with Mir-21 Compounds and Mir-21 Products, including  sole responsibility for all Regulatory Documentation and for obtaining all Approvals. Sanofi will  comply with all Applicable Laws in connection with the Development and Commercialization of  Mir-21 Compounds and Mir-21 Products.  Sanofi (by itself or through its Affiliates,  sublicensees, (sub)contractors or agents, as applicable) will use Commercially Reasonable  Efforts to continue and conduct the HERA Study or to initiate and conduct an Other Fibrosis  POC Study as soon as practicable following the First Amendment Date, and, subject to Sanofi’s  termination rights under Paragraph 4.3 of this First Amendment, Sanofi agrees to use  Commercially Reasonable Efforts to perform the HERA Study or such Other Fibrosis POC  Study until the earlier of (i) Interim Analysis (as such term is defined in the then current                                          4     

 

     Development Plan) if, based on such Interim Analysis, either (A) the HERA Study or such Other   Fibrosis POC Study is unblinded and patients in such study are rolled over into an open-label   extension of such study, or (B) the HERA Study or such Other Fibrosis POC Study is terminated,   or (ii) completion of the HERA Study or such Other Fibrosis POC Study (in either case ((i) or (ii)),   the “Study End Date”); and, in either case, deliver top-line results thereof to Regulus within   [...***...] days after the first availability thereof (Sanofi’s obligations under this sentence, the   “Sanofi Mir-21 Fibrosis POC Program Diligence Obligations”).  For the period beginning on the   First Amendment Date and ending on the IND Transfer Date, Regulus will be responsible for   responding to any requests from Regulatory Authorities regarding the Mir-21 Products, provided   however, that Sanofi shall have a reasonable period to review and comment on any correspondence   or other information in response to such request and Regulus will incorporate any reasonable   comments thereon that are timely received.  From and after the IND Transfer Date, Sanofi will be   solely responsible for making all IND filings for Mir-21 Products and will own all INDs, NDAs,   MAAs and other Regulatory Documentation for Mir-21 Products.                  (b)   Section 5.2 of the Agreement shall apply to Mir-21 Compounds and Mir-21   Products only until such time as Sanofi has delivered to Regulus top-line results from the HERA   Study or Other Fibrosis POC Study, except that Sanofi shall have no obligation to consider   Regulus’ input regarding Sanofi’s activities with respect to Mir-21 Compounds and Mir-21   Products.                 (c)   Section 5.3 of the Agreement shall not apply to Mir-21 Compounds and   Mir-21 Products.    5.    MIR-21 FIBROSIS POC PROGRAM TECHNOLOGY TRANSFER.           5.1   Assignment of Mir-21 Product Specific Patents.  Regulus hereby assigns to   Sanofi all Regulus’s rights, title and interests in and to all Mir-21 Product Specific Patents and  Sanofi hereby accepts such assignment.  Promptly upon request by Sanofi, Regulus shall execute  and deliver such assignments and other documents as may reasonably be required or requested by  Sanofi to vest all rights, title and interests in and to the Mir-21 Product Specific Patents in Sanofi,  including executing further assignments, consents, releases and other commercially reasonable  documentation and providing good faith testimony by affidavit, declaration, in-person or other  proper means in support of any effort by Sanofi to establish, perfect, enforce or defend its rights in  any Mir-21 Product Specific Patents through prosecution of governmental filings, regulatory  proceedings, litigation and other means, including through the prosecution, maintenance,  enforcement and defense of the Mir-21 Product Patents.  Sanofi shall be responsible for preparing  all such assignment and other documents and for recording the assignment to Sanofi of the Mir-21  Product Specific Patents with the relevant patent offices, at Sanofi’s sole expense.  From and after  the First Amendment Date, Sanofi shall be solely responsible for the prosecution, maintenance,  enforcement and defense of the Mir-21 Product Specific Patents (together with any and all Patents  corresponding to the Mir-21 Product Specific Patents that may be filed or issued after the First  Amendment Date), throughout the world, at Sanofi’s sole expense and discretion, and  notwithstanding anything to the contrary set forth in the Agreement, ARTICLE 8 of the Agreement  shall not apply to any Mir-21 Product Specific Patent.                                                    ***Confidential Treatment Requested                                          5     

 

           5.2   Transfer of Mir-21 Product Regulatory Materials.  Within [...***...] days  after the First Amendment Date, Regulus shall provide to Sanofi all existing Regulatory  Documentation for any Mir-21 Product, including, without limitation, [...***...] (the “RG-012   IND”) and all related correspondence with any Regulatory Authorities (collectively, the   “RG-012 Regulatory Materials”).  Regulus will have the right to retain copies of the RG-012   Regulatory Materials for record retention purposes or as required by Applicable Laws.  Regulus   hereby assigns the RG-012 Regulatory Materials, including the RG-012 IND, to Sanofi effective   as of the IND Transfer Date (defined below).  Within [...***...] ([...***...]) Business Days   after the later of the Paragraph 5.3 Confirmation Date and the Paragraph 5.5 Confirmation Date   (as such terms are defined in Paragraph 2.15 of this First Amendment), (a) Regulus shall submit   to the FDA a letter transferring sponsorship of the RG-012 IND to Sanofi in the form attached   hereto as Exhibit A, and (b) Sanofi shall submit to the FDA a letter accepting transfer of   sponsorship of the RG-012 IND from Regulus in the form attached hereto as Exhibit B.  Each   Party shall notify the other Party concurrently with its submission of such letter to the FDA, such   notice to include a copy of such letter.  The date on which Sanofi receives written notice from   the FDA that the FDA accepts the effectiveness of the transfer shall be the “IND Transfer   Date.”  From and after the IND Transfer Date, Sanofi shall assume all regulatory obligations   associated with being the sponsor of the RG-012 IND, including all periodic reporting   obligations, and Regulus shall no longer have any regulatory obligations for the Mir-21 Product   RG-012 (including maintenance of any regulatory approvals or any ongoing requirements in   connection therewith).  In addition to the RG-012 IND, upon Sanofi’s request, Regulus shall   transfer ownership of any RG-012 Regulatory Materials, including but not limited to the items   listed on Schedule 10.2(a).          5.3   Mir-21 Fibrosis POC Program Information.  Within [...***...] days after the   First Amendment Date, Regulus shall provide to Sanofi all items listed in Schedule 5.3 related to   the Mir-21 Fibrosis POC Program and all items described in the second sentence of   Section 10.2(h) related to the Mir-21 Fibrosis POC Program (in each case, to the extent not   previously provided) in the format specified in Schedule 5.3.  For any items for which a format is   not specified in Schedule 5.3, Regulus may provide such items in the format in which such items   exist in Regulus’ possession.  If Sanofi wishes to have any such item converted to a different   format, Sanofi may, by written notice to Regulus, direct that Regulus deliver such item in its   existing format to a Third Party vendor designated by Sanofi for conversion into Sanofi’s desired   format, at Sanofi’s sole expense, and upon Regulus’ delivery of such item to such Third Party   vendor in accordance with Sanofi’s instructions, Regulus will be deemed to have provided such   item to Sanofi.  No later than [...***...] days after the date on which Regulus notifies Sanofi in   writing that it has delivered to Sanofi all such items in accordance with Schedule 5.3, Sanofi shall   (a) notify Regulus of any items it believes are incomplete or missing or (b) confirm that Regulus   has satisfied its obligations under this Paragraph 5.3.  The Technology Transfer and Stand-by   Letter Date will not be deemed to have occurred until Regulus provides to Sanofi all items listed in   Schedule 5.3 and Sanofi confirms to Regulus that it has received and accepted all such items.  If,   after the Technology Transfer and Stand-by Letter Date, Sanofi is required to provide any   Regulatory Authority any data, results or other information related to the Mir-21 Fibrosis POC   Program that was generated by or on behalf of Regulus prior to the Technology Transfer and   Stand-by Letter Date but was not previously transferred to Sanofi pursuant to this Paragraph 5.3,   then, promptly upon Sanofi’s written request, Regulus shall locate the requested data, results or   other information and provide the same to Sanofi.  For clarity, Regulus shall not be obligated to                                                   ***Confidential Treatment Requested                                          6     

 

     generate any new data, results or other information not already in existence, even if any   Regulatory Authority may request such from Sanofi.          5.4   Assignment of Max-Planck Agreement and Wurzburg Agreement.  Subject to   the provisions of this Paragraph 5.4, Regulus will assign to Sanofi, and Sanofi will assume,   (a) the Max-Planck Agreement, including all of Regulus’ rights and obligations thereunder (to   the extent that such obligations arose on or after the First Amendment Date), such assignment   subject to and effective upon Regulus obtaining any required consent of Max-Planck to such   assignment and assumption (the “Max-Planck Consent”) and (b) the Wurzburg Agreement,   including all of Regulus’ rights and obligations thereunder (to the extent that such obligations   arose on or after the First Amendment Date), such assignment subject to and effective upon   Regulus obtaining any required consent of Wurzburg to such assignment and assumption (the   “Wurzburg Consent”).  Regulus shall use commercially reasonable efforts to obtain the Max-  Planck Consent and the Wurzburg Consent as promptly as practicable after the First Amendment   Date.  If Regulus is unable to obtain the Max-Planck Consent and/or the Wurzburg Consent  within [...***...] days after the First Amendment Date, then the Max-Planck Agreement and/or   the Wurzburg Agreement (as applicable) shall not be assigned to or assumed by Sanofi, and the   Max-Planck Agreement and/or the Wurzburg Agreement (as applicable) shall continue to be an   Existing Regulus Agreement for purposes of the Amended Agreement and all payments due   thereunder will be subject to the terms of Paragraph 6.4 of this First Amendment.            5.5   Transfer of Mir-21 Fibrosis POC Program-Specific Materials.  Within   [...***...] days after the First Amendment Date, and subject to the prior execution by the Parties   of a separate agreement governing the quality of the Mir 21 Fibrosis POC Program-specific  materials identified in Schedule 5.5 (the “Quality Agreement”) Regulus shall transfer and assign  or cause to be transferred and assigned to Sanofi such Mir 21 Fibrosis POC Program-specific  materials in a format reasonably acceptable to Sanofi.  The transfer and assignment shall be  memorialized in a material assignment and assumption agreement to be entered into by the Parties  (or in Sanofi’s case by an Affiliate of Sanofi), (the “Material Assignment and Assumption  Agreement”). The Material Assignment Agreement shall contain provisions standard to such  agreements in the pharmaceutical industry, including any provisions necessary for Sanofi to verify  the chain of title of the materials to be transferred and that such materials comply with the Quality  Agreement, cGMP and all other applicable statutory and regulatory requirements.  No later than  [...***...] days after the date on which Regulus notifies Sanofi in writing that it has delivered to  Sanofi all such items in accordance with Schedule 5.5, Sanofi shall (a) notify Regulus of any items  it believes are incomplete or missing or (b) confirm that Regulus has satisfied its obligations under  this Paragraph 5.5.  The Technology Transfer and Stand-by Letter Date will not be deemed to have   occurred until Regulus provides to Sanofi all items listed in Schedule 5.5 and Sanofi confirms to   Regulus that it has received and accepted all such items.  Sanofi shall pay Regulus the   corresponding transfer price listed on Schedule 5.5 for such materials, which amount is equal to  Regulus’ out of pocket costs actually incurred for such materials, plus shipping, handling and  insurance and any applicable sales, excise and other taxes (including VAT or its equivalent),  customs duties and similar governmental charges imposed with respect to the importation, transfer,  use or sale of such materials, all of which shall be the sole responsibility of Sanofi.  Sanofi shall  make payment of the transfer price of such materials, plus shipping, handling, insurance and  applicable taxes, duties and charges, within [...***...] days after receipt of invoice therefor from  Regulus (with reasonable supporting documentation of such out of pocket costs),                                                  ***Confidential Treatment Requested                                          7     

 

     and Regulus may send such invoice any time after Sanofi’s receipt of such materials, or in the   case of any materials listed on Schedule 5.5 which Sanofi does not want to be delivered, Regulus   may send such invoice anytime after execution and delivery by Regulus of the Material   Assignment and Assumption Agreement.          5.6   Access to Regulus Service Providers for Mir-21 POC Programs.  Attached   hereto as Schedule 5.6 is a list of all Third Party service providers with which Regulus has   contracted for development, manufacturing or other services supporting the Mir-21 POC  Programs, Mir-21 Compounds or Mir-21 Products during the 12-month period preceding the  First Amendment Date (“Mir-21 Service Providers”).  Promptly upon written request by Sanofi,  Regulus shall deliver to any Mir-21 Service Provider specified by Sanofi written authorization to  (a) disclose to Sanofi all information specific to the Mir-21 POC Programs, Mir-21 Products and  Mir-21 Compounds generated by such Mir-21 Service Provider on behalf of Regulus that is  within the possession or control of such Mir-21 Service Provider and (b) contract with Sanofi for  the provision of services related to the Mir-21 POC Programs, Mir-21 Products and Mir-21  Compounds.         5.7   Assignment of Domain Name.  As of the First Amendment Date, Regulus  hereby assigns to Sanofi the domain name [...***...]. Promptly following any request therefor  by Sanofi, Regulus shall execute and deliver to Sanofi any assignment or other documents as  may reasonably be required or requested by Sanofi, and carry out all necessary formalities, with  regard to the implementation of such transfer of ownership of such domain name to Sanofi in the  appropriate registries, including providing any authorization codes necessary to make such  transfer effective.  Sanofi shall be responsible for preparing all such assignment or other  documents and for recording the assignment of such domain name, at Sanofi’s sole expense.           5.8   Technical Assistance.  At Sanofi’s request from time to time beginning on the  First Amendment Date and ending [...***...] months after the Technology Transfer and Stand- by Letter Date (the “Technical Assistance Period”), Regulus shall provide reasonable technical  assistance to Sanofi related to the Mir-21 Fibrosis POC Program and the information and  materials transferred to Sanofi pursuant to the preceding provisions of this Paragraph 5.  Sanofi  shall compensate Regulus for such technical assistance at the FTE-Day Rate and shall reimburse  Regulus for out-of-pocket costs (including, without limitation, travel and lodging costs) incurred  by Regulus personnel in providing such assistance; provided, however, that (a) the first  [...***...] hours of such technical assistance shall be provided free of charge (other than  reimbursement of out-of-pocket costs), and (b) “technical assistance” as used in this  Paragraph 5.8 does not include the work required by Regulus to fulfill its obligations under the  other sections of this Paragraph 5.  Regulus will invoice Sanofi on a monthly basis for such  assistance provided and reimbursable costs incurred pursuant to this Paragraph 5.8 (along with  reasonable supporting documentation of such out-of-pocket costs), and Sanofi shall pay all  amounts (except to the extent disputed in good faith) set forth in any such invoice within  [...***...] days of receipt thereof.  After the Technical Assistance Period, Regulus may provide  additional technical assistance as described above in this Paragraph 5.8 upon Sanofi’s reasonable  request, subject to compensation by Sanofi at the FTE-Day Rate and reimbursement by Sanofi of  Regulus’ out-of-pocket costs (including, without limitation, travel and lodging costs) incurred in                                                 ***Confidential Treatment Requested                                          8     

