Document:

Document

Exhibit 10.4

CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY [***], HAS BEEN OMITTED BECAUSE IT IS BOTH (I) NOT MATERIAL AND (II) IS THE TYPE THAT THE REGISTRANT TREATS AS PRIVATE OR CONFIDENTIAL.

 
 

AMENDMENT NUMBER ONE
TO THE
AMENDED AND RESTATED
LICENSE AND COLLABORATION AGREEMENT
 
This Amendment Number One (the “Amendment”) to the Amended and Restated License and Collaboration Agreement is entered into as of the 10th day of June, 2010 (the “Effective Date”) by and among ALNYLAM PHARMACEUTICALS, INC., a Delaware corporation, with its principal place of business at 300 Third Street, Cambridge, Massachusetts 02142 (“Alnylam”), ISIS PHARMACEUTICALS, INC., a Delaware corporation, with its principal place of business at 1896 Rutherford Road, Carlsbad, California 92008 (“Isis”, and each of Alnylam and Isis, a “Licensor” and together, the “Licensors”), and REGULUS THERAPEUTICS INC. (formerly Regulus Therapeutics LLC), a Delaware corporation, with its principal place of business at 1896 Rutherford Road, Carlsbad, California 92008 (“Regulus”).
 
RECITALS
 
WHEREAS, Isis and Alnylam each granted a license to Regulus in accordance with that certain License and Collaboration Agreement dated September 6, 2007 (the “Original License Agreement”), which Original License Agreement was amended and restated on January 1, 2009 (the “Amended License Agreement”);
 
WHEREAS, Isis, Alnylam, and Regulus now desire to amend the Amended License Agreement as provided herein.
 
AGREEMENT
 
NOW, THEREFORE, in consideration of the mutual covenants contained herein, and other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, Isis, Alnylam and Regulus each agrees as follows:
 
1.             DEFINITIONS
 
Capitalized terms used herein and not defined elsewhere herein have the meanings set forth in the Amended License Agreement.
 
2.             PAYMENTS
 
2.1           The following bullet point shall be added as a new second bullet point in the definition of “Exclusivity Period” in the Amended License Agreement:
 
“    with respect to a Royalty-Bearing Product being Commercialized by a Collaborator of Regulus (other than Alnylam or Isis), the Exclusivity Period shall expire at such time as such Collaborator is no longer required to pay Regulus any royalty (not including any amounts 
 

 
paid by Collaborator to Regulus arising from payment obligations to Third Parties) with respect to such  Royalty-Bearing Product; or”
 
2.2           Section 5.2 of the Amended License Agreement shall be deleted and replaced in its entirety by the following:
 
“5.2       Continued Development by Regulus of Development Projects.
 
(a)       Diligence.  If Regulus notifies Licensors pursuant to Section 5.1 that Regulus will continue to pursue the Development and Commercialization of such Development Project (on its own or with a Collaborator, as defined below), then, without limiting the generality of Section 4.1, Regulus will use Commercially Reasonable Efforts to Develop and Commercialize the relevant Development Compounds and Development Therapeutics in the Field.
 
(b)       Third Party Payments.  Regulus will be responsible for all milestones, royalties and other payments payable to Third Parties in respect of the Development, Manufacture and Commercialization of Development Therapeutics in the Field, by Regulus, its Affiliates and Sublicensees, including any amounts payable by either Licensor to Third Parties under the Third Party Rights.  The Parties will use reasonable efforts to [...***...].
 
(c)       Net Sales by Regulus.  Regulus will pay to each Licensor a royalty of [...***...]% of Net Sales of Development Therapeutics which are Royalty-Bearing Products which Net Sales are generated by Regulus rather than a Collaborator, during the relevant Royalty Term (provided, however, that, for the remainder of the relevant Royalty Term following the end of the relevant Exclusivity Period, the royalty rate will be [...***...]%).  Regulus agrees that the royalty described in Section 5.2(c) is payable to each Licensor, regardless of whether a particular Royalty-Bearing Product is covered by such Licensor’s Licensed IP.
 
