Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 1 of 266 PageID #: 13063
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`ARBUTUS BIOPHARMA CORPORATION
`and GENEVANT SCIENCES GmbH,
`
`Plaintiffs,
`
`v.
`
`
`
`MODERNA, INC. and MODERNATX, INC.,
`
`Defendants.
`
`)
`)
`)
`)
`)
`) C.A. No. 22-252-MSG
`)
`) HIGHLY CONFIDENTIAL –
`) OUTSIDE COUNSELS EYES ONLY
`) FILED UNDER SEAL
`
`LETTER TO THE HONORABLE MITCHELL S. GOLDBERG FROM
`NATHAN R. HOESCHEN REGARDING DISCOVERY DISPUTE
`
`John W. Shaw (No. 3362)
`Karen E. Keller (No. 4489)
`Nathan R. Hoeschen (No. 6232)
`SHAW KELLER LLP
`I.M. Pei Building
`1105 North Market Street, 12th Floor
`Wilmington, DE 19801
`(302) 298-0700
`jshaw@shawkeller.com
`kkeller@shawkeller.com
`nhoeschen@shawkeller.com
`Attorneys for Plaintiffs
`
`OF COUNSEL:
`David I. Berl
`Adam D. Harber
`Thomas S. Fletcher
`Jessica Palmer Ryen
`Shaun P. Mahaffy
`Jihad J. Komis
`Anthony H. Sheh
`Matthew W. Lachman
`Philip N. Haunschild
`Falicia Elenberg
`WILLIAMS & CONNOLLY LLP
`680 Maine Avenue S.W.
`Washington, DC 20024
`(202) 434-5000
`Attorneys for Plaintiff Genevant
`Sciences GmbH
`
`Daralyn J. Durie
`Adam R. Brausa
`Eric C. Wiener
`Annie A. Lee
`Shaelyn K. Dawson
`MORRISON & FOERSTER LLP
`425 Market Street
`San Francisco, CA 94105-2482
`(415) 268-6080
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 2 of 266 PageID #: 13064
`
`Kira A. Davis
`MORRISON & FOERSTER LLP
`707 Wilshire Boulevard
`Los Angeles, CA 90017-3543
`(213) 892-5200
`
`David N. Tan
`MORRISON & FOERSTER LLP
`2100 L Street, NW, Suite 900
`Washington, DC 20037
`(202) 887-1500
`Attorneys for Plaintiff Arbutus
`Biopharma Corporation
`
`Dated: January 9, 2024
`
`2
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 3 of 266 PageID #: 13065
`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 3 of 266 PagelD #: 13065
`Nathan R. Hoeschen
`
`ene1105 North MarketStreet, 12Floor
`Wilmington, DE 19801
`(302) 298-0709 — Direct
`nhoeschen@shawkeller.com
`
`
`
`HAW KELLER
`|LP
`
`BY CM/ECF
`The Honorable Mitchell S. Goldberg
`HIGHLY CONFIDENTIAL -
`USS.District Court for the Eastern District of Pennsylvania
`James A. Byrne U.S. Courthouse, Room 17614
`OUTSIDE COUNSEL EYES ONLY
`601 MarketStreet, Philadelphia, PA 19106-1797
`FILED UNDER SEAL
`
`Re:
`
`Arbutus Biopharma Corporation, et. al. v. Moderna, Inc., et. al. C_.A. No. 22-252-MSG
`
`Dear Judge Goldberg:
`
`Plaintiffs move for the production of three limited, relevant categories of documents.
`Plaintiffs first seek a narrow set of regulatory documents for products that use LNPswith the lipid
`molarratios in Plaintiffs’ asserted patent claims—specifically, the chemistry, manufacturing, and
`controls sections (typically contained in Module 3) of Moderna’s “Investigational New Drug”
`applications (“INDs”) and related correspondence with the FDA. These documents, which are
`relevant
`to non-obviousness, willful
`infringement, and damages, can be produced from a
`centralized repository with minimal burden. Second, Plaintiffs seek documents concerning the
`marketing, negotiation, and contracting for batches of Modema’s COVID-19 vaccine that
`Moderna unilaterally declares are “not accused of infringement” because they were allegedly
`manufactured and used abroad. However, such batches, which are accusedof infringement, could
`have been so/d in the U.S. under black-letter law, and are thus subject to damagesin this action.
`Modernacannotprevent discovery aboutthe locus of sale for these batches based on its untested
`say-so. Third, Plaintiffs seek minutes from meetings of, and materials provided to, Moderna’s
`Board of Directors discussing the accused product. This is a narrow category of documents that
`are squarely relevant to damages, and Moderna hasnot asserted any undue burden.