 

     providing such assistance.  Regulus shall act reasonably in considering any request by Sanofi for   such assistance after expiration of the Technical Assistance Period.            5.9   Assignment of Mir-21 Contracts.                  (a)   At Sanofi’s request, Regulus shall take all actions required to either   terminate, or assign to Sanofi, any Contract to which Regulus is a party or to which Regulus or  any of its assets or properties is bound, in each case, relating solely to the Mir-21 POC Programs  or any Mir-21 Compounds and Mir-21 Products (the “Mir-21 Contracts”); provided, however,  that the defined term “Mir-21 Contracts” shall exclude the Max Planck Agreement and the  Wurzburg Agreement (which agreements will be addressed pursuant to Paragraph 5.4 of this  First Amendment).  In addition, Sanofi may request the termination or assignment of any work  orders that are not under Mir-21 Contracts, but that relate solely to the Mir-21 POC Programs or  any Mir-21 Compounds and Mir-21 Products (“Mir-21 Work Orders”), and Regulus shall take  all actions required to assign any such Mir-21 Work Orders to Sanofi.  Regulus shall use its best  efforts to facilitate any negotiations with the counterparties to such Mir-21 Contracts or Mir-21   Work Orders, in each case, to the extent related to any such assignment, provided that the   foregoing shall not be construed to require Regulus to pay to such counterparties any   consideration to the extent related to such assignment that is not otherwise payable by Regulus.               (b)   Sanofi hereby assumes all obligations of Regulus under any Mir-21  Contract assigned to Sanofi (each, an “Assigned Mir-21 Contract”) that arise after the date of  assignment of such Assigned Mir-21 Contract, and Regulus shall remain responsible for all  obligations arising under such Assigned Mir-21 Contract through the date of assignment.  If  Sanofi receives any invoice from the counterparty to any Assigned Mir-21 Contract for any  amount that became due or includes obligations that accrued under such Assigned Mir-21  Contract on or before the date of assignment, then Sanofi shall promptly provide a copy of such  invoice to Regulus, and at Sanofi’s discretion, either (i) Regulus shall pay such invoiced amount  to such counterparty on or before the due date for payment of such invoice, or (ii) Sanofi can pay  the invoiced amount to such counterparty, and in such case, Regulus shall reimburse Sanofi for  such amount or the allocated amount of such invoice for which Regulus is responsible within  [...***...] days after receipt of an invoice from Sanofi for such amount, provided that if Regulus  fails to timely pay or reimburse such amount, then Sanofi may off-set such amount against any  of its payment obligations due under Paragraphs 6.1 and 6.2 of this First Amendment.  Any  invoice from the counterparty to any Assigned Mir-21 Contract that includes obligations accrued  before and after the date of assignment shall be allocated between Sanofi and Regulus and paid  as provided above.  If Regulus receives any invoice from the counterparty to any Assigned  Mir-21 Contract for any amount that became due under such Assigned Mir-21 Contract after the  date of assignment, then Regulus shall promptly provide a copy of such invoice to Sanofi with  payment of any amounts listed in such invoice that accrued prior to the date of such assignment,  and then Sanofi shall be responsible for paying such invoice.           5.10  Closing Certain Clinical Trial Sites.  Promptly after the First Amendment Date,  Regulus will close, or cause its Third Party vendors to close, the Clinical Trial Sites (to the  extent relating to the Mir-21 POC Programs) listed on Schedule 5.10 accordance with all  Applicable Laws.                                                   ***Confidential Treatment Requested                                          9     

 

             5.11  Pharmacovigilence; Safety Database.  As soon as reasonably practicable after    the First Amendment Date, the Parties shall enter into an SDEA (as defined in the Agreement)    substantially in the form as attached hereto as Exhibit C.             5.12  Further Actions.  Notwithstanding anything to the contrary contained herein, for    the 24-month period beginning on the Technology Transfer and Stand-by Letter Date, if Sanofi   discovers Regulus has either provided incorrect, inaccurate or incomplete information required to   be provided under this Article 5, or otherwise failed to perform its duties under this Article 5,   then upon written notice by Sanofi to Regulus, Regulus shall correct any such incorrect,   inaccurate or incomplete information, and cure any failure to perform.      6.    FINANCIAL PROVISIONS.             6.1   Upfront Payment.  In partial consideration for the grant of the Mir-21 License   and the assignments, transfers and other undertakings of Regulus under Paragraph 5 of this First    Amendment, Sanofi shall pay to Regulus an irrevocable, non-refundable upfront fee of    $5 million as follows:                  (a)   $[...***...]  within [...***...] ([...***...]) days following receipt of an   invoice of such amount, which invoice may be sent anytime on or after the First Amendment   Date; and                (b)   $[...***...]   within [...***...] ([...***...]) days following receipt of an   invoice of such amount, which invoice may be sent anytime on or after the Technology Transfer   and Stand-by Letter Date.           6.2   Milestone Payments for Sanofi Mir-21 Fibrosis POC Program.  Sanofi shall   give Regulus written notice of the first achievement (by Sanofi, its sublicensees or their   respective Affiliates) of each of the milestone events set forth below within [...***...] Business   Days after such achievement.  After receiving such written notice of the achievement of any such   milestone event, Regulus shall submit an invoice to Sanofi for the amount of the milestone   payment corresponding to the applicable milestone event set forth below, and Sanofi will pay   Regulus such milestone payment amount within [...***...] days after receipt of such invoice.    Each of the milestone payments set forth below in this Paragraph 6.2 shall be payable only one   time, and only for the first achievement of the applicable milestone event.   Milestone Event                                          Milestone Payment   [...***...] (the “First Milestone Event”)                        $[...***...]   [...***...]* (as applicable, the “Second Milestone Event”)       $[...***...]                           *  If this milestone event is not achieved, but [...***...]                                                     ***Confidential Treatment Requested                                           10      

 

        [...***...], the milestone payment corresponding to this milestone event shall be payable to      Regulus upon [...***...] (as defined in the Agreement) for the Mir-21 Product RG-012,      notwithstanding the non-achievement of such milestone event.  For clarity, if this milestone      event is achieved, then the corresponding milestone event shall be payable to Regulus      regardless of whether or not Sanofi continues the Development of the Mir-21 Product RG-012.          6.3   Applicability of Selected Financial Provisions of Agreement.                  (a)   Sections 6.5, 6.6, 6.7, 6.8.3, 6.9.1, 6.9.2 and 6.14 of the Agreement shall be   inapplicable to the Mir-21 POC Programs, Sanofi Mir-21 Fibrosis POC Program, Mir-21   Compounds and Mir-21 Products.                  (b)   Sections 6.8.1 and 6.9.3 of the Agreement are hereby terminated and of no   further force or effect.                  (c)   Sections 6.15, 6.16, 6.18 and 6.20 of the Agreement shall apply to Mir-21   Products solely to the extent such Mir-21 Products are subject to In-License Royalties, In-License  Milestones and Other In-License Payments under any Existing Regulus Agreement that is not  assigned to Sanofi pursuant to Paragraph 5.4 of this First Amendment.                 (d)   Section 6.17 of the Agreement shall apply to all payments due to Regulus  under this Paragraph 6, provided that Sanofi shall pay the amounts set forth in Paragraph 6.1(a) and  Paragraph 6.1(b) of this First Amendment within [...***...] ([...***...]) days of receipt of the  applicable invoice instead of [...***...] ([...***...]) days as set forth in Section 6.17 of the  Agreement.               (e)   Section 6.21 of the Agreement shall apply to all payments due to Regulus  under this Paragraph 6 that are not paid when due under this First Amendment.               (f)   Section 6.22 of the Agreement shall not apply to any amounts payable by  Sanofi to either of the Founding Companies with respect to any Mir-21 Product.         6.4   Existing Regulus Agreements.                 (a)   Notwithstanding Section 6.10.1 of the Agreement to the contrary, from and  after the First Amendment Date, Sanofi shall be responsible for paying 100% of the In-License  Royalties, In-License Milestones and Other In-License Payments that become due to the  Licensor(s) under the Existing Regulus Agreements (the “Existing Third Party Licensors”) as a  result of the Development or Commercialization of Mir-21 Products by Sanofi or any of its  Affiliates or sublicensees to the extent that such Mir-21 Products are covered by the applicable  Third Party Patents, regardless of whether any such Existing Regulus Agreement is assigned to  Sanofi pursuant to Paragraph 5.4 of this First Amendment or Sanofi enters into a Stand-by License  Agreement with the applicable Existing Third Party Licensor.  With respect to each Existing  Regulus Agreement that is assigned to Sanofi pursuant to Paragraph 5.4 of this First Amendment  or with respect to which Sanofi enters into a Stand-by License Agreement with the applicable  Existing Third Party Licensor, Sanofi shall be solely and directly responsible and liable to the  applicable Existing Third Party Licensor for payment of, and will pay directly to such applicable  Existing Third Party Licensor, all such In-License Royalties, In-License                                                 ***Confidential Treatment Requested                                          11     

 

   Milestones and Other In-License Payments that become due to such Existing Third Party  Licensor under such Existing Regulus Agreement as a result of the Development or  Commercialization of Mir-21 Products by Sanofi or any of its Affiliates or sublicensees.  With  respect to each Existing Regulus Agreement that neither is assigned to Sanofi pursuant to  Paragraph 5.4 of this First Amendment nor is the subject of a Stand-by License Agreement  entered into by Sanofi with the applicable Existing Third Party Licensor, Sanofi shall:                      (i)   notify Regulus in writing of the achievement of any milestone  event listed on Schedule 10.2(j), by a Mir-21 Product with respect to which an In-License  Milestone is due under such Existing Regulus Agreement within [...***...] days after the  achievement thereof;                      (ii)  deliver to Regulus at least [...***...] days before the end of each  Calendar Quarter Sanofi’s good faith forecast of Net Sales (as defined in such Existing Regulus  Agreement) of Mir-21 Products that are subject to In-License Royalty payment obligations under  such Existing Regulus Agreement and the amount of In-License Royalties that would be due  with respect to such estimated Net Sales;                      (iii) deliver to Regulus within [...***...] days after the end of each  Calendar Quarter a report of actual Net Sales (as defined in such Existing Regulus Agreement)  of Mir-21 Products that are subject to In-License Royalty payment obligations under such  Existing Regulus Agreement and the amount of In-License Royalties that would be due with  respect to such actual Net Sales; and                      (iv)  pay to Regulus or, at Sanofi’s election, directly to such Existing  Third Party Licensor and notify Regulus that it has made such direct payment, the applicable In- License Milestones and estimated In-License Royalties (as described in Paragraph 6.4(a)(ii) of  this First Amendment) due under such Existing Regulus Agreement within [...***...]  ([...***...]) days after receipt of invoice from Regulus therefor.  In the event that actual  In-License Royalties (as described in Paragraph 6.4(a)(iii) of this First Amendment) due under  such Existing Regulus Agreement for any Calendar Quarter exceed the estimated In-License  Royalties under such Existing Regulus Agreement for such Calendar Quarter, Regulus will add  the amount of such excess to the invoice issued by Regulus to Sanofi for estimated In-License  Royalties due under such Existing Regulus Agreement for the following Calendar Quarter, and  in the event that the estimated In-License Royalties under such Existing Regulus Agreement for  any Calendar Quarter exceed the actual In-License Royalties due under such Existing Regulus  Agreement for such Calendar Quarter, Regulus shall reflect a credit for the amount of such  excess in the invoice for the estimated In-License Royalties due under such Existing Regulus  Agreement for the following Calendar Quarter.               (b)   With respect to the Founding Company License Agreement, as amended  to date (which will not be assigned to Sanofi), the Parties shall execute a side letter agreement  with the Founding Companies in substantially the form attached hereto as Exhibit D-1 (the  “Founding Company Stand-by License Agreement”).  With respect to any other Existing  Regulus Agreement that is not assigned to Sanofi pursuant to this First Amendment, the Parties  shall execute side letter agreements with the applicable Existing Third Party Licensor(s) in                                                 ***Confidential Treatment Requested                                         12    

 

     substantially the form attached hereto as Exhibit D-2 (together with the Founding Company  Stand-by License Agreement, each, a “Stand-by License Agreement”).         6.5   Future Third Party Agreements.  Notwithstanding Section 6.11 of the  Agreement to the contrary, Sanofi shall be solely responsible for in-licensing or acquiring rights  to any Patent that: (a) is not Controlled by either Party; (b) covers (i) a Target Invention with  respect to Mir-21, (ii) a Compound Invention with respect to any Mir-21 Compound, (iii) a  Method Invention with respect to any Mir-21 Compound or (iv) a Formulation Invention with  respect to any Mir-21 Compound; and (c) Sanofi determines in its sole discretion is, or is likely  to be, necessary for the Development or Commercialization of any Mir-21  Product.   Section 6.11.3 of the Agreement shall not apply to any Future Sanofi Agreement.   Notwithstanding Section 6.12 of the Agreement to the contrary, In-License Royalties, In-License  Milestones and Other In-License Payments payable to Licensors under any Future Sanofi  Agreement with respect to Mir-21 Products shall be allocated 100% to Sanofi, and Sanofi shall  not have the right to reduce any amounts payable to Regulus under the Amended Agreement by  reason of any such In-License Royalties, In-License Milestones and Other In-License Payments.   Regulus shall have no obligation or liability whatsoever with respect to any such In-License  Royalties, In-License Milestones or Other In-License Payments.          6.6   Interest.  Section 6.21 of the Agreement shall apply to any invoiced amount  (except to the extent disputed in good faith) under Paragraph 5 of this First Amendment and any  payment under this Paragraph 6 that is not paid when due (except to the extent disputed in good  faith).     7.    TERMINATION OF MIR-21 LICENSE.            7.1   Termination for Breach of Sanofi Mir-21 Fibrosis POC Program Diligence   Obligations.  Section 9.4.1 of the Agreement is hereby terminated and shall be of no further   force or effect.      8.    REGULUS DEBT.           8.1    Oxford Loan.  Notwithstanding anything herein or in the Agreement to the   contrary, Sanofi hereby acknowledges that: (a) pursuant to the Oxford Credit Agreement,   Regulus has granted to the Collateral Agent, for the benefit of the Lenders (as such terms are   defined in the Oxford Credit Agreement), a first priority security interest in substantially all of   Regulus’ assets, including the Agreement and all proceeds thereof; and (b) pursuant to the   Oxford Consent, the Secured Parties (as defined in the Oxford Consent) have consented to this   First Amendment and to the transfer of the Mir-21 Assigned Assets (as defined in the Oxford  Consent) to Sanofi free and clear of the Secured Parties’ Liens (as defined in the Oxford Credit  Agreement), provided that the Secured Parties will continue to have liens on all proceeds of, and  consideration for, this First Amendment and the transfer of the Mir-21 Assigned Assets that is  received or due to Regulus under the Amended Agreement.  Sanofi hereby acknowledges the  Secured Parties’ liens on the Amended Agreement and the proceeds thereof and the  enforceability of such liens in accordance with Section 9-408 of the Uniform Commercial Code.                                          13     

 

           8.2   Amendment of Section 13.1(c) of Agreement.  Section 13.1(c) of the Agreement   is hereby amended and restated to read in its entirety as follows: “Regulus may assign or transfer   its rights under Article 6 (but no liabilities) to a Third Party in connection with a royalty   factoring transaction or upon a default under a secured loan facility under which Regulus is a   borrower to the lenders or collateral agent under such loan facility.”    9.    WAIVER AND RELEASE.            9.1   Sanofi Waiver and Release.  Sanofi, on behalf of itself and its Affiliates and   their respective directors, officers, stockholders, employees and agents (collectively, the “Sanofi   Parties”) and its and their respective successors and assigns, hereby irrevocably releases,   remises, and forever discharges the Regulus Parties (as defined below) of and from (and   covenants not to sue the Regulus Parties for) any and all debts, demands, actions, causes of   action, suits, accounts, covenants, contracts, agreements, claims, controversies, disputes,   obligations, judgments, rights, damages, costs, losses, expenses (including attorneys’ fees), liens,   or liabilities of any and every nature whatsoever, both at law or in equity, whether known or   unknown, fixed or contingent, that arose at any time prior to the First Amendment Date, or that   hereafter could arise based on any act, fact, transaction, cause, matter, or thing that occurred   prior to the First Amendment Date, related to the Regulus Parties; provided, however, that the   foregoing release shall not release the Regulus Parties from their obligations under the Amended   Agreement or any other agreement and document executed pursuant to or in connection with the   Amended Agreement.  Sanofi, on behalf of itself and the Sanofi Parties, hereby waives, and   Sanofi and the Sanofi Parties shall be deemed to have waived, the benefits of: (i) Section 1542 of   the Civil Code of the State of California, which provides as follows: “A general release does not   extend to claims that the creditor does not know or suspect to exist in his or her favor at the time   of executing the release and that if known by him or her must have materially affected his or her   settlement with the debtor”; and (ii) any law or common law principle of similar effect in any   other jurisdiction.          9.2   Regulus Waiver and Release.  Regulus, on behalf of itself and its Affiliates and   their respective directors, officers, stockholders, employees and agents (collectively, the   “Regulus Parties”) and its and their respective successors and assigns, hereby irrevocably   releases, remises, and forever discharges the Sanofi Parties of and from (and covenants not to sue   the Sanofi Parties for) any and all debts, demands, actions, causes of action, suits, accounts,   covenants, contracts, agreements, claims, controversies, disputes, obligations, judgments, rights,   damages, costs, losses, expenses (including attorneys’ fees), liens, or liabilities of any and every   nature whatsoever, both at law or in equity, whether known or unknown, fixed or contingent, that   arose at any time prior to the First Amendment Date, or that hereafter could arise based on any   act, fact, transaction, cause, matter, or thing that occurred prior to the First Amendment Date,   related to the Sanofi Parties; provided, however, that the foregoing release shall not release the   Sanofi Parties from their obligations under the Amended Agreement or any other agreement and   document executed pursuant to or in connection with the Amended Agreement.  Regulus, on   behalf of itself and the Regulus Parties, hereby waives, and Regulus and the Regulus Parties   shall be deemed to have waived, the benefits of: (i) Section 1542 of the Civil Code of the State of   California, which provides as follows: “A general release does not extend to claims that the  creditor does not know or suspect to exist in his or her favor at the time of executing the release                                         14     