(d)       Net Sales by a Collaborator of Regulus.  With respect to Net Sales by a Collaborator of Regulus (other than Alnylam or Isis), Regulus will pay to each Licensor a royalty of [...***...]% of Net Sales of such Development Therapeutics which are Royalty-Bearing Products; provided, that (i) the agreement with such Collaborator requires such Collaborator to make royalty payments to Regulus of at least [...***...]% of Net Sales (after any payments required to be made by Regulus to Third Parties) and (ii) the length of the Exclusivity Period with respect to such Collaborator is no shorter than the Exclusivity Period which would apply to Net Sales by Regulus under Section 5.2(c) above ((i) and (ii) being collectively referred to as “Consistent Sublicense Terms”).  Notwithstanding the foregoing, if the agreement with such Collaborator does not contain Consistent Sublicense Terms or if Regulus chooses at the time of, or prior to, entering into such agreement to have this sentence apply in lieu of the first sentence of this Section 5.2(d), such choice to be delivered in writing to Alnylam and Isis within thirty (30) days of entering into such sublicense agreement (a “Sublicense Income Agreement”), then (x) Isis, Alnylam and Regulus will each receive the [...***...] of (I) [...***...]% of [...***...] (A) [...***...] received by Regulus on the basis of such [...***...] pursuant to such Sublicense Income Agreement, and (B) [...***...] made to Third Parties as described in [...***...], and (II) [...***...]% 
 

***Confidential Treatment Requested

 
of Net Sales of such Development Therapeutics, and (y) Alnylam and Isis will be entitled to receive additional payments from Regulus in accordance with Section 5.2(e) below.  “Collaborator” means a Third Party sublicensee or other partner of Regulus which partner receives from Regulus a sublicense, participates with Regulus in a collaboration, receives from Regulus a technology transfer or otherwise obtains from Regulus rights related to Develop or Commercialize miRNA Compounds, miRNA Therapeutics, or miRNA Antagonists. A “Collaborator” will be considered a “Sublicensee” for purposes of this Agreement.
 
(e)           Sublicense Income.  With respect to each Sublicense Income Agreement, Regulus shall pay [...***...] of Sublicense Income received by Regulus to Alnylam and [...***...] of Sublicense Income received by Regulus to Isis.  “Sublicense Income” means all fees and other payments received by Regulus from a Collaborator in connection with a Sublicense Income Agreement, but excluding (i) debt, credit or lease financing (provided, however, that (x) any discount to market will not be excluded from the definition of Sublicense Income and (y) in the event that any portion of such debt, credit or lease is forgiven, such debt, credit, or lease will be deemed Sublicense Income in the amount of such forgiveness), (ii) the fair market value of any equity investments in Regulus, (iii) the bona fide reimbursement of future research and development funding by a third party (as specified in the Sublicense Income Agreement) at direct cost, (iv) the bona fide reimbursement of future out-of-pocket costs of patent filing, prosecution and maintenance, and patent defense, and (v) royalties for which compensation is paid to Alnylam and Isis pursuant to Section 5.2(d).  For purposes of clarity, payments for specific events associated with sales such as net sales-based milestones or unit-based milestones will not be excluded from Sublicense Income.  Notwithstanding the foregoing, the $[...***...] [...***...] payments to Regulus from [...***...] pursuant to [...***...] research collaboration will not be considered Sublicense Income.
 
(f)            Full Consideration.  Regulus agrees that the royalties described in Sections 5.2(c) and 5.2(d) and the Sublicense Income provisions contained in Section 5.2(e) are payable to each Licensor, regardless of whether a particular Royalty-Bearing Product is covered by such Licensor’s Licensed IP.  Each Party agrees and acknowledges that such royalty structure (i) is freely entered into by such Party, (ii) is a fair reflection of the value received by Regulus from the licenses granted by the Licensors, and (iii) is a reasonable allocation of the value received by Regulus from each Licensor, due to the difficulty of determining the extent to which Licensor’s Licensed IP covers or has enabled each Royalty-Bearing Product.”
 
3.             BUY OUT
 
3.1           Buy-Out.  Any and all references in the Amended License Agreement to the term “Buy-Out” are null and void.
 

***Confidential Treatment Requested

4.             MISCELLANEOUS
 
4.1           Other Terms.  All other terms and conditions of the Amended License Agreement shall remain in full force and effect.  The Amendment Number One to the Amended and Restated License and Collaboration Agreement entered into among Regulus and the Licensors on June 7, 2010 is superseded and replaced by this Amendment and is deemed void ab initio.
 
4.2           Counterparts.  This Agreement may be executed in any number of counterparts, each of which will be deemed an original, and all of which together will constitute one and the same instrument.
 
[Remainder of Page Intentionally Left Blank]
 

    IN WITNESS WHEREOF, the Parties hereby execute this Amendment Number One to the Amended and Restated License and Collaboration Agreement as of the date first written above.
 