`
`Ps 163-67, Ex. 1 at 9-10). Despite criticizing Plaintiffs’ LNP technology both
`publicly and in this case, Moderna repeatedly sought FDA approval to perform human testing
`using LNPs within the scope of Plaintiffs’ asserted patent claims. Modemapublicly has admitted
`to performing such studies using LNPs within Plaintiffs’ claimed ratios, Ex. 2 at 1322-24; Ex. 3
`at 3327-28. The INDsseeking approval to perform these humanstudies contain detailed, non-
`public statements that discuss the patented technology, report on studies with the technology, and
`providescientific justifications for use of Plaintiffs’ claimed lipid molar ratios and components.
`
`There is no genuine dispute that Moderna’s INDsare relevant.
`
`5; Ex. 6 at 28-29. Ex. 7 at *767. And Moderna repeatedly has demandedthat Plaintiffs also produce INDs
`
`sponsored by Plaintiffs’ predecessors. While Plaintiffs agreed to produce such documents, Ex. 8
`at 1, Moderna hassteadfastly refused to produce the requested IND excerpts, despite admitting
`that it maintains them in a centralized repository, minimizing any production burden on Moderna.
`
`Any such minimal burden is vastly outweighed by the documents’ substantial relevance.
`For example, by reflecting Moderna’s widespread copying of the patented inventions, Moderna’s
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 4 of 266 PageID #: 13066
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`SHAW KELLER LLP
`
`Page 2
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`INDs provide “compelling evidence” nullifying its obviousness defenses, to the extent Moderna
`is not estopped from raising them in light of its failed IPRs. Adv. Display Sys., Inc. v. Kent State
`Univ., 212 F.3d 1272, 1285 (Fed. Cir. 2000). Moderna’s INDs are also relevant to willful
`infringement by demonstrating its knowledge of, and history with, the patents and patented
`technology. Georgetown Rail Equip. Co. v. Holland L.P., 867 F.3d 1229, 1245 (Fed. Cir. 2017).
`Even divorced from these legal theories, Moderna’s INDs likely contain statements directly
`commenting on the technology at issue in this case, and are plainly relevant for that reason as well.
`
`Moderna offers no valid reason the requested IND sections should not be produced. First,
`Moderna asserts that certain INDs (from 2017) are irrelevant to copying and willfulness because
`Moderna’s work was conducted pursuant to an unauthorized sublicense from Acuitas, D.I. 1 ¶¶
`32–34, or based on publicly available information. Setting aside that this argument does not
`address the full scope of non-public INDs that Plaintiffs seek, Moderna’s attorney argument does
`not render its INDs non-discoverable. Nor does the fact that certain IND studies may have been
`conducted pursuant to a license change their relevance to willful infringement here, which
`concerns activities beyond the scope of the license. Georgetown Rail, 867 F.3d at 1245. And none
`of this addresses the fact that the requested documents contain Moderna’s indisputably relevant
`statements regarding the patented technology.
`
`Moderna also objects that the INDs concern non-accused products. But the requested INDs
`include information about
`
`Exs. 2–6. Regardless, there is no rule limiting discovery to the accused product only. See, e.g.,
`Eli Lilly & Co. v. Wockhardt Ltd., 2010 WL 2605855, at *5 (S.D. Ind. June 22, 2010) (compelling
`production of IND for another formulation). “[C]ourts have allowed discovery to include non-
`accused products where a party either demonstrates the relevance of the non-accused products to
`the allegations and or their reasonable similarity to the accused product,” as Plaintiffs have done
`here, and “Delaware federal district courts . . . have concluded that discovery into non-accused
`products, particularly prior to the filing of final contentions, is permissible as long as it is narrowly
`tailored.” LKQ Corp. v. Kia Motors Am., Inc., 2023 WL 3455315, at *3 (N.D. Ill. May 15, 2023);
`Invensas Corp. v. Renesas Elecs. Corp., 287 F.R.D. 273, 283 (D. Del. 2012); Elm 3DS Innovations,
`LLC v. Samsung Elecs. Co., Ltd., 2015 WL 13902870, at *1–2 (D. Del. June 30, 2015). Moderna’s
`INDs for products using Plaintiffs’ lipid ratios are precisely the sort of “narrowly tailored,” highly
`relevant discovery that poses minimal burden, and should be compelled.
`
`Sales Discovery (RFPs 60, 64, 69, 74, 75, 81, 83, Ex. 9 at 14–18; Interrog. 11, Ex. 10).