 

     and that if known by him or her must have materially affected his or her settlement with the   debtor”; and (ii) any law or common law principle of similar effect in any other jurisdiction.    10.   MISCELLANEOUS.          10.1  Mutual Representations and Warranties.  Each Party hereby represents and   warrants to the other Party as of the First Amendment Date that:                (a)   it has the power and authority and the legal right to enter into this First  Amendment and perform its obligations hereunder, and that it has taken all necessary action on  its part required to authorize the execution and delivery of this First Amendment and the  performance of its obligations hereunder;               (b)   this First Amendment has been duly executed and delivered on behalf of  such Party and constitutes a legal, valid and binding obligation of such Party and is enforceable  against it in accordance with its terms subject to the effects of bankruptcy, insolvency or other  laws of general application affecting the enforcement of creditor rights and judicial principles  affecting the availability of specific performance and general principles of equity, whether  enforceability is considered a proceeding at law or equity;                (c)   with the exception of the Max-Planck Consent, the Wurzburg Consent and  any required consent to the assignment by Regulus to Sanofi of any other Mir-21 Fibrosis POC  Program contract listed in Schedule 10.1(c), all necessary consents, approvals and authorizations  of all Regulatory Authorities and other Third Parties required to be obtained by such Party in  connection with the execution and delivery of this First Amendment and the performance of its  obligations hereunder have been obtained, including, without limitation, the Oxford Consent; and                (d)   the execution and delivery of this First Amendment and the performance  of such Party’s obligations hereunder (i) do not conflict with or violate any requirement of  Applicable Law or any provision of the certificate of incorporation, bylaws or any similar  instrument of such Party, as applicable, in any material way, and (ii) do not conflict with, violate,  or breach or constitute a default or require any consent (other than the Wurzburg Consent) not  already obtained under, any Contract or court or administrative order by which such Party is  bound.          10.2  Representations of Regulus.  Regulus hereby represents and warrants to Sanofi  as of the First Amendment Date that:               (a)   Schedule 10.2(a) sets forth, as of the First Amendment Date, a list of all  INDs or other governmental registrations of Regulus or any of its Affiliates (and all applications  therefor) by or pending with the FDA relating Mir-21 Compounds, Mir-21 Products and  Companion Diagnostics for use with Mir-21 Products (such INDs and other governmental  registrations, the “Mir-21 INDs”).                 (b)   Regulus is the sole and exclusive owner of the Mir-21 INDs, all of which:  are held in the name of Regulus and are in good standing, subsisting, not abandoned and valid.   The execution, delivery and performance by Regulus of this Agreement, and the consummation                                         15     

 

     of the transactions contemplated hereby and the performance of the obligations hereunder, will   result in the transfer to Sanofi of all rights, title and interests in and to the Mir-21 INDs.                (c)   Neither Regulus, nor any of its officers, directors or employees (nor, to the   Knowledge of Regulus, any other Representatives of Regulus) have made a fraudulent statement   or knowingly made an untrue statement of material fact to the FDA or any other Governmental   Authority with respect to any Mir-21 Product or any Regulatory Documentation with respect to   any Mir-21 Product, or failed to disclose a material fact required to be disclosed to any   Governmental Authority, or committed an act, made a statement or failed to make a statement   that, at the time such disclosure was made, would reasonably be expected to provide a basis for   any investigation by, and no such investigation has been instituted or threatened by the FDA or   any other Governmental Authority with respect to any Mir-21 Product or any Regulatory   Documentation with respect to any Mir-21 Product.               (d)   Regulus has conducted the Mir-21 POC Programs in compliance in all  material respects with the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 301 et seq., and  applicable regulations promulgated thereunder by the FDA (collectively, “FDA Act”), and such  applicable United States Laws governing the development, manufacture and commercialization  of Mir-21 Compounds and Mir-21 Products.                (e)   All Mir-21 Compounds and Mir-21 Products have been and are being  developed, manufactured, tested, packaged, labeled and distributed by, or on behalf of, Regulus  in compliance in all material respects with applicable United States Laws, including the FDA  Act, including those FDA regulations relating to: (i) “good laboratory practices,” “good clinical  practices” and “good manufacturing practices,” each as defined under the FDA Act and  applicable United States Laws; (ii) FDA regulations for investigational drugs in the United  States; (iii) FDA regulations for the conduct of clinical studies of investigational new drugs and  the protection of human subjects participating in such clinical studies, including applicable Laws  pertaining to informed consent; (iv) FDA regulations for labeling of investigational new drugs in  the United States; (v) FDA regulations for record keeping with respect to investigational new  drugs in the United States; and (vi) filing of reports with the FDA with respect to investigational  new drugs.  For the avoidance of doubt, the words “by or on behalf of Regulus,” when used in  this Paragraph 10.2(e), shall not include any action taken by a Third Party unless that action is or  was taken with Regulus’ knowledge and at its express written direction.                (f)   Regulus has not received written notice of, and is not subject to, any  material adverse inspection, finding of non-compliance, compelled or voluntary recall,  investigation, penalty for corrective or remedial action or other compliance or enforcement  action, in each case relating to the Mir-21 POC Programs or any Mir-21 Compounds and Mir-21  Products or to the facilities of Regulus where the Mir-21 POC Programs or any development  activities with respect to Mir-21 Compounds and Mir-21 Products were conducted, by the FDA  or any other Governmental Authority.  There are no pending or threatened Legal Proceedings by  the FDA or any other Governmental Authority against Regulus relating to the Mir-21 POC  Programs or any Mir-21 Compounds and Mir-21 Products or to the facilities of Regulus where  the Mir-21 POC Programs or any development activities with respect to Mir-21 Compounds and  Mir-21 Products were conducted.                                         16     

 

                 (g)   Schedule 10.2(g) sets forth a list of all Third Parties contracted by  Regulus who have performed part, or all, of any pre-clinical studies, clinical studies,  manufacturing, release testing, packaging or storage services with respect to either any Mir-21  Compound or Mir-21 Product in connection with the Mir-21 Fibrosis POC Program (each a  “CRO”).  To the Knowledge of Regulus, (i) no CRO has received written notice of, and is not  subject to, any material adverse inspection, finding of non-compliance, compelled or voluntary  recall, investigation, penalty for corrective or remedial action or other compliance or  enforcement action, in each case, relating specifically to the Mir-21 Fibrosis POC Program or  any Mir-21 Compounds and Mir-21 Products developed by or on behalf of Regulus in  connection with the Mir-21 Fibrosis POC Program and (ii) there are no pending or threatened  Legal Proceedings by the FDA or any other Governmental Authority against any CRO relating to  the Mir-21 Fibrosis POC Program or any Mir-21 Compounds or Mir-21 Products developed by  or on behalf of Regulus in connection with the Mir-21 Fibrosis POC Program or to the facility of  CRO in which any such Mir-21 Compound or Mir-21 Product is manufactured, packaged or  stored.                (h)   Schedule 10.2(h) sets forth a list of all clinical trials and preclinical  studies conducted by or under the direction of Regulus related to the Mir-21 POC Programs or  any Mir-21 Compounds or Mir-21 Products.  Regulus shall make available to Sanofi true, correct  and complete materials relating to all such clinical trials and preclinical studies conducted in  connection with the Mir-21 Fibrosis POC Program that are in its possession and control pursuant  to the format and timelines set forth in Paragraph 5.3 and, upon Sanofi’s written request, will  make available to Sanofi true, correct and complete materials relating to any such listed study  conducted in connection with the Mir-21 Oncology POC Program that are in its possession and  control.                 (i)   Schedule 10.2(i) sets forth a list of all of the Mir-21 Contracts to be  assigned (specifically excluding the Existing Regulus Agreements) and Regulus’ good faith  current estimate of amounts due under any such Mir-21 Contracts to be assigned to Sanofi.                 (j)   Regulus has provided to Sanofi true, complete and unredacted copies of  the Founding Company License Agreement (including all amendments thereto), the Max Planck  Agreement and the Wurzburg Agreement, each as in effect as of the First Amendment Date.  The  financial terms set forth in the Max Planck Agreement and the Wurzburg Agreement constitute  the only financial obligations of Regulus to Max Planck and Wurzburg, respectively, with  respect to any Mir-21 Compound or Mir-21 Product, including the development or  commercialization thereof.  As of the Amendment Date, Schedule 10.2(j) sets forth all In- License Royalties, In-License Milestones and Other In-License Payments that could become due  to Existing Third Party Licensors, as a result of the Development or Commercialization of Mir  21 Products by Sanofi or any of its Affiliates or sublicensees.                 (k)   Schedule 10.2(k) sets forth a true and complete list of the Mir-21 Product  Specific Patents. Other than the Mir-21 Product Specific Patents, Regulus does not have any  ownership interest in any Product Specific Patents directed to Mir-21 or to any Mir-21  Compound or Mir-21 Product.                                          17     

 

                 (l)   Schedule 10.2(l) sets forth a true and complete list of the Regulus Core   Technology Patents.          10.3  Communication Plan.  Regulus and Sanofi shall mutually agree in good faith on  the form of any written communication to be sent to participating sites in the HERA Study, and  Regulus shall deliver such written communication to each such site promptly following Sanofi’s  request.         10.4  Press Release.  Regulus shall issue a press release announcing the execution of   this First Amendment in substantially the form attached hereto as Exhibit E.           10.5  Notices.  All notices and other communications to Regulus under Section 13.5 of   the Agreement shall be addressed as follows:                Regulus Therapeutics Inc.               10614 Science Center Drive                San Diego, California 92121                USA               Attention: Chief Scientific Officer               Facsimile: +1 (858) 202-6363                With a copy to:                Attention: General Counsel               Facsimile: +1 (858) 202-6363    or to such other address as Regulus may have furnished to Sanofi in writing in accordance with   Section 13.5 of the Agreement.          10.6  Effect of First Amendment.  Except as expressly amended by this First   Amendment, the Agreement shall remain in full force and effect in accordance with its terms.    That certain Letter Agreement between the Parties effective as of July 3, 2018, is hereby   terminated and shall be of no further force or effect.          10.7  Counterparts.  This First Amendment may be executed in two or more   counterparts, each of which will be deemed an original, and all of which together will constitute   one and the same instrument.                                 [Signature page follows.]                                           18     

 

             IN WITNESS WHEREOF,  the Parties hereto have caused this First Amendment to be    executed by their duly authorized representatives as of the First Amendment Date.   REGULUS THERAPEUTICS INC.              SANOFI    By:       /s/ Joseph P. Hagan          By:       /s/ Alban de La Sabliere    Name:      Joseph P. Hagan             Name:     Alban de La Sabliere      Title:       President & CEO           Title:    Global Head of BD&L                                                                                                    19      

 

SCHEDULES       Schedule 5.3       Mir-21 Fibrosis POC Program Information      Schedule 5.5       Mir-21 Fibrosis POC Program-Specific Materials      Schedule 5.6       Mir-21 Fibrosis POC Program Service Providers      Schedule 5.10      Clinical Trial Sites to be Closed      Schedule 10.1(c)   Consents      Schedule 10.2(a)   Mir-21 INDs      Schedule 10.2(g)   CROs      Schedule 10.2(h)   Clinical Trials and Preclinical Studies      Schedule 10.2(i)   Mir-21 Contracts      Schedule 10.2(j)   In-License Milestones and Other In-License Payments      Schedule 10.2(k)   Mir-21 Product Specific Patents      Schedule 10.2(l)   Regulus Core Technology Patents   EXHIBITS       Exhibit A          Form of RG-012 IND Sponsorship Transfer Letter      Exhibit B          Form of RG-012 IND Sponsorship Transfer Acceptance Letter      Exhibit C          Form of SDEA      Exhibit D-1        Form of Founding Company Stand-by License Agreement      Exhibit D-2        Form of Stand-by License Agreement      Exhibit E          Form of Press Release                                                                    20.    

 

                                SCHEDULE 5.3                       Mir 21 Fibrosis POC Program Information                                           FUNCTION      DELIVERABLES                SPECIFIC INFO           FORMAT                                            REQUIRED BY SUCH                                            DELIVERABLE  [...***...]       [...***...]                  [...***...]                      [...***...]       [...***...]                                               [...***...]       [...***...]                                               [...***...]       [...***...]                  [...***...]                                                                                                                                            Schedules Page 1 of 53                                               ***Confidential Treatment Requested  

 

                                         [...***...]                           [...***...]                                [...***...]                                    [...***...]                                                                                   Schedules Page 2 of 53                                               ***Confidential Treatment Requested  

 

                [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                                                     Schedules Page 3 of 53                                               ***Confidential Treatment Requested  

 

                [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                  [...***...]                                                            Schedules Page 4 of 53                                               ***Confidential Treatment Requested  

 

                                         [...***...]                           [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]                                   Schedules Page 5 of 53                                               ***Confidential Treatment Requested  

 

                                                                     [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                                                    [...***...]       [...***...]                                              [...***...]                                   Schedules Page 6 of 53                                               ***Confidential Treatment Requested  

 

                [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                                                    [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                                    [...***...]       [...***...]                                                                                     Schedules Page 7 of 53                                               ***Confidential Treatment Requested  

 

  [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                                                     Schedules Page 8 of 53                                               ***Confidential Treatment Requested  

 

                [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                                                    [...***...]       [...***...]                  [...***...]                                                            Schedules Page 9 of 53                                               ***Confidential Treatment Requested  

 

                                         [...***...]                           [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                                                     Schedules Page 10 of 53                                               ***Confidential Treatment Requested  

 

  [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]                                   Schedules Page 11 of 53                                               ***Confidential Treatment Requested  

 

                         [...***...]                                            Schedules Page 12 of 53                  ***Confidential Treatment Requested  

 

                                         [...***...]                           [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]                                   Schedules Page 13 of 53                                               ***Confidential Treatment Requested  

 

                [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                              [...***...]  [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                                                     Schedules Page 14 of 53                                               ***Confidential Treatment Requested  

 

                [...***...]                                                    [...***...]       [...***...]                  [...***...]                           [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                                                    [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]                                   Schedules Page 15 of 53                                               ***Confidential Treatment Requested  

 

                                         [...***...]                     [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]  [...***...]       [...***...]                  [...***...]                     [...***...]                                   Schedules Page 16 of 53                                               ***Confidential Treatment Requested  

 

                                         [...***...]                           [...***...]       [...***...]                  [...***...]                     [...***...]                                   Schedules Page 17 of 53                                               ***Confidential Treatment Requested  

 