 
												
	 	 	ALNYLAM PHARMACEUTICALS, INC.
	 	 	 	 
	 	 	By:	/s/ Barry Greene
	 	 	 	Name: Barry Greene
	 	 	 	Title: President and Chief Operating Officer
	 	 	 
	 	 	 
	 	 	ISIS PHARMACEUTICALS, INC.
	 	 	 	 
	 	 	 	 
	 	 	By:	/s/ B. Lynne Parshall
	 	 	 	Name: B. Lynne Parshall
	 	 	 	Title: Chief Operating Officer and CFO
	 	 	 
	 	 	 
	 	 	REGULUS THERAPEUTICS INC.
	 	 	 
	 	 	 
	 	 	By:	/s/ Kleanthis G. Xanthopoulos
	 	 	 	Name: Kleanthis G. Xanthopoulos, Ph.D.
	 	 	 	Title: President and Chief Executive Officerexhibit105-sdx753896xv4x

Exhibit 10.5    CERTAIN CONFIDENTIAL INFORMATION CONTAINED IN THIS DOCUMENT, MARKED BY [***],  HAS BEEN OMITTED BECAUSE IT IS BOTH (I) NOT MATERIAL AND (II) IS THE TYPE THAT THE  REGISTRANT TREATS AS PRIVATE OR CONFIDENTIAL.     1.             EXECUTION COPY  AMENDMENT NUMBER TWO  TO THE  AMENDED AND RESTATED  LICENSE AND COLLABORATION AGREEMENT    This Amendment Number Two (the “Amendment”) to the Amended and Restated License  and Collaboration Agreement is entered into as of the 25th day of October, 2011 (the “Effective  Date”) by and among ALNYLAM PHARMACEUTICALS, INC., a Delaware corporation, with its  principal place of business at 300 Third Street, Cambridge, Massachusetts 01242 (“Alnylam”),  ISIS PHARMACEUTICALS, INC., a Delaware corporation, with its principal place of business at 2855  Gazelle Court, Carlsbad, California 92010 (“Isis”, and each of Alnylam and Isis, a “Licensor” and  together, the “Licensors”), and REGULUS THERAPEUTICS INC. (formerly Regulus Therapeutics  LLC), a Delaware corporation, with its principal place of business at 3545 John Hopkins Court,  San Diego, California 92121 (“Regulus”).  RECITALS  WHEREAS, Isis and Alnylam each granted a license to Regulus in accordance with that  certain License and Collaboration Agreement dated September 6, 2007 (the “Original License  Agreement”), which Original License Agreement was amended and restated on January 2, 2009,  and further amended on June 10, 2010 (the “Amended License Agreement”); and   WHEREAS, Isis, Alnylam, and Regulus now desire to further amend the Amended License  Agreement to, among other things, allow Regulus to perform research and development with  respect to miRNA Mimics as provided below.  AGREEMENT   NOW, THEREFORE, in consideration of the mutual covenants contained herein, and other  good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged,  Isis, Alnylam and Regulus each agrees as follows:  1. DEFINITIONS  Capitalized terms used herein and not defined elsewhere herein have the meanings set forth  in the Amended License Agreement.  2. LICENSES   2.1 Section 2.2(b) of the Amended License Agreement shall be deleted and replaced in  its entirety by the following:  

 