`Moderna also refuses to produce discovery concerning sales of the batches that it unilaterally
`deems non-infringing under 35 U.S.C. § 271(a) because they were not manufactured or used in the
`U.S. Ex. 11 at 1. Moderna disregards Plaintiffs’ allegations that Moderna’s sales of these batches
`occurred in the U.S., e.g., D.I. 1 ¶¶ 50–54, 70, and defies binding precedent stating that such U.S.
`sales are infringing acts. E.g., Caltech v. Broadcom Ltd., 25 F.4th 976, 993 (Fed. Cir. 2022);
`Carnegie Mellon Univ. v. Marvell Tech. Grp., Ltd., 807 F.3d 1283, 1310 (Fed. Cir. 2015). Sales
`“for products manufactured, delivered, and used entirely abroad,” may “be found to have occurred
`in the United States”—and thus infringing under § 271(a)—“where a substantial level of sales
`activity occur[ed]” in the U.S. Ex. 12 at Appx184, aff’d in relevant part Caltech, 25 F.4th at 992.
`And products “not made or used in, or imported into, the United States” may infringe if there is a
`“domestic location of sale.” CMU, 807 F.3d at 1310. Determining where a sale occurred is a fact-
`specific inquiry, in which courts have considered (1) where a contract or sale was negotiated; (2)
`where purchase orders and payments issue or are received; (4) where a contract was executed; (5)
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 5 of 266 PageID #: 13067
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`SHAW KELLER LLP
`
`Page 3
`
`where contingent actions under a contract occur; (6) where specific orders are negotiated or
`finalized; (7) where marketing activities occur or are directed; and/or (8) where testing or design
`work underlying the sale occurred. See, e.g., Caltech, 25 F.4th at 976; Halo Elecs., Inc. v. Pulse
`Elecs., Inc., 831 F.3d 1369, 1378 (Fed. Cir. 2016); CMU, 807 F.3d at 1308; Ex. 13.
`
`Moderna ignores this precedent, and refuses discovery, by baldly declaring its sales
`occurred abroad. Ex. 14 at 1. Moderna improperly confuses its unilateral view of the merits of
`infringement with discoverability. Plaintiffs are not obligated to accept Moderna’s untested
`assertions, but are “entitled to discover the extent to which [Moderna] has engaged in foreign sales
`activities” to determine if sales of products made and used abroad in fact “occurred within the
`U.S.” McGinley v. Luv N’Care, Ltd., 2018 WL 9814589, at *5 (W.D. La. Sept. 10, 2018).
`Plaintiffs are “not required to prove [their] case” for infringing sales “before being entitled to such
`discovery.” Apeldyn Corp. v. AU Optronics Corp., 2010 WL 11470585, at *1 (D. Del. Apr. 12,
`2010) (compelling “worldwide sales data”); Pos. Techs., Inc. v. Sony Elecs., Inc., 2013 WL
`707914, at *6 (N.D. Cal. Feb. 26, 2013) (“It would be improper under Rule 26 to expect Plaintiff
`to show that the discovery it seeks is admissible when it has not yet obtained the discovery.”).
`Moderna cannot dispute that significant sales activities occurred at its U.S. headquarters, key
`testing and design work occurred in the U.S., and employees executed contracts in the U.S.
`Moderna should be compelled to produce documents and information concerning the sales of its
`COVID-19 vaccine that it contends were for batches manufactured and used abroad, and not to
`limit discovery to batches manufactured or used in the U.S, as it has in response to each of
`Plaintiffs’ requests.1
`
`Board Materials (RFP 130, Ex. 1 at 2). Moderna refuses to produce minutes of meetings
`of, and materials provided to, its Board of Directors discussing the accused product. Moderna has
`acknowledged that this request “is narrowly circumscribed,” Ex. 15 at 7, and has not disputed
`relevance. Nor could it. Such materials are directly relevant to damages, as planning and strategy
`around the accused product are evidence about the hypothetical negotiation. Indeed, Moderna’s
`CEO testified before Congress that its Board made strategic sales decisions, including agreeing to
`give an unsolicited $2.9 billion discount to the U.S. Government. Ex. 16, 54:5-22, 83:9. Moderna
`also has not asserted burden, as such materials generally are centrally stored. Ex. 15 at 10.