                                  SCHEDULE 5.5                     Mir 21 Fibrosis POC Program-Specific Materials                 Quantity*      Book value                   Comments  [...***...]        [...***...]        [...***...]                      [...***...]  [...***...]        [...***...]        [...***...]                      [...***...]  [...***...]        [...***...]        [...***...]                      [...***...]  [...***...]        [...***...]        [...***...]                      [...***...]  [...***...]        [...***...]        [...***...]                      [...***...]  [...***...]        [...***...]        [...***...]                      [...***...]  [...***...]        [...***...]        [...***...]                      [...***...]                 [...***...]        [...***...]                        *Quantity listed does not include the stability samples, reference samples, and reference  standards (including the primary API standard), the ownership of each of which shall also be  transferred to Sanofi [[...***...]], even if Sanofi chooses that such samples remain in their  current location.                                                                          Schedules Page 18 of 53                                               ***Confidential Treatment Requested  

 

                                  SCHEDULE 5.6                     Mir 21 Fibrosis POC Program Service Providers  Manufacturing  [...***...]  [...***...]  [...***...]  [...***...]  Clinical Operations  [...***...]  [...***...]  [...***...]  [...***...]  [...***...]  [...***...]  [...***...]  [...***...]  [...***...]  [...***...]  Pre-Clinical  [...***...]  [...***...]  [...***...]  [...***...]  [...***...]  Regulatory  [...***...]                                                                          Schedules Page 19 of 53                                               ***Confidential Treatment Requested  

 

                                   SCHEDULE 5.10                             Clinical Trial Sites to be Closed  Protocol  #          Site #    PI Name           Site Name  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]                                  Schedules Page 20 of 53                                                ***Confidential Treatment Requested  

 

   [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]  [...***...]    [...***...]   [...***...]           [...***...]                                                                            Schedules Page 21 of 53                                                ***Confidential Treatment Requested  

 

                                SCHEDULE 10.1(c)                                     Consents  Vendors who require some form of consent to assign contract:   [[...***...]      [...***...]   [...***...]   [...***...]]                                                                           Schedules Page 22 of 53                                               ***Confidential Treatment Requested  

 

                                           SCHEDULE 10.2(a)                                 Mir 21 INDs                 IND and Orphan designations  [...***...]  [...***...]  [...***...]    Clinicaltrials.gov registrations  [...***...]  [...***...]  [...***...]    EudraCT registrations  [...***...]                                                                      Schedules Page 23 of 53                                             ***Confidential Treatment Requested  

 

                                SCHEDULE 10.2(g)                                      CROs  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]                                Schedules Page 24 of 53                                               ***Confidential Treatment Requested  

 

[...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]                                 Schedules Page 25 of 53                                               ***Confidential Treatment Requested  

 

  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]  [...***...]                                                  [...***...]                                                                          Schedules Page 26 of 53                                               ***Confidential Treatment Requested  

 

                                SCHEDULE 10.2(h)                         Clinical Trials and Preclinical Studies                                MIR-21 FIBROSIS POC PROGRAM             STUDY ID                               TITLE / DESCRIPTION  Clinical Trials                   [...***...]                        [...***...]   [...***...]                        [...***...]   [...***...]                        [...***...]   [...***...]                        [...***...]    [...***...]                        [...***...]   Preclinical Studies               [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                 Schedules Page 27 of 53                                               ***Confidential Treatment Requested  

 

  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]   [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]   [...***...]                        [...***...]  [...***...]                        [...***...]                                Schedules Page 28 of 53                                               ***Confidential Treatment Requested  

 

  [...***...]                        [...***...]                                      MIR-21 FIBROSIS              STUDY ID                               TITLE / DESCRIPTION  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]   [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                Schedules Page 29 of 53                                               ***Confidential Treatment Requested  

 

[...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                Schedules Page 30 of 53                                               ***Confidential Treatment Requested  

 

[...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                Schedules Page 31 of 53                                               ***Confidential Treatment Requested  

 

[...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                Schedules Page 32 of 53                                               ***Confidential Treatment Requested  

 

[...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]   [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                     MIR-21 ONCOLOGY  STUDY ID                       TITLE / DESCRIPTION  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                Schedules Page 33 of 53                                               ***Confidential Treatment Requested  

 

[...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                Schedules Page 34 of 53                                               ***Confidential Treatment Requested  

 

[...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                Schedules Page 35 of 53                                               ***Confidential Treatment Requested  

 

[...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]  [...***...]                        [...***...]                                       MIR-21 OTHER  STUDY ID                       TITLE / DESCRIPTION  [...***...]                        [...***...]   [...***...]                        [...***...]                                                                          Schedules Page 36 of 53                                               ***Confidential Treatment Requested  

 

                                               SCHEDULE 10.2(i)                                                 Mir 21 Contracts                                                                      Estimated Contract Value ($ USD)                                                                              As of 11/5/2018                                                                   Total                        Remaining                                                                            Cash Paid Expense                                                                 Contract                        Contract                                                                            to Date*  to Date*    Category     Protocol   Vendor            Description          Value                          Value   [[...***...]     [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]  [...***...]       [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                                                Schedules Page 37 of 53                                                                             ***Confidential Treatment Requested  

 

                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]  [...***...]       [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]  [...***...]       [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]                 [...***...]    [...***...]    [...***...]                    [...***...]   [...***...]   [...***...]    [...***...]]    * If expense to date exceeds cash paid to date, Regulus shall be responsible for outstanding accounts payable as of the First  Amendment Date.  If cash paid to date exceeds Regulus expense to date, Sanofi will not reimburse Regulus for such prepaid expenses.                                                                                                          Schedules Page 38 of 53                                                                             ***Confidential Treatment Requested  

 

                                              SCHEDULE 10.2(j)                       In License Milestones and Other In-License Payments  Agreement     Patent     Sublicense           Milestones                Royalties               Expenses     Income           Event          Amount  Max-       [...***...]       [...***...]    [...***...]              [...***...]   [...***...]  Planck                              [...***...]              [...***...]  Agreement                           [...***...]              [...***...]                                      [...***...]              [...***...]                                      [...***...]                  Wurzburg   [...***...]       [...***...]    [...***...]              [...***...]   [...***...]  Agreement                           [...***...]              [...***...]                                      [...***...]              [...***...]                                      [...***...]              [...***...]                                      [...***...]              [...***...]                                      [...***...]              [...***...]                                      [...***...]              [...***...]                                       Schedules Page 39 of 53                                                   ***Confidential Treatment Requested  

 

                                                                               [...***...]  Ionis (Isis) [...***...]     [...***...]    [...***...]                       [...***...]  &  Alnylam  License  Agreement                                                                                  Schedules Page 40 of 53                                                   ***Confidential Treatment Requested  

 

                                                                    SCHEDULE 10.2(k)                                       Mir 21 Product Specific Patents             Regulus-owned     Regulus                            Application   Official                Status    Country                              Patent Number  Issue Date    Owner    Reference                           Number      Filing Date  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]   [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]   [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]   [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]                                            Schedules Page 41 of 53                                                          ***Confidential Treatment Requested  

 

                            [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]   [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]   [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                 [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                            Schedules Page 42 of 53                                                          ***Confidential Treatment Requested  

 

                            [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]                                            Schedules Page 43 of 53                                                          ***Confidential Treatment Requested  

 

                            [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]   [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                 [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]   [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                            Schedules Page 44 of 53                                                          ***Confidential Treatment Requested  

 

                            [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]   [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                 [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]    [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]                                            Schedules Page 45 of 53                                                          ***Confidential Treatment Requested  

 

                            [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                 [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                   [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                 [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                            Schedules Page 46 of 53                                                          ***Confidential Treatment Requested  

 

                            [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]    [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                            Schedules Page 47 of 53                                                          ***Confidential Treatment Requested  

 

                            [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                 [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                [...***...]     [...***...]   [...***...]    [...***...]          [...***...]   [...***...]         [...***...]   [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                 [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]  [...***...]     [...***...]   [...***...]    [...***...]          [...***...]                             [...***...]                                                                                                                                                                                                    Licensed from Wuerzburg                   Client Attorney                Application Official Publication Publication Patent Issue                      Status Country                                                      Owner    Reference Reference              Number   Filing Date Number Date     Number  Date    [...***...]  [...***...] [...***...] [...***...] [...***...]  [...***...]                     [...***...] [...***...] [...***...]                                                                      [...***...]  [...***...] [...***...] [...***...] [...***...]  [...***...]                                     [...***...]                                                                                       [...***...]  [...***...] [...***...] [...***...] [...***...]  [...***...]                                     [...***...]                                                                                       [...***...]  [...***...] [...***...] [...***...] [...***...]  [...***...]                                     [...***...]                                                                                       [...***...]  [...***...] [...***...] [...***...] [...***...]  [...***...]                     [...***...] [...***...] [...***...]                                                                                                              Schedules Page 48 of 53                                                          ***Confidential Treatment Requested  

 

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                       [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]                           [...***...]     [...***...]     [...***...]                                                                                        [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]                           [...***...]     [...***...]     [...***...]                                                                                        [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]                           [...***...]     [...***...]     [...***...]                                                                                      [...***...]  [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]                           [...***...]     [...***...]     [...***...]                                                                                        [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]                           [...***...]     [...***...]     [...***...]                                                                                        [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]    [...***...]     [...***...]    [...***...]     [...***...]     [...***...]   [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]    [...***...]     [...***...]    [...***...]     [...***...]     [...***...]   [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]    [...***...]     [...***...]    [...***...]     [...***...]     [...***...]   [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]    [...***...]     [...***...]    [...***...]     [...***...]     [...***...]   [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]    [...***...]     [...***...]    [...***...]     [...***...]     [...***...]   [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]                                                   [...***...]                                                                                                               [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]                                                   [...***...]                                                                                                               [...***...]     [...***...]    [...***...]     [...***...]     [...***...]      [...***...]                                                   [...***...]                                                                                                               [...***...]                [...***...]     [...***...]     [...***...]      [...***...]                                                   [...***...]                                                                                                               [...***...]                [...***...]     [...***...]     [...***...]      [...***...]                                                   [...***...]                                                                                                                                                                   Schedules Page 50 of 53                                                                           ***Confidential Treatment Requested  

 

                           [...***...]     [...***...]    [...***...]     [...***...]    [...***...]      [...***...]    [...***...]     [...***...]    [...***...]     [...***...]     [...***...]                                                                                                                             Schedules Page 51 of 53                                                                             ***Confidential Treatment Requested  

 

                                                                                              SCHEDULE 10.2(l)                                                     Regulus Core Technology Patents     Client       Attorney                                 Application   Official Filing Publication Publication Patent                                  Status       Country                                                                     Issue Date   Owner    Reference     Reference                                Number        Date           Number     Date        Number  [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]                                                       [...***...]                                                                                                                              [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]        [...***...]    [...***...]     [...***...]     [...***...]     [...***...]    [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]                               [...***...]     [...***...]     [...***...]                                                                                                      [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]        [...***...]    [...***...]     [...***...]     [...***...]     [...***...]   [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]        [...***...]    [...***...]     [...***...]     [...***...]     [...***...]   [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]        [...***...]    [...***...]     [...***...]     [...***...]     [...***...]   [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]        [...***...]    [...***...]     [...***...]     [...***...]     [...***...]   [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]                               [...***...]     [...***...]     [...***...]                                                                                                      [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]                               [...***...]     [...***...]     [...***...]                                                                                                      [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]        [...***...]    [...***...]     [...***...]     [...***...]     [...***...]   [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]                               [...***...]     [...***...]     [...***...]                                                                                                      [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]                               [...***...]     [...***...]     [...***...]                                                                                                    [...***...]  [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]                               [...***...]     [...***...]     [...***...]                                                                                                      [...***...]       [...***...]       [...***...]        [...***...]       [...***...]       [...***...]        [...***...]    [...***...]     [...***...]     [...***...]     [...***...]                                                            Schedules Page 52 of 53                                                                                 ***Confidential Treatment Requested  

 

         [...***...]      [...***...]    [...***...]   [...***...]   [...***...]    [...***...]   [...***...]    [...***...]   [...***...]   [...***...]    [...***...]    [...***...]      [...***...]    [...***...]   [...***...]   [...***...]    [...***...]   [...***...]    [...***...]   [...***...]   [...***...]    [...***...]    [...***...]      [...***...]    [...***...]   [...***...]   [...***...]    [...***...]   [...***...]    [...***...]                                                                                                              [...***...]                                                                                                                        Schedules Page 53 of 53                                                                    ***Confidential Treatment Requested  

 

                                                                                                                 EXHIBIT A                     Form of RG-012 IND Sponsorship Transfer Letter                                                            CHANGE IN SPONSOR OF AN APPLICATION                                Transfer of [...***...]    Regulus Therapeutics Inc. hereby transfers all rights and obligations for [...***...] to Genzyme  Corporation, 50 Binney Street, Cambridge, Massachusetts 02142 USA.     Effective <<Date>> the ownership and all rights and responsibilities to the above referenced  investigational new drug application shall transfer to Genzyme Corporation.                                                      ***Confidential Treatment Requested      

 

                                        EXHIBIT B                  Form of RG-012 IND Sponsorship Transfer Acceptance Letter                                                              CHANGE IN SPONSOR OF AN APPLICATION                                 Acceptance of [...***...]    Genzyme Corporation, 50 Binney Street, Cambridge, Massachusetts 02142 USA hereby accepts all  rights and obligations for [...***...] from Regulus Therapeutics Inc.     Effective <<Date>> the ownership and all rights and responsibilities to the above referenced  investigational new drug application are accepted by Genzyme Corporation, 50 Binney Street,  Cambridge, Massachusetts 02142 USA.                                                        ***Confidential Treatment Requested      

 

                 EXHIBIT C  Form of SDEA                   

 

    Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use  in Fibrosis                                  SAFETY DATA EXCHANGE AGREEMENT                                               for        therapeutic MicroRNA Mir-21 Compounds and Products for use in Fibrosis                                            between              SANOFI-AVENTIS RECHERCHE & DEVELOPPEMENT S. A                                               and                              REGULUS THERAPEUTICS INC             Authorized by:         SANOFI-AVENTIS Recherche & REGULUS THERAPEUTICS INC        Développement S.A. duly represented by       SANOFI GLOBAL       PHARMACOVIGILANCE (SANOFI GPV)]          Signature:                              Signature:                                                            Name: Stephen LIN, MD                   Name:                                                                Position: Chief Safety Officer, Head of Position:          Sanofi GPV                                                                                                                                     Date:          Date:                                                                                                 Page 1 of 21                                                                                                         