 2.      ***Confidential Treatment Requested     “(b) Request to License miRNA Mimics and Additional miRNA Precursor Antagonists.   Regulus may request a worldwide, royalty-bearing, sublicenseable (in accordance with  Section 2.5), exclusive license in the Field, under each Licensor’s Licensed IP, to Develop,  Manufacture and Commercialize specific miRNA Mimics or specific miRNA Precursor  Antagonists that are not then Approved Mimics or Approved Precursor Antagonists, and  miRNA Therapeutics containing such miRNA Mimics or  miRNA Precursor Antagonists, by providing written notice to the applicable Licensor(s)  thereof on a miRNA Mimic-by-miRNA Mimic or miRNA Precursor Antagonist by- miRNA Precursor Antagonist basis.  Such license is subject to (i) review and affirmative  approval by the applicable Licensor(s), which approval may be withheld by a Licensor in  such Licensor’s sole discretion, and (ii) compliance with relevant Third Party Rights.   [...***...].  For the avoidance of doubt, Regulus’ rights to such miRNA Mimic or miRNA  Precursor Antagonist will be limited as set forth in Section 2.2(d) unless and until the  affirmative approval of the relevant Licensor(s) and any required consents or approvals  from Third Parties have been obtained and Regulus agrees to comply with all Third Party  Rights with respect to each such miRNA Mimic or miRNA Precursor Antagonist, even to  the extent inconsistent with this Agreement.  Each miRNA Mimic and miRNA Precursor  Antagonist that is approved by both Licensors pursuant to this Section 2.2(b) shall upon  such approval be deemed an “Approved Mimic” or “Approved Precursor Antagonist” for  all purposes under this Agreement.”  2.2 The following will be added to the Amended License Agreement as Section 2.2(d);  “(d) Research Grant.  Subject to the terms and conditions of this Agreement (including  but not limited to Section 2.4), Isis and Alnylam hereby grant to Regulus a worldwide,  royalty-bearing, sublicensable (in accordance with Section 2.5) nonexclusive license in the  Field, under each Licensor’s Licensed IP, to Research miRNA Mimics; provided, however,  that in exercising its rights under this Section 2.2(d) or under Section 2.2(b) hereof using  the Alnylam Licensed IP, Regulus shall at all times comply with Alnylam’s “Guidelines  for Evaluation of Clinical Candidates” (the “Clinical Candidate Guidelines”)”, attached to  this Agreement as Schedule 2.2(d), as such Clinical Candidate Guidelines may be  reasonably revised by Alnylam from time to time and provided to Regulus.  2.3 Section 2.3 of the Amended License Agreement shall be deleted and replaced in its  entirety by the following:  “2.3 Licenses Granted to Licensors Under Regulus IP.  Subject to the terms and  conditions of this Agreement, including but not limited to the license granted to Regulus  under Section 2.2(d) and to Third Party Rights:  (a) Regulus hereby grants to Alnylam a worldwide, exclusive, royalty-free,  perpetual and irrevocable license, with the right to grant sublicenses, under the  Regulus IP (except for Regulus IP claiming the exact composition, i.e. specific  sequence combined with chemistry, of a miRNA Mimic discovered by Regulus) a  solely to the extent necessary or useful to research, discover, develop, make, have  made, use, sell, offer to sell and/or otherwise commercialize (i) a double-stranded  oligonucleotide or analog thereof that are not miRNA Antagonists, Approved  Precursor Antagonists, or Approved Mimics (“Double-Stranded Oligos”) and (ii)  any product containing a Double-Stranded Oligo that are not miRNA Antagonists,  

 

 3.      ***Confidential Treatment Requested     Approved Precursor Antagonists, or Approved Mimics (the “Alnylam Field”);  provided that in no event shall the rights granted above in any way restrict or  otherwise prohibit Regulus from Researching, Developing, Manufacturing and  Commercializing miRNA Mimics covered by such Regulus IP.  (b) Regulus hereby grants to Isis a worldwide, exclusive, royalty-free perpetual  and irrevocable license, with the right to grant sublicenses, under the Regulus IP  (except for Regulus IP claiming the exact composition, i.e. specific sequence  combined with chemistry, of a miRNA Mimic discovered by Regulus) solely to the  extent necessary or useful to research, discover, develop, make, have made, use,  sell, offer to sell and/or otherwise commercialize (i) single-stranded  oligonucleotide or analogs thereof that are not miRNA Antagonists, Approved  Precursor Antagonists, or Approved Mimics and (ii) any product containing single- stranded oligonucleotides or analogs thereof that are not miRNA Antagonists,  Approved Precursor Antagonists, or Approved Mimics (the “Isis Field”); provided  that in no event shall the rights granted above in any way restrict or otherwise  prohibit Regulus from Researching, Developing, Manufacturing and  Commercializing miRNA Mimics covered by such Regulus IP.  2.4 Section 2.5(a) is hereby deleted and replaced in its entirety by the following:  “(a)” Right to Sublicense  (i) Subject to Third Party Rights, Regulus will have the right to grant to its  Affiliates and Third Parties sublicenses under the licenses granted in Section 2.2(a)(i),  2.2(a)(ii), 2.2(a)(iii) and 2.2(b).  (ii) Subject to Third Party Rights, Regulus will have the right to grant to its  Affiliates and Third Parties sublicenses under the licenses granted in Section 2.2(d);  provided, however, that (x) any such sublicense to a Third Party shall be solely for the  purposes of allowing such Third Party to evaluate the technology being so sublicensed and  (y) such sublicense shall not include any technology transfer from Regulus to such Third  Party nor shall Regulus convey to such Third Party detailed information about any  chemistry or delivery technology licensed to Regulus by Alnylam.”  2.5 Section 3.1 is hereby deleted and replaced in its entirety by the following:  “3.1 Technology Transfer to Regulus.  At each meeting of the Collaboration Working  Group the representatives will discuss new Know-How and Patent Rights of Isis and  Alnylam that are included in such Licensor’s Licensed Patents and Licensed Know-How  hereunder at the level of detail necessary to enable Regulus to effectively practice such  Patent Rights and Know-How; provided, however, that Regulus shall not transfer,  sublicense, disclose details of, or otherwise convey to any Third Party any details regarding  Know-How and Patent Rights licensed to Regulus by Alnylam with respect to the delivery  of oligonucleotides except with respect to a Development Therapeutic  containing an  Approved Mimic on a product-by-product basis for the sublicenses granted to such Third  Parties.”  