`
`Moderna’s sole basis to resist production has been shifting counter-demands. Plaintiffs
`agreed to produce the same scope of Board materials requested from Moderna, plus more. Ex. 15
`at 4. So Moderna demanded yet more: first that Plaintiffs produce their and their predecessors’
`board materials concerning not just the accused product, but effectively every LNP made in their
`two-decade-plus history. Then, Moderna demanded that Plaintiffs and non-party Roivant produce
`documents discussing lipid molar ratios and the asserted patents. Ex. 15 at 2. This conditioning
`is improper. Genentech, Inc. v. Trustees of Univ. of Pa., 2011 WL 7074208, at *1 (N.D. Cal. June
`10, 2011). The documents Plaintiffs seek are targeted and plainly relevant to damages. Courts
`routinely compel defendants in patent litigation to produce board materials regarding the accused
`product, and Plaintiffs respectfully request the Court follow suit here. E.g., Vasudevan Software,
`Inc. v. MicroStrategy Inc., 2013 WL 597655, at *1 (N.D. Cal. Feb. 15, 2013) (ordering production
`of board minutes); Unilin Beheer B.V. v. NSL Trading Corp., 2015 WL 12698382, at *9 (C.D. Cal.
`Feb. 27, 2015) (ordering investigation into board minutes and other financial documents).
`
`1 Plaintiffs have also sought samples of such batches. D.I. 161.
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 6 of 266 PageID #: 13068
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`SHAW KELLER LLP
`
`Page 4
`
`Respectfully submitted,
`/s/ Nathan R. Hoeschen
`Nathan R. Hoeschen (No. 6232)
`
`cc:
`
`Clerk of the Court (by CM/ECF)
`All counsel of record (by CM/ECF & e-mail)
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 7 of 266 PageID #: 13069
`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 7 of 266 PagelD #: 13069
`
`
`
`
`EXHIBIT 1
`EXHIBIT 1
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 8 of 266 PageID #: 13070
`
`HIGHLY CONFIDENTIAL – OUTSIDE COUNSEL EYES ONLY
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`ARBUTUS BIOPHARMA CORPORATION
`and GENEVANT SCIENCES GmbH,
`
`
`
`
`Plaintiffs,
`
`
`MODERNA, INC. and MODERNATX, INC.,
`
`
`
`Defendants.
`
`v.
`
`
`
`
`
`)
`)
`)
`)
`) C.A. No. 22-252-MSG
`
`)
`) CONTAINS INFORMATION
`) MODERNA DESIGNATED HIGHLY
`) CONFIDENTIAL – OUTSIDE
`) COUNSEL EYES ONLY
`
`
`
`
`PLAINTIFFS’ THIRD SET OF REQUESTS
`FOR PRODUCTION TO DEFENDANTS (NOS. 128–173)
`
`Pursuant to Federal Rules of Civil Procedure 26 and 34, Plaintiffs Arbutus Biopharma
`
`Corporation (“Arbutus”) and Genevant Sciences GmbH (“Genevant”) direct the following
`
`requests for production to Defendants Moderna, Inc. and ModernaTX Inc. (collectively,
`
`“Moderna” or “Defendants”). Responses to these requests shall be served upon Plaintiffs’
`
`undersigned counsel within 30 days of service of these requests, or at such time and location as
`
`may be mutually agreed upon by the parties. Copies shall be produced as they are kept in the
`
`ordinary course of business, including their labeling as to the source of the documents. Pursuant
`
`to Fed. R. Civ. P. 26(e), these requests are continuing and require supplemental answers.
`
`DEFINITIONS & INSTRUCTIONS
`
`Plaintiffs incorporate herein by reference as though fully set forth herein the Definitions
`
`and Instructions of Plaintiffs’ First Set of Requests for Production to Defendants (Nos. 1–98)
`
`served December 20, 2022.
`
`1
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 9 of 266 PageID #: 13071
`
`HIGHLY CONFIDENTIAL – OUTSIDE COUNSEL EYES ONLY
`
`1.
`
`The “2013 Moderna-AstraZeneca Agreement” refers to the 2013 agreement
`
`between Moderna and AstraZeneca related to the development of “mRNA therapeutics.” See,
`
`e.g., https://news.modernatx.com/news/news-details/2013/AstraZeneca-and-Moderna-
`
`Therapeutics-Announce-Exclusive-Agreement-to-Develop-Pioneering-Messenger-RNA-
`
`Therapeutics-in-Cardiometabolic-Diseases-and-Cancer/default.aspx; https://www.
`
`astrazeneca.com/media-centre/press-releases/2013/astrazeneca-moderna-therapeutics-
`
`cardiometabolic-diseases-cancer-treatment-21032013.html#!; https://www.sec.gov/Archives/
`
`edgar/data/1682852/000095012318009738/filename5.htm.