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis                                   Table of Contents  ARTICLE 1. RECITAL ............................................................................................................... 3  ARTICLE 2. DEFINITIONS ....................................................................................................... 4  ARTICLE 3. GENERAL PROVISIONS ..................................................................................... 4  3.1.  Purpose and Scope ............................................................................................................ 4  3.2.  Common language ............................................................................................................ 4  3.3.  Overall governance ........................................................................................................... 5  3.4.  Product .............................................................................................................................. 5  3.5.  Territory ............................................................................................................................ 5  ARTICLE 4. PHARMACOVIGILANCE SYSTEM AND COMPLIANCE .............................. 5  4.1.  Regional or National QPPV or Local Contact Person for Pharmacovigilance ................ 5  4.2.  Contacts ............................................................................................................................ 5  4.3.  PV procedures and PV system ......................................................................................... 5  4.4.  Contractors & sub-contractors .......................................................................................... 6  4.5.  Training ............................................................................................................................ 6  4.6.  Safety database ................................................................................................................. 6  4.7.  Safety report: DSUR ........................................................................................................ 6  4.8.  ICSR exchange ................................................................................................................. 6  4.9.  Emerging safety issues, alerts, crisis or regulatory actions for safety reasons ................. 7  4.10. Regulatory inspection ....................................................................................................... 7  4.11. Audits ............................................................................................................................... 7  4.12. Compliance and notification of late submissions to regulatory authorities ..................... 8  ARTICLE 5. SDEA LIFE CYCLE .............................................................................................. 8  5.1.  Business continuity plan ................................................................................................... 8  5.2.  Dispute resolution, jurisdiction and governing law .......................................................... 8  5.3.  Confidential information .................................................................................................. 9  5.4.  Data privacy ..................................................................................................................... 9  5.5.  Record retention and management ................................................................................... 9  5.6.  Amendment and variation ................................................................................................ 9  5.7.  Term and termination ..................................................................................................... 10  APPENDICES ............................................................................................................................ 11  APPENDIX 1: DEFINITIONS .................................................................................................. 11  APPENDIX 2: PRODUCTS AND TERRITORIES .................................................................. 15  APPENDIX 3: ABBREVIATIONS ........................................................................................... 16  APPENDIX 4: CONTACTS ...................................................................................................... 17  APPENDIX 5: SDEA VERSION HISTORY ............................................................................ 21                                                                        Page 2 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis  ARTICLE 1. RECITAL  This Safety Data Exchange Agreement (SDEA) is entered into and made effective on last  party signature date, (the « Effective Date ») by and between SANOFI-AVENTIS  RECHERCHE & DEVELOPPEMENT S.A. (SAR&D)) having its registered office at 1,  Avenue Pierre Brossolette - 91380 Chilly-Mazarin, France and represented for the purposes  hereof by the Sanofi Global Pharmacovigilance department (“SANOFI GPV”) and  REGULUS THERAPEUTICS INC., a Delaware Corporation, having its registered office at  10614 Science Center Drive, San Diego, California 92121-1121. and represented for the  purposes hereof by REGULUS.  SAR&D and REGULUS, are each individually referred herein as a “Party” and collectively  as the “Parties”.         On 21-Jun-2010, the REGULUS and SANOFI (an affiliate of SAR&D) entered into a  Collaboration and License Agreement for therapeutic MicroRNA Compounds and Products  pursuant to which both Parties agreed to conduct a Research Program to identify one or more  Licensed Compounds for a limited number of Collaboration Targets and REGULUS granted  SANOFI exclusive rights to Licensed Compounds and Products arising from the Research  Program. On 16-Jul-2012, REGULUS and SANOFI amended the original agreement under  which the Parties agreed to expand the scope of the Research Program; On 04-Feb-2014, the  Second Amended and Restated collaboration and License Agreement was made and entered  into (the “Master Agreement”). Subject to the Master Agreement, REGULUS granted to  SANOFI a worldwide, royalty bearing, exclusive license, with the right to grant sublicenses,  under the Regulus Know-How and REGULUS Patents to Research, Develop, make, have  made, use, gain Approval, Commercialize, sell, offer for sale, have sold, export and import  Mir-21 and  Mir-221/222 Compounds, Mir-21/ Mir-221/222 Products, and Companion  Diagnostics for use with Mir-21/ Mir-221/222 Products; in each case, in the Product Field (the  “Mir-21 License”; “Mir-221/222 License”). Except as otherwise specified in the R&D Plan or  a POC Program Plan, the Parties acknowledge and agree that SANOFI will be solely  responsible for the manufacturing, stability testing and supply of finished drug Product.  Regulus has suspended the Mir-21 Fibrosis POC Program and has requested that Sanofi  restructure the Agreement and take responsibility for obligations of Regulus under the  Agreement, including the administration and expense of clinical trials related to the Mir-21  Fibrosis POC Program; Sanofi has agreed to restructure the Master Agreement as it pertains to  the Mir-21 POC Programs, Mir-21 Compounds, and Mir-21 Products, as requested by  Regulus and on the terms and subject to the conditions set forth in the First Amendment to the  Master Agreement effective as of XX-November 2018.  The Parties entered into this SDEA to set forth the rules governing the timely exchange of  pharmacovigilance data (the PV Data) so that both SANOFI GPV and REGULUS, as  Marketing authorization holder (MAH), sponsor, Investigational New Drug (IND), or  Clinical Trial Application (CTA) holder for the Product can fulfill their regulatory reporting  obligations with respect to pharmacovigilance in their respective territories. Where the name  ‘SANOFI’ is used in this SDEA, it refers generally to the SANOFI group of companies,  including all Affiliates.  This SDEA constitutes the entire agreement between the Parties regarding the subject matter  hereof and supersedes all previous versions of the SDEA and / or any specific PV operating  procedures regarding the Products, whether written or oral, agreed upon by and between the  Parties.   The Parties and their respective Affiliates are bound by, and shall act in accordance with, the  provisions set out in this SDEA except to the extent that they conflict with any legal or  regulatory requirements applicable to either Party in a given Territory.                                                                   Page 3 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis   The Parties further understand that the purpose of this SDEA is not to modify the Master  Agreement, but, rather to further define their respective roles in respect of the subject matter  hereof.  In the event of any conflict of interpretation between the Master Agreement and this SDEA,  the Master Agreement shall prevail except in relation with the pharmacovigilance rules and  obligations set forth in this SDEA.   The Appendices to this SDEA comprise part of and shall be construed in accordance with the  terms of this SDEA. In the event of any inconsistency between the Appendices to this SDEA  and the terms of this SDEA, the terms of this SDEA shall prevail.  ARTICLE 2. DEFINITIONS   Pharmacovigilance terms used in this SDEA are those terms used and defined by the  International Conference on Harmonization (ICH) and adopted by regulatory authorities and  associated guidelines concerning medicinal products for human use, as amended from time to  time. Such definitions are deemed to be incorporated by reference into this SDEA.  In the event of any inconsistencies between the defined terms set out herein and those adopted  by the ICH or EMA or the United States Food and Drug Administration (FDA), the terms of  this SDEA shall prevail.  The defined terms from the Master Agreement shall prevail except for pharmacovigilance  definitions and provisions.   Definitions are included in the Appendix 1 of this SDEA.   ARTICLE 3. GENERAL PROVISIONS    3.1. Purpose and Scope  The purpose of this SDEA is to:  •  Define responsibilities, format, content, methods of transmission and timelines for safety     information exchange for the Products, (as such term is hereinafter specifically defined for     the purpose hereof),  •  And thus to enable the Parties, and their respective Affiliates as necessary, to comply with     their regulatory reporting obligations under applicable laws in their respective Territory.  The scope of the SDEA relates to the pharmacovigilance surveillance of the Product, the  collection and exchange of PV Data associated with the use of the Product.    3.2. Common language  All information exchanged between the Parties shall always be provided in English.  Therefore, any document to be provided by one Party to the other under the specific  provisions of this SDEA (whether from regulatory authorities or other sources as specified  herein) in a language other than English shall be translated into English by the Party providing  the document.                                                                      Page 4 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis   3.3. Overall governance   The Parties have a legal and / or regulatory responsibility to oversee and manage the safety of  the Products. The following regulations or guidance related to pharmacovigilance, as may be  updated from time to time, are referenced to determine overall governance of this SDEA: United  States (“US”) Food and Drug Administration (“FDA”) Code of Federal Regulations (“CFR”)  Title 21 (“FDA 21 CFR”), Health Canada Food and Drug Regulations, Japan Ministry of Health,  Labour and Welfare (“MHLW”), Pharmaceutical and Medical Devices Agency (“PMDA”)  Pharmaceutical Affairs Law, International Conference on Harmonization (“ICH”) of Technical  Requirements for Registration of Pharmaceuticals for Human Use, pertinent European Union  (“EU”) Regulations, Directives, and Guidance and local regulations as needed. Hereinafter  defined as (the “Applicable Regulations”) in this SDEA.   3.4. Product  Shall mean the products listed in Appendix 2 of this SDEA.   3.5. Territory  Shall mean the territories listed in Appendix 2 of this SDEA.    ARTICLE 4. PHARMACOVIGILANCE SYSTEM AND COMPLIANCE  SANOFI GPV will be MAH and establish a pharmacovigilance system and ensure compliance.   4.1. Regional or National QPPV or Local Contact Person for Pharmacovigilance  Where national or local regulations in the Territory require a nominated or responsible  individual who has specific legal obligations for PV at a national or local level, the Party  responsible for that Territory shall designate an appropriately qualified individual to fulfil this  role. The Parties agree to provide reasonable assistance to such individuals in complying with  their legal and regulatory obligations and responsibilities.    4.2. Contacts  Contact details for personnel responsible for administration of this SDEA are listed in Appendix  4 of this SDEA. Any changes to contact information (fax, phone number, mail or email  addresses, and contact person(s) for a given Party must be provided to the other Party in writing  as soon as possible after the change occurs. The change of contact information shall not require  the Parties to sign a formal written amendment.   4.3. PV procedures and PV system  Each Party must have an appropriate pharmacovigilance system in place in order to comply with  the safety reporting obligations as provided in the Applicable Regulations and under this SDEA.  The other Party may verify the existence of such a system by appropriate and reasonable means,  including, but not limited to, by regular or ad hoc meetings, and minuted telephone conferences,  the use of questionnaires or audits (also refer to Article 4.10 “Audit”).                                                                         Page 5 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis   In addition, quality management processes and quality control may be used for such purposes.  Exchange of partner compliance measurements may be also used.    4.4. Contractors & sub-contractors  Each Party may delegate its responsibilities hereunder in whole or in part to its respective  Affiliates or to a third party of it choosing duly authorized to manage safety data related to  this SDEA, the Party will ensure that such contractors and sub-contractors fulfil the  requirements of this SDEA and are bound by confidentiality clause in their agreements with  such contractors and sub-contractors involved in activities covered by this SDEA.  Notwithstanding such delegation the delegating Party remains responsible for the actions of  the contractor.   4.5. Training  The Parties shall ensure that all relevant members of their staff performing tasks linked to this  SDEA, including contractors, are adequately trained on the processes relating to their  responsibilities in pharmacovigilance. A copy of the training documentation can be provided  upon request from the other Party. Basic pharmacovigilance training is mandatory for all staff  upon joining the company and annually thereafter.    4.6. Safety database  SANOFI GPV   shall establish and maintain the Global Safety Database, which shall be the  central safety repository for the applicable Licensed Compounds/Products. REGULUS shall  not have direct, physical access to the Global Safety Database.  Upon request from SANOFI GPV, REGULUS will promptly transfer all safety information  regarding the applicable Licensed Compounds or Products, including, if applicable, adverse  events, and drug exposure during pregnancy data that it has regarding the Licensed  Compounds or Products to SANOFI GPV for entry into the Global Safety Database.   4.7. Safety report: DSUR   SANOFI GPV is responsible to prepare, establish and submit to the competent authorities the  DSUR for the clinical study RG-012.   SANOFI GPV sent the final executive summary of DSUR copy to REGULUS at time of the  distribution of the DSUR.    4.8. ICSR exchange  SANOFI GPV is responsible of the collect, treatment and submission of the ICSRs for the  product.   SANOFI GPV sent to REGULUS SUSARs occurred in the studies, in CIOMS I format by  email.  The timelines are applied below to share SUSAR with REGULUS for RG-012:    Type of Report exchange  SANOFI GPV to REGULUS  Serious Related Adverse Events (“SAE”) from interventional clinical studies  Fatal or life-threatening related Within [...***...] ([...***...]) calendar days of Receipt Date   SAEs  All other related SAEs   Within [...***...] ([...***...]) calendar days of Receipt Date                                                ***Confidential Treatment Requested                                                                    Page 6 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis   4.9. Emerging safety issues, alerts, crisis or regulatory actions for safety reasons  The Parties agree to inform each other promptly of any Emerging Safety Issue (i.e. leading to  changes in the known risk-benefit balance of the Product and / or impact on public health),  regulatory inquiries or regulatory action, alert or crisis linked to the safety of the Product and to  collaborate together to manage the situation and to protect public health.   Examples of Regulatory actions and / or inquiries and / or expected or pending actions for  safety reasons include, but are not limited to:     • Marketing authorization withdrawal or suspension,      • Failure to obtain a marketing authorization renewal,      • Restrictions on distribution,      • Clinical trial suspension, or protocol amendment for safety and / or efficacy reasons,      • Dosage modification for safety reasons,      • Changes in target population or indications for safety reasons,      • Formulation changes for safety reasons, or      • Modification of the investigator brochure and / or core safety data sheet and / or labeling        for safety reasons, or     • Existence of counterfeits etc.  Any of these and other important safety information need to be reported to the other Party as  soon as possible and no later than [...***...] business days depending on the nature of issue.    4.10. Regulatory inspection  Each Party agrees to notify the other Party as soon as possible of any intention by a regulatory  authority to perform a pharmacovigilance-related inspection. Each party agrees to provide the  other Party with necessary information in order to comply with any requests in relation to such  an inspection.   Each Party agrees to take remedial action in a timely manner to correct any act or omission  identified by the regulatory authority inspection to the inspected Party   4.11. Audits  Either Party is entitled, at its own expense, to audit the other Party to monitor compliance with  the requirements set forth in this SDEA and in Applicable Regulations:  i) In case of any actual or suspected material lack of compliance with (including any breach of)  the terms and conditions of this SDEA and / or of the Applicable Regulations (the "For Cause  Audit").   ii) If one Party is chosen through the risk-based approach audit strategy of the other Party (the  “Routine Audit”)  In each of the situations listed in this Article i) and ii), one Party (the "Auditing Party"), may  initiate an audit of the other Party (the "Audited Party") by reasonable advance written notice of  not less than [...***...] ([...***...]) calendar days, except in case a serious event necessitates  an urgent extraordinary audit, to the Audited Party. Such audit shall be conducted during  normal business hours and not more than once a year for situation i and ii.  Each Party shall make available, and shall provide assigned auditors with access to,  pharmacovigilance department staff and relevant personnel, its Safety Database, relevant                                                ***Confidential Treatment Requested                                                                    Page 7 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in Fibrosis  facilities, procedures, and records and any approved subcontractors in order to verify compliance with  this SDEA and all Applicable Regulations.   Any such audit may either be performed by the internal employees of the Parties or by a third-party  auditor. In any situation, the auditors will have reasonable qualifications and experience in  Pharmacovigilance auditing.  The Parties shall discuss and collaborate as necessary to resolve any audit findings or observations and  implement corrective and preventative actions (CAPA) to rectify any non-compliance identified by the  auditors. Both Parties shall follow-up on open CAPAs as needed until completion.  All information provided, reviewed or received during the course of an audit, including any and all  data received or observations made from such audit, shall be treated as Confidential Information and  shall not be used for any purpose other than the audit by the receiving Party.   4.12. Compliance and notification of late submissions to regulatory authorities  Where a Party does not submit any information in the scope of this SDEA in the necessary  timeframes, the other Party may request root cause analysis and further information regarding, for  example, quality management processes, quality control and compliance measurements, not to be  unreasonably withheld. A Party may request that the defaulting Party takes appropriate CAPA, as  necessary, to prevent a recurrence. Any CAPA taken shall be documented and provided to the other  Party. If there is any detection of trends of increasing or persistent non-compliance with the  provisions of this SDEA, both Parties shall agree in writing on mechanisms to solve the issues and  monitor improvement over time.  CAPA will be requested by the other Party when Individual Case Safety Report (ICSR) or Periodic  Safety Report (PSR) are not exchanged in a timely manner and result in late submission to a  regulatory authority.   ARTICLE 5. SDEA LIFE CYCLE    5.1. Business continuity plan  Both Parties agree to have documented and tested measures in place to ensure contingency planning  for the tasks and responsibilities outlined in this SDEA.   5.2. Dispute resolution, jurisdiction and governing law  The Parties shall endeavor to settle amicably any dispute arising out of the interpretation or  performance of this SDEA. In case no amicable settlement of the dispute can be reached within a  reasonable timeframe including by involving the respective pharmacovigilance senior management of  the Parties, then the dispute shall be resolved in accordance with the relevant dispute resolution  provisions of the Master Agreement governing the Applicable Law and Dispute.  Resolution shall  apply with respect to any claim, dispute or controversy of whatever nature arising out of or relating to  this SDEA.                                                                           Page 8 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis   5.3. Confidential information   All information exchanged orally or in writing under this SDEA shall be considered as confidential  (“Confidential Information”), and neither Party may disclose any Confidential Information to any  third parties.   The provisions of this article shall not apply to a Party that proves that the information falls into  any of the following categories:         (a)  Information which is, or which will be generally available to the public other than as a             result of disclosure by a Party         (b)  Information which is known to a Party and is further evidenced by written records,             before receipt under this SDEA        (c)  Information which is disclosed in good faith to a Party by a third party under no             obligation of confidentiality vis-à-vis the other Party        (d)  Information which is legally required to be disclosed by a Party by any judicial             authority, provided that in that latter case this Party informs the other Party             immediately and shall furnish only that portion of the information which is legally             required to be disclosed         (e)  Information which is clearly identified as being necessary to a third party, as long as             such third party is bound by written confidential disclosure undertakings to SANOFI             GPV or to REGULUS with provisions at least commensurate with those in this             SDEA.  The restrictions contained in this article 5.3 shall continue to apply after termination of this SDEA  without limit in time.    5.4. Data privacy   Both Parties shall collect, use, and disclose Safety Information governed by this SDEA in  compliance with applicable privacy and data protection laws, rules, and regulations. Each Party  shall implement all reasonable physical, technical, and administrative safeguards to protect PV  Data information from loss, misuse, and unauthorized access, disclosure, alteration, destruction and  to ensure that data privacy legislations are followed. The Parties shall notify each other promptly of  any suspected breach of this clause.   5.5. Record retention and management  Both Parties shall maintain reports and all source documentation related to PV Data, as well as  other information necessary to monitor the safety of the Products, for a time period required by  their respective internal procedures and / or Applicable Regulations, whichever is longer.  All source documentation shall be made available to the other Party in reasonable time frame upon  request. Prior to destroying any safety records, a Party will notify the other Party of its intention to  do so, affording the other Party the opportunity to retain such records if it so wishes.  This Article shall remain in full force and effect for [...***...] after termination of this SDEA.   5.6. Amendment and variation  The Parties understand and agree that the procedures set out in this SDEA may be amended at any  time, by mutual written agreement between the Parties, to ensure that they comply with Applicable  Regulations to improve compliance with pharmacovigilance activities covered by this SDEA. Upon  the written request of either Party, the Parties shall meet within [...***...] ([...***...]) calendar  days of such request to renegotiate in good faith the provisions in                                                   ***Confidential Treatment Requested                                                                        Page 9 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis   question. The amended SDEA will not take effect until reviewed and signed by authorized  representatives of each Party.  No variation of this SDEA, with the exception of the Appendices attached, shall be valid  unless it is in writing and signed by or on behalf of each of the Parties. Any variation of the  Appendices shall not require this SDEA to be re-issued and signed, but shall require the  written acknowledgement of both Parties.  Changes of contact persons (cf. Appendix 4 to this SDEA), of fax or telephone numbers, or of  mail or e-mail addresses shall not require signing an amendment and shall only be notified  unilaterally in writing by one Party to the other Party.   Changes that could impact the distribution of safety information (e.g., of expedited and  periodic safety reports) must be communicated without delay.   5.7. Term and termination  The term of this SDEA will commence on the “Effective Date” and shall continue in force  for as long as both of the Parties have a legitimate interest in Products or until both Parties  agree to terminate this SDEA. For the avoidance of doubt, those obligations, which by their  nature are on-going regulatory requirements, for example, maintaining records and supporting  product complaint investigations, [Article 5.3] Confidentiality; [Article 5.5] Record Retention  and Management shall survive.   Upon and subsequent to the expiration or earlier termination of this SDEA, SANOFI GPV  shall forward to REGULUS, within [...***...]  ([...***...]) Business Day, any Safety  Information received regarding the Product and in exceptional cases, provide support to the  other Party regarding inspection requests after termination of the SDEA.                                                  ***Confidential Treatment Requested                                                                   Page 10 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis  APPENDICES   APPENDIX 1: DEFINITIONS    “Adverse Event” or “AE” shall mean any untoward medical occurrence in a patient or                          clinical trial subject administered Product and which does not                          necessarily have a causal relationship with this treatment.                           An AE can therefore be any unfavorable and unintended sign                          (e.g. an abnormal laboratory finding), symptom, or disease                          temporally associated with the use of a Product, whether or not                          considered related to the Product.                           In addition to the foregoing, in the context of clinical trials an                          AE will also mean events associated with and / or possibly                          attributable to the clinical trial protocol design or clinical trial                          procedures.  “Adverse Event of Special Interest” or “AESI” shall mean an adverse event (serious or                          non-serious) of scientific and medical concern specific to the                          Product, for which ongoing monitoring and rapid                          communication by the investigator to the relevant sponsor of                          the clinical trial may be appropriate. Such events may require                          further investigation in order to characterize and understand                          them.  “Affiliate or Affiliated Company(/ies)”  shall mean any company which controls, is                          controlled by or is under common control of SANOFI or                          REGULUS. For the purposes hereof, “control” shall mean the                          direct or indirect ownership of at least fifty per cent (50%) of                          the voting share capital of any company or the power to                          designate a majority of the members of its principal                          management body.  “Adverse Reactions” or “ADR”:  shall mean                            Regarding pre-approval clinical experience:                          “All noxious and unintended responses to medicinal product                          related to any dose should be considered adverse drug                          reactions.”                          The phrase “responses to a medicinal product” means that a                          causal relationship between a medicinal product and an adverse                          event is at least a reasonable possibility (i.e., the relationship                          cannot be ruled out).                           Regarding marketed medicinal products:                           “An ADR is a response to a drug which is noxious and                          unintended and which occurs at any doses normally used in                          man for prophylaxis, diagnosis, therapy of disease or for                          modification of physiological function.”  “Data Lock Point”:      shall mean the date designated as the cut-off date for data to be                          included in the periodic safety reports for the Product (e.g.                          DSUR,  Semi-annual Safety Reports (SASR)) based on the                          development international birth date.                                                                   Page 11 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis  “Emerging Safety Issue” (as per Guideline on good pharmacovigilance practices (GVP)                          Module IX): A safety issue considered by a marketing authorization                          holder to require urgent attention by the competent authority because                          of the potential major impact on the risk-benefit balance of the                          medicinal product and / or on patients’ or public health, and the                          potential need for prompt regulatory action and communication to                          patients and healthcare professionals. Examples include:                          • major safety issues identified in the context of ongoing or newly                          completed studies, e.g. an unexpectedly increased rate of fatal or life-                         threatening adverse events;                          • major safety issues identified through spontaneous reporting or                          published in the scientific literature, which may lead to considering a                          contra-indication, a restriction of use of the medicinal product or its                          withdrawal from the market;                          • major safety-related regulatory actions outside the EU, e.g. a                          restriction of the use of the medicinal product or its suspension.  “ICSR”                  shall mean the document summarizing all available information                          related to an individual case safety report at a specific point of time.                          An Individual Case Safety Report (ICSR) is considered valid as soon                          as the four minimal elements are cumulatively available:                    1.    An identifiable patient                     2.    An identifiable reporter                    3.    At least one suspect medicinal Product concerned by this SDEA                    4.    At least one suspected adverse reaction or a special reporting                          situation as defined below (see PV data)  “Pharmacovigilance or (PV) Data” shall mean the following sources and circumstances :                             •  Serious Adverse Events (as defined below) from solicited                                reporting schemes including interventional studies, i.e., the                                solicited serious adverse events whether or not causally related                                to the Products.                             •  Adverse Events of Special Interest (AESIs) (as defined                                above).                              •  Adverse Event (AE) associated with a suspected or confirmed                                falsified medicinal Products or with a quality defect of a                                medicinal Products.                              •  The following special situations, even when no AE has                                occurred: suspected interaction(s), Products, or Products                                metabolite(s), exposure to embryos, fetuses or children via                                parent (including breastfeeding), lack of therapeutic efficacy,                                intentional or unintentional overdose of the Products, misuse                                and / or abuse of the Products including off label use (i.e. use                                outside the terms of the marketing authorization), medication                                errors (e.g. erroneous dispensing), events occurring during                                occupational                                                                        Page 12 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in Fibrosis                                exposure, suspected transmission via the medicinal Products of an                               infectious agent.                            •  Unintended beneficial effects, Safety Signals as defined hereafter                               and any other information relevant to the safety of the Products.  “Non-Valid ICSR”        shall mean a document summarizing all available information related to                          an individual case safety report at a specific point of time which is                          missing one of the four minimal elements (see ICSR definition above):                          aside from at least one active substance or suspect medicinal Product                          concerned by this SDEA.  “Receipt Date/Day 0”    shall mean the first day when a Party or any entity acting on behalf of                          such Party gains knowledge of an ICSR, whether valid or non-valid,                          irrespective of whether the information is received during a weekend or                          public holiday. This date is considered as Day “0” for reporting of valid                          ICSR to the EMA or any other competent authority.  “Risk”                 shall mean any risk relating to the quality, safety or efficacy of the                         Product as regards patient’ health or public health and any risk of                         undesirable effects on the environment.   “Safety Signal”         shall mean information that arises from one or multiple sources                          (including observations and experiments) which suggests a new                          potentially causal association or a new aspect of a known association                          between an intervention and an event or set of related events, either                          adverse or beneficial that is judged to be of sufficient likelihood to                          justify verification action.   “Serious Adverse Event” or “SAE”    A serious adverse event is any untoward medical                          occurrence that at any dose:                          •  Results in death;                         •  Is immediately life-threatening (which means): the patient was at                            risk of death at the time of the event; it does not refer to an event                            which hypothetically might have caused death if it was more                            severe);                         •  Requires inpatient hospitalization or prolongation of existing                            hospitalization;                         •  Results in persistent or significant disability and / or incapacity;                           •  Is a congenital anomaly or birth defect, or                          •  Is an Important Medical Event (IME): Medical and scientific                             judgment should be exercised in deciding whether an event is a                             serious adverse event and therefore subject to the expedited                             reporting set out in this SDEA such as important medical events that                             may not be immediately life-threatening or result in death or                             hospitalization but may jeopardize the patient or may require                             intervention to prevent one of the other outcomes listed in the                             definition above. Examples of such events are intensive treatment in                             an emergency room or at home for allergic bronchospasm,                                                                          Page 13 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis                              blood dyscrasias, convulsions that do not result in                             hospitalization, or development of drug dependency or drug                             abuse (ICH topic E2A).                                                                     Page 14 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in  Fibrosis   APPENDIX 2: PRODUCTS AND TERRITORIES  Protocol study number: RG-012    Products   Therapeutic MicroRNA compounds and products:          •  Mir-21 Compounds for the use in Fibrosis          •  Mir-21 Products for the use in Fibrosis    Territories  Worldwide                                                                     Page 15 of 21    