 

 4.      ***Confidential Treatment Requested     2.6 Exhibit 1 to the Amended License Agreement is hereby amended by adding the  following Defined Term:  “Double-Stranded Oligo” will have the meaning set forth in Section 2.3(a).”  2.7 Section 1.59 of Exhibit 1 of the Amended License Agreement shall be deleted and  replaced in its entirety by the following:  “miRNA” means a structurally defined functional RNA molecule usually between  [...***...] and [...***...] nucleotides in length, which is derived from an endogenous,  genetically-encoded non-coding RNA which is predicted to be processed into a hairpin  RNA structure that is a substrate for the double-stranded RNA-specific ribonuclease  Drosha and subsequently is predicted to serve as a substrate for the enzyme Dicer, a  member of the RNase III enzyme family; including, without limitation, those miRNAs  exemplified in miRBase (http://microrna.sanger.ac.uk/).  To the extent [...***...] for  purposes of this Agreement; provided, however, that nothing contained herein shall require  any Party hereto to [...***...].  3. Section 1.62 of Exhibit 1 of the Amended License Agreement shall be deleted and replaced  in its entirety by the following:  “miRNA Mimic” means a single-stranded or double-stranded oligonucleotide with the  same or substantially similar-base composition and sequence (including chemically  modified bases) as a particular natural miRNA and which is designed to mimic the activity  of such miRNA.  For clarity, miRNA Mimic excludes a double-stranded oligonucleotide  which functions or is designed to function as an siRNA.  4. MISCELLANEOUS  4.1 Other Terms.  All other terms and conditions of the Amended License Agreement  shall remain in full force and effect.  4.2 Counterparts.  This Agreement may be executed in any number of counterparts,  each of which will be deemed an original, and all of which together will constitute one and the  same instrument.  [Remainder of Page Intentionally Left Blank]    

 

              IN WITNESS WHEREOF, the Parties hereby execute this Amendment Number Two to the  Amended and Restated License and Collaboration Agreement as of the date first written above.  ALNYLAM PHARMACEUTICALS, INC.  By:  /s/ Laurence E. Reid   Name: L. Reid  Title: Chief Business Officer  ISIS PHARMACEUTICALS, INC.  By:  /s/ B. Lynne Parshall   Name: B. Lynne Parshall  Title: Chief Operating Officer and Chief  Financial Officer   REGULUS THERAPEUTICS INC.  By:  /s/ Kleanthis G. Xanthopoulos   Name: Kleanthis G. Xanthopoulos  Title: President and CEO      

 

                                                                                                                                ***Confidential Treatment Requested           Schedule 2.2(d)  Guidelines for Evaluation of Clinical Candidates  In vivo Dosing Requirements:  Formulation [...***...]  • May be tested at Regulus or collaborators in [...***...]   [...***...]   [...***...]   [...***...]  • Need approval for testing in [...***...]   Written approval may be obtained from Alnylam after the following information is  provided:  a very brief description on the experiment with the following  information:  - Purpose of experiment  - Specify formulation (and microRNA)  - What type of testing (in vitro or in vivo with details of which cell- line/species)  - [...***...]  Publication Guidelines:  • All draft publications, including but not limited to manuscripts, abstracts, posters,  PowerPoint (or any other presentation media format) presentations disclosing data related  to a formulation component must be submitted for approval, [...***...] in advance of being  submitted to any outside entity, to [...***...].  • Each draft publication submitted for approval should be in its final form taking into  consideration the following guidelines:  To the extent allowable, no [...***...], such as [...***...] shall be included  [...***...]

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00327-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00327-of-00352.parquet"}]]