`
`REQUESTS FOR PRODUCTION
`
`REQUEST FOR PRODUCTION NO. 128
`
`All documents that estimate, define, describe, assess, study, or summarize the market for
`
`the Accused Product, including but not limited to company reports or studies, third-party
`
`research, or other information related to the market for the Accused Product.
`
`REQUEST FOR PRODUCTION NO. 129
`
`All documents and other information relating to the pricing strategies for the Accused
`
`Product, including, but not limited to, the factors, information, and/or data that Moderna
`
`considered in developing pricing strategies for the Accused Product.
`
`REQUEST FOR PRODUCTION NO. 130
`
`All documents and communications created, prepared, and/or reviewed for or by
`
`Moderna’s Board of Directors, or any committee of such Board, related to the Accused Product,
`
`including, but not limited to, meeting minutes of Moderna’s Board of Directors, presentations
`
`prepared for or provided to Moderna’s Board of Directors, or financial analyses or projections
`
`about sales of the Accused Product provided to Moderna’s Board of Directors.
`
`2
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 10 of 266 PageID #: 13072
`
`HIGHLY CONFIDENTIAL – OUTSIDE COUNSEL EYES ONLY
`
`REQUEST FOR PRODUCTION NO. 160
`
`All documents and communications relating to the conception, reduction to practice,
`
`research, or development of the subject matter disclosed and/or claimed in WO 2023/019181 and
`
`any priority application thereto (including U.S. Provisional Application No. 63/232,128 listed on
`
`the cover of WO 2023/019181), including but not limited to laboratory notebooks, notes,
`
`records, logs, files, invention disclosures, or other documents generated by or at the direction of
`
`any named inventors, and all laboratory notebooks, notes, records, logs, files, invention
`
`disclosures, or other documents in which any named inventors made any entries.
`
`REQUEST FOR PRODUCTION NO. 161
`
`All documents and communications regarding the disclosure in WO 2023/019181
`
`concerning the effect of adding steric stabilizers, such as polyethylene glycol (PEG)
`
`
`
`
`
`
`
`
`
`REQUEST FOR PRODUCTION NO. 162
`
`All documents and communications regarding the disclosure in WO 2023/019181 of
`
`“turbulent mixing (‘T-mix’),” “vortex mixing (“V-mix”),” or “microfluidic mixing.”
`
`REQUEST FOR PRODUCTION NO. 163
`
`Documents sufficient to show the lipid composition and/or lipid molar ratio for all
`
`Investigational New Drug Applications submitted by Moderna to the U.S. Food & Drug
`
`Administration and Moderna’s reasons for selecting the lipid composition and lipid molar ratio.
`
`9
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 11 of 266 PageID #: 13073
`
`HIGHLY CONFIDENTIAL – OUTSIDE COUNSEL EYES ONLY
`
`REQUEST FOR PRODUCTION NO. 164
`
`Documents sufficient to show the lipid composition and/or lipid molar ratio for all
`
`Investigational New Drug Applications submitted by Moderna to the U.S. Food & Drug
`
`Administration using (1) 50 mol % to 65 mol % cationic lipid; (2) 4 mol % to 10 mol % of
`
`phospholipid; (3) 30 mol % to 40 mol % cholesterol or derivative thereof; and (4) 0.5 mol % to
`
`2 mol % PEG-lipid or conjugated lipid that inhibits aggregation of particles, and Moderna’s
`
`reasons for selecting the lipid composition and lipid molar ratio.
`
`REQUEST FOR PRODUCTION NO. 165
`
`Documents sufficient to show the lipid composition and/or lipid molar ratio for all
`
`Investigational New Drug Applications submitted by Moderna to the U.S. Food & Drug
`
`Administration using (1) 50 mol % to 65 mol % cationic lipid; (2) 3 mol % to 15 mol % of
`
`phospholipid; (3) 30 mol % to 40 mol % cholesterol or derivative thereof; and (4) 0.5 mol % to
`
`2 mol % PEG-lipid or conjugated lipid that inhibits aggregation of particles, and Moderna’s
`
`reasons for selecting the lipid composition and lipid molar ratio.
`
`REQUEST FOR PRODUCTION NO. 166
`
`Documents sufficient to show the LNP manufacturing process for all Investigational New
`
`Drug Applications submitted by Moderna to the U.S. Food & Drug Administration wherein the
`
`proposed product comprised LNPs.
`
`REQUEST FOR PRODUCTION NO. 167
`
`Documents sufficient to show the lipid composition and lipid molar ratio for all
`
`Investigational New Drug Applications submitted by Moderna to the U.S. Food & Drug
`
`Administration wherein the proposed product comprised LNPs.