 

   APPENDIX 3: ABBREVIATIONS      ADR              Adverse Drug Reaction      AE               Adverse Experience and / or Event      CTA              Clinical Trial Application      DSUR             Development Safety Update Report      GPV              Global Pharmacovigilance       EEA              European Economic Area      EMA              European Medicines Agency      EU               European Union      ICH              International Conference on Harmonization      ICSR             Individual Case Safety Report      IND              Investigational New Drug      INN              International Non-proprietary Name      MAH              Marketing Authorization Holder      PBRER            Periodic Benefit Risk Evaluation Report      PSMF             Pharmacovigilance System Master File      PSR              Periodic Safety Report      PV               Pharmacovigilance      QPPV             Qualified Person for PV      RA               Regulatory Authority      SAE              Serious Adverse Event      SDEA             Safety Data Exchange Agreement      SOP              Standard Operating Procedure                                                                         Page 16 of 21                                                                                     

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in Fibrosis    APPENDIX 4: CONTACTS  SANOFI Entities         USA                                   USA                               France       Genzyme                               SANOFI                            SANOFI       675 West Kendall St                   55 Corporate Drive                1 avenue Pierre Brossolette       Cambridge, MA 02142                   Box 5925                          91385 CHILLY-MAZARIN                                              Bridgewater, NJ 08807             Cedex        Chief Safety Officer - Head of Global Pharmacovigilance (GPV)        Stephen LIN, MD                 EU-Qualified Person for Pharmacovigilance (EU-QPPV)       Eric TEO, MD         Deputy Qualified Person for Pharmacovigilance (Deputy QPPV)          General Medicines       Nathalie Rabault           Diabetes/ Cardiovascular/ Generics       Leslie Dondey-Nouvel         Rare diseases/ Multiple Sclerosis/ Immunology/ Oncology/ Consumer Healthcare       Hadj Benzerdjeb         Contacts in case of emerging safety issue / PV alert or crisis / Regulatory inspections, audit / Regulatory Authorities       queries               Head of GPV: Stephen Lin            And QPPV:  EU-QPPV-Office-Sanofi@sanofi.com       Cc: WW-PV-SDEA-Team@sanofi.com              Contacts for SDEA related topics and contact update (to reach SDEA Managers in charge of the SDEA)       Generic SDEA email box : WW-PV-SDEA-Team@sanofi.com               ICSR transmission from HANSAmed to SANOFI GPV including sending of ICSR reconciliation listings         For marketed products:         cl-Partners-CPV@sanofi.com         back-up in case of transmission failure: fax: +33 1 60 49 70 70                  This mailbox is also to be used for medical questions regarding ICSRs.         Please send ICSRs preferably by e-mail in form of a pdf attachment transformed from word.         Issues with ICSR distribution from SANOFI GPV to HANSAmed                                                                                                       Page 17 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in Fibrosis                   CL-GPE-Distribution@sanofi.com         Dear Investigator Letters (DIL) transmission (if applicable) to SANOFI GPV          CL-GPE-Distribution@sanofi.com         Contact for Global Labeling         LabelingExcellence@sanofi.com         Contact for compliance topics and compliance report         GPE-PVQTC-Compliance@sanofi.com         Periodic Reports collaboration (from PSR preparation including corresponding questionnaire to Periodic Report        finalization)         WW-GPV-GlobalPeriodicReports@sanofi.com         Aggregate Safety Reports distribution (except DSUR) to SANOFI GPV         GPE-PVDM-PSR_DISTRIBUTION@sanofi.com         Other Aggregate Safety Reports collaboration including DSUR distribution to SANOFI GPV         WW-PV-SDEA-Team@sanofi.com         Contact for Safety Signal/ Risks         PVSignal-Management@sanofi.com                                                                                                        Page 18 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in Fibrosis                             REGULUS THERAPEUTICS INC CONTACTS      Address:      Head of Pharmacovigilance      Contact in case of safety signal, alert, crisis or emerging safety issue, regulatory inspection, audit, regulatory      authority request      Name       Tel:       Cell:       Fax:       E-mail:             Qualified person for Pharmacovigilance (if partner XXX has rights in EU territory)      Name       Tel:       Cell:       Fax:       E-mail:            PSUR, DSUR, SASR contact (PSR planning, collaboration and distribution)      Name      Tel:       Fax:       E-mail             SDEA contact      Name      Tel:       Fax:       E-mail:       Other: ....             Investigator Brochure and / or Labeling contact      Name      Tel:                                                                                           Page 19 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in Fibrosis      Fax:      E-mail:      Other: ....        ICSR / Monthly reconciliation transmission from SANOFI GPV to REGULUS          Verify if specific e mail address where Sanofi shall send reconciliation listings          to          Email: ..........          (Fax: .........)                                                                         Page 20 of 21    

 

Global SDEA between SANOFI GPV and REGULUS for therapeutic MicroRNA Mir-21 Compounds and Products for use in Fibrosis    APPENDIX 5: SDEA VERSION HISTORY  Date (dd-   Version     Description of amendment / variation / revision of the SDEA  mmm-        number   yyyy)  Last Party 1.0          Global SDEA between SANOFI GPV and REGULUS THERAPEUTICS INC  Signature  Date                                                                                                                                                  Page 21 of 21    

 