`
`10
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 12 of 266 PageID #: 13074
`
`HIGHLY CONFIDENTIAL – OUTSIDE COUNSEL EYES ONLY
`
`
`
`Respectfully submitted,
`
`/s/ Emily S. DiBenedetto
`John W. Shaw (No. 3362)
`Karen E. Keller (No. 4489)
`Nathan R. Hoeschen (No. 6232)
`Emily S. DiBenedetto (No. 6779)
`SHAW KELLER LLP
`I.M. Pei Building
`1105 North Market Street, 12th Floor
`Wilmington, DE 19801
`(302) 298-0700
`jshaw@shawkeller.com
`kkeller@shawkeller.com
`nhoeschen@shawkeller.com
`edibenedetto@shawkeller.com
`Attorneys for Plaintiffs
`
`
`
`OF COUNSEL:
`David I. Berl
`Adam D. Harber
`Thomas S. Fletcher
`Shaun P. Mahaffy
`Jessica Palmer Ryen
`Anthony H. Sheh
`Jihad J. Komis
`Philip N. Haunschild
`WILLIAMS & CONNOLLY LLP
`680 Maine Avenue S.W.
`Washington, DC 20024
`(202) 434-5000
`Attorneys for Plaintiff Genevant
`Sciences GmbH
`
`Daralyn J. Durie
`Adam R. Brausa
`Eric C. Wiener
`Annie A. Lee
`Shaelyn K. Dawson
`MORRISON & FOERSTER LLP
`425 Market Street
`San Francisco, CA 94105-2482
`(415) 268-6080
`
`Kira A. Davis
`MORRISON & FOERSTER LLP
`707 Wilshire Boulevard
`Los Angeles, CA 90017-3543
`(213) 892-5200
`
`David N. Tan
`MORRISON & FOERSTER LLP
`2100 L Street, NW, Suite 900
`Washington, DC 20037
`(202) 887-1500
`Attorneys for Plaintiff Arbutus
`Biopharma Corporation
`
`Dated: August 3, 2023
`
`
`
`
`
`13
`
`

`

`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 13 of 266 PageID #: 13075
`
`HIGHLY CONFIDENTIAL – OUTSIDE COUNSEL EYES ONLY
`
`CERTIFICATE OF SERVICE
`
`I, Emily S. DiBenedetto, hereby certify that on August 3, 2023, this document was served
`
`on the persons listed below in the manner indicated:
`
`BY EMAIL:
`Jack B. Blumenfeld
`Brian P. Egan
`MORRIS, NICHOLS, ARSHT & TUNNELL LLP
`1201 North Market Street
`P.O. Box 1347
`Wilmington, DE 19899
`(302) 658-9200
`jblumenfeld@morrisnichols.com
`began@morrisnichols.com
`
`James F. Hurst
`KIRKLAND & ELLIS LLP
`300 North LaSalle
`Chicago, IL 60654
`(312) 862-2000
`james.hurst@kirkland.com
`
`Alina Afinogenova
`KIRKLAND & ELLIS LLP
`200 Clarendon Street
`Boston, MA 02116
`(617) 385-7500
`alina.afinogenova@kirkland.com
`
`
`Patricia A. Carson, Ph.D.
`Jeanna M. Wacker
`Mark C. McLennan
`Nancy Kaye Horstman
`KIRKLAND & ELLIS LLP
`601 Lexington Avenue
`New York, NY 10022
`(212) 446-4800
`patricia.carson@kirkland.com
`jeanna.wacker@kirkland.com
`mark.mclennan@kirkland.com
`kaye.horstman@kirkland.com
`
`Yan-Xin Li
`KIRKLAND & ELLIS LLP
`555 California Street, 27th Floor
`San Francisco, CA 94104
`(415) 439-1400
`yanxin.li@kirkland.com
`
`
`
`
`
`/s/ Karen E. Keller
`John W. Shaw (No. 3362)
`Karen E. Keller (No. 4489)
`Nathan R. Hoeschen (No. 6232)
`Emily S. DiBenedetto (No.