                                       EXHIBIT D-1                    Form of Founding Company Stand-by License Agreement                                                                             [DATE]         Regulus Therapeutics Inc.   10614 Science Center Drive    San Diego, California 92121   Attention:  Chief Scientific Officer   Facsimile: +1 (585) 202-6363             With a copy to: General Counsel   Facsimile: +1 (585) 202-6363    Alnylam Pharmaceuticals, Inc.  300 Third StreetCambridge, MA 02142    Ionis Pharmaceuticals, Inc.  2855 Gazelle Court  Carlsbad, CA 92010      Re: Stand-by License Arrangement with Sanofi     Ladies and Gentlemen:     Reference is hereby made to that certain Amended and Restated License and Collaboration  Agreement by and among Alnylam Pharmaceuticals, Inc. (“Alnylam”) and Ionis Pharmaceuticals,   Inc. (formerly known as Isis Pharmaceuticals, Inc.) (“Ionis”, and each of Alnylam and Ionis, a   “Licensor” and together, the “Licensors”), on the one hand, and Regulus Therapeutics Inc.   (“Regulus”), on the other hand, dated January 1, 2009, as amended by (a) Amendment Number One   to the Amended and Restated License and Collaboration Agreement, dated as of June 10, 2010, by   and among the Licensors and Regulus, (b) Amendment Number Two to the Amended and Restated   License and Collaboration Agreement, dated as of October 25, 2011, by and among the Licensors   and Regulus and (c) Amendment Number Three to the Amended and Restated Licensed and   Collaboration Agreement, dated as of August 2, 2013, by and among the Licensors and Regulus   (collectively, the “Alnylam-Ionis License”).  Pursuant to the Alnylam-Ionis License, each of the   Licensors licensed, both exclusively and non-exclusively, to Regulus certain of its Licensed IP in the   Field to Research miRNA Mimics, to Develop and Manufacture miRNA Compounds and miRNA   Therapeutics and to Commercialize miRNA Therapeutics, with respect to each, in the Field   throughout the world (each as defined in the Alnylam-Ionis License).      On February 4, 2014, Regulus entered into that certain Second Amended and Restated Collaboration   and License Agreement (the “Sanofi-Regulus License”) with Sanofi, a company organized under   the laws of France, having a place of business at 54, rue la Boétie, 75008, Paris, France, registered in                                                                                       

 

     the Paris Trade and Company Register under no. 395 030 844 (“Sanofi”), pursuant to which, among   other things, Regulus assumed responsibility for all activities under each POC Program Plan (other   than Sanofi Program Activities) through the Achievement of Proof of Concept (each as defined in   the Sanofi-Regulus License).  Regulus has now suspended the Mir-21 Fibrosis POC Program and   has requested that Sanofi amend, and Sanofi has agreed to amend, the Sanofi-Regulus License as it  pertains to the Mir-21 POC Programs, Mir-21 Compounds and Mir-21 Products, to provide for,   among other things: (a) Sanofi to take responsibility for the obligations of Regulus under the Sanofi- Regulus License with respect to the Mir-21 Fibrosis POC Program, Mir-21 Compounds and Mir-21  Products, including the administration and expense of clinical trials related to the Mir-21 Fibrosis  POC Program (each as defined in the Sanofi-Regulus License); and (b) except as set forth in Section   8 of this Letter Agreement, the license and sublicense granted by Regulus to Sanofi with respect to   Mir-21 Compounds and Mir-21 Products to be royalty-free.        As a condition to entering into the amended Sanofi-Regulus License (once amended, the “Amended   Sanofi-Regulus License”), Sanofi requests that Regulus and each of the Licensors execute this letter  agreement (this “Letter Agreement”) where indicated below, memorializing their agreement to the  following:     Term. The provisions of this Letter Agreement shall be effective from the date of this Letter   Agreement written above. This Letter Agreement shall terminate immediately upon (a) Sanofi   providing each of the Licensors with an Option Declination Notice as set forth in Section 0 hereof or   (b) Sanofi and each of the Licensors executing a New License Agreement as set forth in Section 0   hereof.      No Consent Required to Sublicense. To the extent that the Licensors’ consent is required in order for   Regulus to sublicense any of the rights granted by Regulus to Sanofi in the Amended Sanofi- Regulus License, each Licensor hereby acknowledges that Regulus may grant such sublicenses to  Sanofi and hereby approves the sublicensing of such rights to Sanofi.      No Opt-In Right. Each Licensor acknowledges that Regulus’ decision to suspend the Mir-21 Fibrosis   POC Program and request that Sanofi amend the Sanofi-Regulus License to take responsibility for   Regulus’ obligations under the Sanofi-Regulus License with respect to the Mir-21 Fibrosis POC   Program, Mir-21 Compounds and Mir-21 Products, including the administration and expense of   clinical trials related to the Mir-21 Fibrosis POC Program (each as defined in the Sanofi-Regulus   License), does not give either of the Licensors the right to make an Opt-In Election (as defined in the   Alnylam-Ionis License) under Section 5 (Right to Opt-In) of the Alnylam-Ionis License and that   neither of the Licensors will make any such claim with respect to the Mir-21 Fibrosis POC Program  (as defined in the Sanofi-Regulus License) now or at any time in the future.       No Breach by Regulus. Each Licensor confirms that, as of the date of this Letter Agreement: (a) the   Alnylam-Ionis License remains in full force and effect; (b) such Licensor has not given any notice to   Regulus, and is not otherwise aware, of any breach by Regulus under the Alnylam-Ionis License;  and (c) such Licensor has not taken any action or omitted to take any action that could be deemed a  breach of its obligations under the Alnylam-Ionis License.                                                                                                                                                                          

 

  Amendments to Alnylam-Ionis License. Regulus shall give prompt written notice to Sanofi, together with  a written summary of outstanding issues if Sanofi so requests, of any notice received from or given to the  Licensors or either of them of any proposed amendments or proposed modifications of, or any proposed  waivers under, the Alnylam-Ionis License.  Except in the case of an uncured material breach by Sanofi or  Regulus, Regulus and the Licensors agree that they will not amend the Alnylam-Ionis License so as to  terminate or diminish the rights granted to Regulus under the Alnylam-Ionis License and sublicensed by  Regulus to Sanofi under the Amended Sanofi-Regulus License, if any, in a manner that would diminish or  undermine Sanofi’s rights under the Sanofi-Regulus License or this Letter Agreement without the prior  written consent of Sanofi.    Breach of the Alnylam-Ionis License. In the event of any breach by Regulus of the Alnylam-Ionis License  that gives rise to the Licensors’ right to terminate the Alnylam-Ionis License, each Licensor shall  promptly provide written notice to Sanofi of such breach (such notice to be provided concurrently with  the first notice to Regulus of such breach), and Sanofi shall have the right, but not the obligation, to  attempt to cure such breach on behalf of Regulus within the time periods set forth in the Alnylam-Ionis  License. During the cure periods set forth in the Alnylam-Ionis License, the Licensors shall not terminate  the Alnylam-Ionis License with respect to Regulus as a result of such breach.      Direct License Upon Termination of the Alnylam-Ionis License. In the event that the Alnylam-Ionis  License terminates for any reason, including material breach by Regulus, each Licensor shall promptly  notify Sanofi and Sanofi shall have the right and option to obtain directly from the Licensors, acting  jointly, a license under the Licensed IP (as defined in the Alnylam-Ionis License) with respect to Mir-21  Compounds and Mir-21 Products on substantially the same terms and conditions as set forth in the  Alnylam-Ionis License, as amended by Section 0 of this Letter Agreement (such right, the “License  Option”), including with respect to the rights granted to Regulus in Section 2.2(b) of the Alnylam-Ionis  License.  Sanofi may exercise the License Option by providing a written notice to the Licensors thereof  (the “Option Election Notice”) within [...***...] ([...***...]) days from the date that a Licensor first  notifies Sanofi that the Alnylam-Ionis License has terminated (the “Alnylam-Ionis License Termination  Date”). If Sanofi elects not to exercise the License Option, it shall provide written notice thereof (the  “Option Declination Notice”) to the Licensors within [...***...] ([...***...]) days from the Alnylam- Ionis License Termination Date. If Sanofi does not provide an Option Election Notice to the Licensors  within [...***...] ([...***...]) days from the Alnylam-Ionis License Termination Date, then Sanofi will  be deemed to have delivered the Licensors an Option Declination Notice. If Sanofi exercises the License  Option, then the Licensors shall enter into an exclusive license agreement directly with Sanofi (the “New  License Agreement”) under the Licensed IP (as defined in the Alnylam-Ionis License) with respect to  Mir-21 Compounds and Mir-21 Products that was licensed to Regulus under the terminated Alnylam- Ionis License on substantially the same terms and conditions as those set forth in the Alnylam-Ionis  License, as amended by Section 0 of this Letter Agreement. Effective during the period beginning on the  Alnylam-Ionis License Termination Date and ending on (a) the date that Sanofi provides the Option  Declination Notice (if Sanofi declines the License Option) or (b) the date of execution of the New License  Agreement (if Sanofi elects the License Option) (such period, the “Interim Period”), the Licensors shall  automatically grant, and hereby do grant, to Sanofi a temporary continuation of the rights that Sanofi had  as sublicensee of the Licensed IP (as defined in the Alnylam-Ionis License) under the Amended Sanofi- Regulus License prior to termination of the Alnylam-Ionis License (such                                                         ***Confidential Treatment Requested                                                                                         

 

     rights, the “Temporary License”). Notwithstanding anything herein to the contrary, under both the   New License Agreement and the Temporary License, (i) the scope and territory of the license granted   to Sanofi shall be the same as that granted to Sanofi pursuant to the Amended Sanofi-Regulus License,   (ii) the financial terms shall be as set forth in Section 0 of this Letter Agreement and (iii) the Licensors  shall not have any obligations that are greater than or inconsistent with the obligations of the Licensors   under the Alnylam-Ionis License.       Financial Terms of Sublicense, New License Agreement and Temporary License.  With respect to Net   Sales (as defined in the Sanofi-Regulus License) of Mir-21 Products that are Royalty-Bearing Products  (as defined in the Alnylam-Ionis License), whether pursuant to the sublicense under the Licensed IP  (as defined in the Alnylam-Ionis License) granted by Regulus to Sanofi pursuant to the Amended  Sanofi-Regulus License or the license under the Licensed IP granted by the Licensors to Sanofi  pursuant to any New License Agreement or Temporary License (as applicable), Sanofi shall (i)  directly pay Alnylama royalty of [...***...]% of Net Sales of such Royalty-Bearing Products during   the relevant Royalty Term (as defined below) and (ii) directly pay Ionis a royalty of [...***...]% of   Net Sales of such Royalty-Bearing Products during the relevant Royalty Term (as defined below).  For   clarity, the Licensors agree that the royalty payable by Sanofi to each Licensor with respect to Mir-21   Products that are Royalty-Bearing Products (whether pursuant to the sublicense under the Licensed IP   granted by Regulus to Sanofi pursuant to the Amended Sanofi-Regulus License or the license under   the Licensed IP granted by the Licensors to Sanofi pursuant to any New License Agreement or   Temporary License, as applicable), shall be calculated based on Net Sales as such term is defined in   Appendix 1 to the Sanofi-Regulus License (and not based on Net Sales as such term is defined in the   Alnylam-Ionis License).  Sanofi agrees that the royalty described in this Section 0 is payable to each   Licensor, regardless of whether a particular Mir-21 Product that is a Royalty-Bearing Product is   covered by such Licensor’s Licensed IP.  The Licensors hereby agree that, notwithstanding any   provision of the Alnylam-Ionis License to the contrary, and except for the royalty set forth above in   this Section 0, neither Regulus nor Sanofi shall have any royalty, sublicense income or other payment   obligations to the Licensors with respect to the Development, Manufacture or Commercialization of   Mir-21 Compounds and Mir-21 Products, including, without limitation, with respect to any payment   paid or payable by Sanofi to Regulus pursuant to the Amended Sanofi-Regulus License.  Sanofi agrees   to be bound by Section 8 of the Alnylam-Ionis License, mutatis mutandis, with respect to its royalty   payment obligations under this Section 0.  The Licensors will not be required to share any such   royalties with Regulus.         Royalties under this Section 0 will be payable with respect to a Mir-21 Product that is a  Royalty-Bearing Product on a Royalty-Bearing Product-by-Royalty-Bearing Product and country-by-  country basis from the First Commercial Sale (as defined in the Amended Sanofi-Regulus License) of   a Mir-21 Product that is a Royalty-Bearing Product in a country until the date that is the latest of   (a) the time during which the applicable Regulatory Authority in such country is not permitted to grant   Regulatory Approval for a generic equivalent of such Royalty-Bearing Product, and (b) the expiration   of the last to expire Valid Claim (as defined in the Alnylam-Ionis License) within the Regulus Patents  (as defined below) that Cover (as defined in the Alnylam-Ionis License) (i) the Manufacture (as   defined in the Alnylam-Ionis License) of such Royalty-Bearing Product in such country or (ii) the use,   sale or other Commercialization (as defined in the Alnylam-Ionis License) of such Royalty-Bearing   Product in such country (such period, the “Royalty Term”).  For purposes of this Section 0, “Regulus  Patents” shall mean, collectively: (A) the Patent Rights (as defined in the Alnylam-Ionis License)  included in, as applicable, (1) the Licensed IP sublicensed by                                                      ***Confidential Treatment Requested                                                                                      

 

     Regulus to Sanofi pursuant to the Amended Sanofi-Regulus License or (2) the Licensed IP licensed  by the Licensors to Sanofi pursuant to any New License Agreement or Temporary License (as  applicable); and (B) any other Regulus Patents (as defined in the Sanofi-Regulus License), which,  for clarity and solely for purposes of this Section 0, shall include the Mir-21 Product Specific Patents  (as defined in the Amended Sanofi-Regulus License).     Interpretation under Sanofi Ionis Agreement.  Notwithstanding the Amended Sanofi-Regulus   License, Ionis and Sanofi hereby agree that any Oligonucleotide, as such term is defined under that   certain License Agreement dated June 27, 2014 between Ionis and Sanofi-Aventis Deutschland  GmbH, a wholly owned subsidiary of Sanofi, (such License Agreement the “Sanofi-Ionis   Agreement”), that, prior to the Amended Sanofi-Regulus License, was deemed to be a Third Party- Oligonucleotide under the Sanofi-Ionis Agreement, shall continue to be deemed Third Party-  Oligonucleotides for purposes of the Sanofi-Ionis Agreement.    Assignment of Alnylam-Ionis License. Each Licensor agrees that if it assigns its rights under the   Alnylam-Ionis License, or any of the intellectual property licensed to Regulus thereunder, such   Licensor shall cause the applicable assignee to be bound by the terms of this Letter Agreement   applicable to such Licensor.            Notices.  Any notices required or permitted under this Letter Agreement shall be in writing, shall   specifically refer to this Letter Agreement, and shall be sent by recognized national overnight   courier, or registered or certified mail, postage prepaid, return receipt requested, to the following   addresses:            If to Regulus:          Regulus Therapeutics Inc.                                 10614 Science Center Drive                                  San Diego, California 92121                                 Attention: Chief Scientific Officer                                    With a copy to:         General Counsel            If to Alnylam:          Alnylam Pharmaceuticals, Inc.                                 300 Third Street                                 Cambridge, MA 02142                                 Attention: Chief Operating Officer                                          With a copy to:         General Counsel                                          If to Ionis:            Ionis Pharmaceuticals, Inc.                                 2855 Gazelle Court                                 Carlsbad, CA 92010                                 Attention Chief Operating Officer                                          With a copy to:         General Counsel                                                                                                                        

 