`SHAW KELLER LLP
`I.M. Pei Building
`1105 North Market Street, 12th Floor
`Wilmington, DE 19801
`(302) 298-0700
`jshaw@shawkeller.com
`kkeller@shawkeller.com
`nhoeschen@shawkeller.com
`edibenedetto@shawkeller.com
`Attorneys for Plaintiffs
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`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 14 of 266 PageID #: 13076
`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 14 of 266 PagelD #: 13076
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`EXHIBIT 2
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`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 15 of 266 PagelD #: 13077
`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 15 of 266 PageID #: 13077
`NO setece
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`es THERAPY
`
`Molecular Therapy
`Original Article
`
`Preclinical and Clinical Demonstration
`of Immunogenicity by mRNA Vaccines
`against H1ON8 and H/Ng Influenza Viruses
`
`Kapil Bahl,' Joe J. Senn,’ Olga Yuzhakov,' Alex Bulychev,’ Luis A. Brito,* Kimberly J. Hassett,! Michael E. Laska,”
`Mike Smith,? Orn Almarsson,* James Thompson,” Amilcar (Mick) Ribeiro,! Mike Watson,! Tal Zaks,”
`and Giuseppe Ciaramella'
`
`1Valera, A Moderna Venture, 500 Technology Square, Cambridge, MA 02139, USA; 7Moderna Therapeutics, 200 Technology Square, Cambridge, MA 02139, USA
`
`antigenic proteins (antigenic shift) and sustainable person to person
`transmission are hallmarks of pandemic influenza strains.’ Such
`strains can spread quickly and cause widespread morbidity and
`mortality in humansdue to high pathogenicity and little to no pre
`existing immunity. Recent cases (2013) of avian to human transmis
`sion of avian influenza A virus subtypes included H7N9, H6N1, and
`HI10N8.°* Thecase fatality rate in over 600 cases of H7N9infections
`was ~30%.'”” Mostrecently, the World Health Organization reported
`another 120 cases since September2016 resulting in 37 deaths.'” To
`date, H10N8infection in man has been limited; yet, of the three
`reported cases, two werefatal.’'
`
`the World Health Organization confirmed 120
`Recently,
`new humancases of avian H7N9 influenza in China resulting
`in 37 deaths, highlighting the concern for a potential pandemic
`and the need for an effective, safe, and high-speed vaccine
`production platform. Production speed and scale of mRNA-
`based vaccines make them ideally suited to impede potential
`pandemic threats. Here we show that
`lipid nanoparticle
`(LNP)-formulated, modified mRNA vaccines, encoding hem-
`agglutinin (HA) proteins of H10N8 (A/Jiangxi-Donghu/346/
`2013) or H7N9 (A/Anhui/1/2013), generated rapid and robust
`immune responses in mice, ferrets, and nonhuman primates,
`as measured by hemagglutination inhibition (HAI) and micro-
`neutralization (MN)assays. A single dose of H7N9 mRNApro-
`Thelimitedefficacy ofexisting antiviral therapeutics (i.e., oseltamivir
`tected mice fromalethal challenge and reduced lung viral titers
`and zanamivir) makes vaccination the most effective meansofprotec
`tion againstinfluenza.'° Conventional influenza vaccines induce pro
`in ferrets. Interim results from a first-in-human,escalating-
`dose, phase 1 H10N8 study show very high seroconversion
`tection by generating HA specific neutralizing antibodies, the major
`correlate of protection, against the globular head domain.'*'” Such
`rates, demonstrating robust prophylactic immunity in hu-
`mans. Adverse events (AEs) were mild or moderate with only
`vaccines utilize the HA protein, administered as a subunit, split
`a few severe and no serious events. These data show that
`virion, inactivated whole virus, or live attenuated virus. A majority
`LNP-formulated, modified mRNAvaccines can induce protec-
`of approved influenza vaccines are produced in embryonated chicken
`tive immunogenicity with acceptable tolerability profiles.
`eggs orcell substrates. This process takes several months and relies on
`the availability of sufficient supplies of pathogen free eggs and adap
`tation of the virus to grow within its substrate.'°'’ The 5 6 months
`required to produce enoughvaccine to protect a substantial propor
`tion of the population consumes muchof the duration of the often
`devastating first wave of a pandemic.'* This mismatch between the
`speeds of vaccine production and epidemic spread drives the search
`for vaccine platforms that can respondfaster.”
`
`INTRODUCTION
`Several avian influenza A viruses (H5N1, H10N8, H7N9, and H1N1)
`havecrossed the species barrier, causing severe and often fatal respi
`ratory disease in humans. Fortunately, most of these strains are not
`able to sustain person to person transmission.’ However, lessons
`learned from these outbreaks demonstrated that new approaches
`are needed to address potential future pandemic influenza outbreaks.”
`
`Two major glycoproteins, crucial for influenza infection, are hemag
`glutinin (HA) and neuraminidase (NA); both are expressed on the sur
`face of the influenza A virion.’ HA mediates viral entry into hostcells
`by binding tosialic acid containing receptorson the cell mucosal sur
`face and the fusion ofviral and host endosomal membranes.*
`
`The segmented influenza A genome permits re assortment and ex
`change of HA (or NA) segments between different influenza strain
`subtypes during concomitanthost cell infection. Generation of novel
`
`Using mRNA complexed with protamine (RNActive, Curevac),
`Petsch et al.’ demonstrated that intradermal (ID) vaccination of
`mice with RNActive encoding full length HA from influenza virus
`HINI (A/Puerto Rico/8/1934) induced effective seroconversion and
`
`Received 23 January 2017; accepted 24 March 2017;
`http://dx.doi.org/10.1016/j.ymthe.2017.03.035.
`Correspondence: Giuseppe Ciaramella, Valera, 500 Technology Square, Cam-
`bridge, MA 02139, USA.
`E-mail: giuseppe.ciaramella@valeratx.com
`
`1316
`
`Molecular Therapy Vol. 25 No 6 June 2017 © 2017 The Authors.
`This is an open access article under the CC BY NC ND license (http://creativecommons.org/licenses/by ne nd/4.0/).
`
`@® CrossMark
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`Case 1:22-cv-00252-MSG Document 194-3 Filed 01/16/24 Page 16 of 266 PageID #: 13078
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`www.moleculartherapy.org
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`virus neutralizing antibodies in all vaccinated animals. Immunity was
`long lasting and protected both young and old animals from lethal
`challenge with the H1N1, H3N2, and H5N1 strains of the influenza
`A virus.20 Efficacy of these RNActive vaccines was also shown in fer
`rets and pigs.21
`
`The use of a delivery system can dramatically reduce the doses needed
`to generate potent immune responses, without an additional conven
`tional adjuvant. Lipid nanoparticles (LNPs) have been used exten
`sively for the delivery of small interfering RNA (siRNA), and they
`are currently being evaluated in late stage clinical trials via intrave
`nous administration.22
`
`Exogenous mRNA can stimulate innate immunity through Toll like
`receptors (TLRs) 3, 7, and 8 and cytoplasmic signal recognition pro
`teins RIG I and MDA5.23,24 The adjuvant effect of stimulating innate
`immunity may be advantageous for purified protein vaccines, but
`indiscriminate immune activation can inhibit mRNA translation,
`reducing antigen expression and subsequent immunogenicity.25,26
`This can be overcome by replacing uridine nucleosides with naturally
`occurring base modifications, such as pseudouridine and 5 methylcy
`tidine.27–29 Recently, we30 and others31 have shown how LNP encap
`sulated modified mRNA vaccines can induce extraordinary levels of
`neutralizing immune responses against the Zika virus in mice and
`nonhuman primates, respectively.
`
`In this study, we evaluated the immunogenicity of two LNP formu
`lated, modified mRNA based influenza A vaccines encoding the
`HA of H10N8 (A/Jiangxi Donghu/346/2013) and H7N9 (A/Anhui/
`1/2013) in animals and H10N8 HA mRNA in humans from an
`ongoing trial. In the animal studies, we show that both vaccines
`generated potent neutralizing antibody titers in mice, ferrets, and cyn
`omolgus monkeys (cynos) after a single dose. Additionally, a single
`dose of H7N9 HA mRNA protected mice from an autologous lethal
`challenge and reduced lung viral titers in ferrets. Encouraged by these
`findings, a first in human, dose escalating, phase 1 trial is ongoing,
`with interim results reported here that confirm the observed, preclin
`ical immunogenicity data with a safety profile consistent with other
`non live vaccines.
`
`RESULTS
`H10N8 and H7N9 HA mRNA Immunogenicity in Mice
`In vitro protein expression for both H10N8 HA (H10) and H7N9 HA
`(H7) mRNA vaccines were confirmed by transfection of HeLa cells.
`Western blot of resulting cell lysates demonstrated a 75 kDa band
`for both constructs using the corresponding HA specific antibodies
`(Figure S1), consistent with previous reports for other HAs.22 Due
`to a lack of glycosylation, both H10 HA and H7 HA protein controls
`had a molecular weight of 62 kDa.
`
`Hemagglutination inhibition (HAI), IgG1, and IgG2a titers were
`measured after a single 10 mg dose of either formulated H10 or H7
`mRNA in BALB/c mice immunized ID. HAI titers were below the
`limit of detection (<10) at day 7 but increased well above baseline
`
`by day 21 (Figure 1A). Unlike HAI, both anti H10 and anti H7
`IgG1 and IgG2a titers were detected on day 7 (Figures 1B and 1C).
`For H10, IgG1 and IgG2a titers continued to increase until day 21
`and were maintained at day 84. For H7, both IgG1 and IgG2a anti
`body titers increased 10 fold between day 21 and day 84