        If to Sanofi:           Sanofi                                54, rue la Boétie                                75008 Paris, France                                 Attention: General Counsel                                Facsimile:  +33 1 53 77 43 03          With a copy to:         Sanofi                                9 Rue du Président Allende,                                 94256 Gentilly Cedex, France                                Attention: License Management                                Facsimile: +33 1 53 77 48 51                                   All notices under this Letter Agreement are effective upon receipt.  Each party hereto may change its  contact information immediately upon written notice to the other parties in the manner provided in this  Section 0.    Miscellaneous.         Governing Law. This Letter Agreement is governed by and construed in accordance with the laws  of the State of New York irrespective of any conflicts of law principles. The parties to this Letter  Agreement hereby irrevocably submit to the jurisdiction of the state courts located in New York City,  New York, USA for the purpose of any dispute arising between the parties in connection with this Letter  Agreement.         Amendment and Waiver. The parties may only amend, supplement or otherwise modify this Letter  Agreement through a written instrument signed by all parties. The waiver of any rights or failure to act in  a specific instance relates only to that instance and is not an agreement to waive any rights or failure to act  in any other instance.         Assignment of this Letter Agreement. This Letter Agreement may not be assigned (i) by Regulus  without first obtaining the prior written consent of both Sanofi and the Licensors or (ii) by Sanofi or the  Licensors without first obtaining the prior written consent of the other, which consent may not be  unreasonably withheld or delayed. In no event will Sanofi or the Licensors be required to obtain Regulus’  prior written consent in order to assign this Letter Agreement. Notwithstanding the foregoing, this Letter  Agreement may be assigned by a party to an affiliate or in connection with a merger, consolidation, sale  of all of the equity interests of the party, or a sale of all or substantially all of the assets of such party to  which this Letter Agreement relates, with respect to each, without reference to the foregoing consent  rights.          Confidentiality. The terms of this Letter Agreement and the existence, nature and content of any  negotiations between the parties relating to a New License Agreement shall not be disclosed by any party  hereto without the prior written consent of the other parties.         Construction. The parties hereto acknowledge and agree that: (i) each party and its counsel have  reviewed and negotiated the terms and provisions of this Letter Agreement and have contributed to its  revision; (ii) the rule of construction to the effect that any ambiguities are resolved against the drafting  party shall not be employed in the interpretation of this Letter Agreement; and                                                                                         

 

   (iii) the terms and provisions of this Letter Agreement shall be construed fairly as to all parties  hereto and not in favor of or against any party, regardless of which party was generally responsible  for the preparation of this Letter Agreement.         Severability. If any provision of this Letter Agreement is held invalid or unenforceable for  any reason, the invalidity or unenforceability does not affect any other provision of this Letter  Agreement, and the parties shall negotiate in good faith to modify the Letter Agreement to preserve  (to the extent possible) their original intent.          Status. The status of each party under this Letter Agreement shall be that of an independent  contractor. Nothing in this Letter Agreement is intended or shall be deemed to constitute a partner,  agency, employer-employee, or joint venture relationship between or among the parties or, except as  expressly provided in this Letter Agreement, to grant any party the authority to bind or contract any  obligation in the name of or on the account of any other party or to make any statements,  representations, warranties or commitments on behalf of any other party.         Further Assurances. Each party hereto agrees to execute, acknowledge and deliver such  further instructions, and to do all such other acts, as may be necessary or appropriate in order to  carry out the purposes and intent of this Letter Agreement.         Counterparts. This Letter Agreement may be executed by facsimile and in one or more  counterparts, each of which is an original, and all of which together are one instrument.          Interpretation. Unless a context otherwise requires, wherever used, (i) the singular shall  include the plural, the plural the singular; (ii) the use of any gender shall be applicable to all genders;  (iii) the word “or” is used in the inclusive sense (and/or); and (iv) the word “including” is used  without limitation and shall mean “including without limitation.”         Headings.  All headings are for convenience only and do not affect the meaning of any  provision of this Letter Agreement.                         [Remainder of this page intentionally left blank]                                                                                       

 

   Please sign and return a copy of this Letter Agreement to us to acknowledge our mutual  agreement on this matter. Thank you for all of your assistance.    Sincerely,      SANOFI                                    Name:   Title:     ACKNOWLEDGED AND AGREED:      REGULUS THERAPEUTICS INC.                                    Name:   Title:       ALNYLAM PHARMACEUTICALS, INC.                                    Name:   Title:             IONIS PHARMACEUTICALS, INC.                                    Name:   Title:         

 

                                  EXHIBIT D-2                        Form of Stand-by License Agreement                          STANDBY LETTER AGREEMENT              This Letter Agreement (this “Letter Agreement”) is entered into as of [__], 2018  (the “Letter Agreement Effective Date”) by and among [____________________] a  [_____________________], with a principal place of business at [__________________]   (“LICENSOR”), and SANOFI, a société anonyme duly organized and validly existing  under the laws of the Republic of France, for and on behalf of itself and its Affiliates  (“SANOFI”).  LICENSOR, and SANOFI shall be individually referred to as a “Party” and  collectively as the “Parties.”                                     RECITALS                WHEREAS, Regulus Therapeutics Inc., a company duly organized and existing  under the laws of the State of Delaware (“REGULUS”) has licensed from LICENSOR  certain patents and other intellectual propery rights under a license agreement entered into  by and between REGULUS and LICENSOR      executed as of [____________] (the  “Regulus License Agreement”); and         WHEREAS, On February 4, 2014, Regulus entered into that certain Second  Amended and Restated Collaboration and License Agreement (the “Sanofi-Regulus  License”) with SANOFI, pursuant to which, among other things, Regulus assumed  responsibility for all activities under each POC Program Plan (other than SANOFI Program  Activities) through the Achievement of Proof of Concept (each as defined in the SANOFI- Regulus License).  Regulus has now suspended the Mir-21 Fibrosis POC Program and has  requested that SANOFI amend, and SANOFI has agreed to amend, the Sanofi-Regulus  License as it pertains to the Mir-21 POC Programs, Mir-21 Compounds and Mir-21  Products, to provide for, among other things: (a) SANOFI to take responsibility for the  obligations of Regulus under the Sanofi-Regulus License with respect to the Mir-21  Fibrosis POC Program, Mir-21 Compounds and Mir-21 Products, including the  administration and expense of clinical trials related to the Mir-21 Fibrosis POC Program  (each as defined in the Sanofi-Regulus License); and (b) the license and sublicense granted  by Regulus to SANOFI with respect to Mir-21 Compounds.                                                                                 

 

         As a condition to entering into the First Amendment to the Sanofi-Regulus License  (the “First Amendment”), SANOFI requests that Licensors execute this letter agreement  (this “Letter Agreement”) where indicated below, memorializing their agreement to the  following:                                      NOW THEREFORE, in consideration of the mutual covenants herein contained  and other good and valuable consideration, the receipt and sufficiency of which is hereby  acknowledged, the Parties agree as follows:          1.    Capitalized Terms.  Except as set forth herein, capitalized terms used  without definition in this Letter Agreement have the meanings assigned to them in the First  Amendment.                2.    No Breach by Regulus. Licensor confirms that, as of the date of this Letter  Agreement: (a) the Regulus License Agreement remains in full force and effect; (b)  Licensor has not given any notice to Regulus, and is not otherwise aware, of any breach by  Regulus under the Regulus License Agreement; and (c) Licensor has not taken any action  or omitted to take any action that could be deemed a breach of its obligations under the  Regulus License Agreement.             3.    Step-In Rights. LICENSOR  shall notify SANOFI in writing within  [...***...]  business days if the Regulus License Agreement terminates for any reason  (each, an “In-License Termination Notice”). Unless SANOFI notifies LICENSOR in  writing that it does not wish to get a direct license to the LICENSOR intellectual property,  then upon the termination of the Regulus License Agreement the LICENSOR will be  deemed to have automatically granted SANOFI a direct license (the “Step-in License”) to  [identify, develop, make, have made, import, export, use, have used, market, offer for sale  and sell pharmaceutical products in the Field under the LICENSOR Patents], under the  same financial terms as contained in [Section X] of the LICENSOR License Agreement,  provided, however, that (x) SANOFI is not at fault with respect to the material breach  underlying any such termination; and (y) if the material breach underlying the In-License  Termination Notice is financial in nature, SANOFI must pay LICENSOR to cure such  breach within [...***...] days of being notified by LICENSOR that the Step-in License has  been granted.                    4.    Notices.  Any notice or request required or permitted to be given under or in  connection with this Letter Agreement shall specifically refer to this Letter Agreement, and  shall be deemed to have been sufficiently given if in writing and personally delivered or  sent by certified mail (return receipt requested), facsimile transmission (receipt verified), or  overnight express courier service (signature required), prepaid, to the Party for which such  notice is intended, at the address set forth for such Party below:                                              ***Confidential Treatment Requested                                                                                 

 

                      In the case of SANOFI, to:                     SANOFI                     54 rue La Boétie                     75008 Paris, FRANCE                     Attention: General Counsel                     Facsimile No.:  +33 1 53 77 43 03                                          In the case of LICENSOR, to:                     [______________]                     [______________]                     [______________]                     Attention: [______________]                     Facsimile No.: [______________]                                            or to such other address for such Party as it shall have specified by like notice to the other  Parties, provided that notices of a change of address shall be effective only upon actual  receipt thereof.  All notices under this Letter Agreement shall be deemed effective upon  receipt.          5.    No Waiver of Rights.  Any waiver of any rights or failure to act in a  specific instance shall not operate or be construed as an agreement to waive any rights or  fail to act in any other instance, whether or not similar.          6.    Severability.  In case any one or more of the provisions contained in this  Letter Agreement shall, for any reason be held to be invalid, illegal, or unenforceable in  any respect, such invalidity, illegality, or unenforceability, shall not affect any other  provision of this Letter Agreement, and the Parties shall negotiate in good faith to modify  this Letter Agreement to preserve (to the extent possible) their original intent.                                                                                 

 

         7.    Counterparts.  This Letter Agreement, or any part thereof requiring signing  by the Parties, may be executed in separate counterparts, each of which shall be an original  as against any Party whose signature appears thereon but all of which together shall  constitute one and the same instrument.  A facsimile transmission of the signed Letter  Agreement, and those parts thereof requiring signing by the Parties, shall be legal and  binding on the Parties.          8.    Amendments.  No amendment or modification of or supplement to the  terms of this Letter Agreement shall be binding on a Party unless reduced to writing and  signed by all Parties.          9.    Entire Agreement.  This Letter Agreement sets forth the entire agreement  among the Parties as to the subject matter hereof and supersedes all prior and  contemporaneous agreements, understandings, negotiations and discussions, whether oral  or written, between the Parties as to the subject matter hereof.  This Letter Agreement and  all disputes arising out of or related to this Letter Agreement, or the performance,  enforcement, breach or termination hereof, and any remedies relating thereto, shall be  construed, governed, interpreted and applied in accordance with the laws of the state of  New York, without regard to conflict of laws principles.                                [Signature page follows]                                                                                

 

           IN WITNESS WHEREOF, the Parties hereto have caused this Letter Agreement to be  executed by their respective duly authorized officers as of the dates listed below.                                            [LICENSOR]                             SANOFI                                           By                                                                         By                                  Name                                                                      Name                                Title                                                                     Title                               Date                                                                      Date                                                                                                                                                                                                            

 

                                        EXHIBIT E                                    Form of Press Release                                   Regulus Announces Successful Restructuring of Sanofi Collaboration                  Sanofi Will Assume Development of RG-012 for Alport syndrome  LA JOLLA, Calif., November     [], 2018 – Regulus Therapeutics Inc. (Nasdaq: RGLS), a  biopharmaceutical company focused on the discovery and development of innovative medicines targeting  microRNAs, today announced that it has amended and restructured its Collaboration and License  Agreement with Sanofi (the “Amendment”).  Under the terms of the Amendment, Regulus has granted  Sanofi a worldwide exclusive license to develop and commercialize its investigational drug, targeting  miR-21 for all indications, including Alport syndrome. Under the Amendment, Sanofi will assume all  future costs and development activities associated with the advancement of RG-012, currently in Phase II  for Alport syndrome.     Under the terms of the Amendment, Regulus is eligible to receive approximately $7 million in upfront  and material transfer payments.  Regulus is also eligible to receive up to $40 million in development  milestone payments.  In addition, Sanofi will reimburse Regulus for certain out-of-pocket transition  activities and assume Regulus’ upstream license royalty obligations.      “We are pleased with Sanofi’s election to assume ongoing and future development of the RG-012  program in order to apply their expertise in rare diseases and to bring it forward as a potential new therapy  for patients with Alport syndrome.” said Jay Hagan, President and Chief Executive Officer of Regulus.  “We look forward to a rapid transition of the program to Sanofi and their ongoing clinical development,  while we continue to focus on our stated near-term objectives.  Specifically, we believe this restructuring  will improve our net cash position, yielding near term cash proceeds, eliminating RG-012-related spend  over the next several years, and will enable us to focus our resources on our other promising programs  targeting significant unmet medical needs in Autosomal Dominant Polycystic Kidney Disease and  Hepatitis B virus.”   About Alport Syndrome   Alport syndrome is an inherited form of kidney disease caused by mutations in the type IV collagen genes  (Col4A3, Col4A4 and Col4A5). Type IV collagen is important for maintaining the integrity of the  glomerular basement membrane (GBM), a vital component in the kidney structure and filtration process.  The genetic mutation in the collagen gene results in thickening in the GBM and impairment of glomerular  filtration. Alport syndrome patients experience a progressive loss of kidney function, which ultimately  leads to end stage renal disease requiring dialysis or kidney transplantation, or may even lead to death.  Alport syndrome can also cause hearing loss and eye abnormalities during late childhood or early  adolescence.  ACE (angiotensin-converting enzyme) inhibitors, although not approved for the indication,  are emerging as standard of care in patients with Alport syndrome to treat proteinuria, or abnormal  amounts of protein in the urine, an indicator of chronic kidney disease.  Alport syndrome represents a  high unmet medical need with no approved therapy.  miR-21 is believed to play a role in the disease     

 

                                                                                 progression and is up-regulated in Col4A3 deficient mouse models of Alport syndrome, other  renal fibrosis models and human CKD patients.  The role of miR-21 has been validated through  genetic knock-out models and anti-miRs targeting miR-21 have reduced the severity of fibrosis  in two distinct preclinical rodent models.     About RG-012   RG-012 is an investigational, single stranded, chemically modified oligonucleotide that binds to  and inhibits the function of miR-21 for the treatment of Alport syndrome. In preclinical studies,  RG-012 has demonstrated potent inhibition of miR-21 in vitro and in vivo, a decrease in the rate  of progression of renal fibrosis, an increase in the lifespan of the Col4A3 deficient mice by up to  fifty percent.  In May 2017, Regulus completed a Phase I multiple-ascending dose, or MAD,  study in 24 healthy volunteers (six-week repeat dosing) to determine safety, tolerability and PK  of RG-012 prior to chronic dosing in patients. In Phase I clinical studies to date there were no  serious adverse events, or SAEs, reported. Preliminary data from the first patients through a renal  biopsy study followed by an open-label extension were encouraging, with kidney tissue  concentrations achieved that would be predictive of therapeutic benefit based on animal disease  models. In addition, modulation of the target, miR-21, was observed. RG-012 has received  orphan designation in both the U.S. and Europe.    About Regulus    Regulus Therapeutics Inc. (Nasdaq: RGLS) is a biopharmaceutical company focused on the  discovery and development of innovative medicines targeting microRNAs.  Regulus has  leveraged its oligonucleotide drug discovery and development expertise to develop a pipeline  complemented by a rich intellectual property estate in the microRNA field.  Regulus maintains  its corporate headquarters in La Jolla, CA.  For more information, please visit  http://www.regulusrx.com.    Forward-Looking Statements    Statements contained in this press release regarding matters that are not historical facts are  "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act  of 1995, including statements associated with the expected ability of Regulus to undertake  certain activities and accomplish certain goals and objectives (including with respect to long  term sustainability, the reduction of its cash burn, and advancement of its pipeline and  programs).  Because such statements are subject to risks and uncertainties, actual results may  differ materially from those expressed or implied by such forward-looking statements. Words  such as "believes," "anticipates," "plans," "expects," "intends," "will," "goal," "potential" and  similar expressions are intended to identify forward-looking statements. These forward-looking  statements are based upon Regulus' current expectations and involve assumptions that may never  materialize or may prove to be incorrect.  Actual results and the timing of events could differ  materially from those anticipated in such forward-looking statements as a result of various risks  and uncertainties, which include, without limitation, risks associated with the process of  discovering, developing and commercializing drugs that are safe and effective for use as human  therapeutics, and in the endeavor of building a business around such drugs.  These and other      

 

                                                                                 risks concerning Regulus' financial position and programs are described in additional detail in  Regulus filings with the Securities and Exchange Commission.  All forward-looking statements  contained in this press release speak only as of the date on which they were made. Regulus  undertakes no obligation to update such statements to reflect events that occur or circumstances  that exist after the date on which they were made.    Investor Relations Contact:  Dan Chevallard  Chief Financial Officer  858-202-6376  dchevallard@regulusrx.com

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