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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`
`Moderna Therapeutics, Inc.
`
`Petitioner
`
`v.
`
`Protiva Biotherapeutics, Inc.
`
`Patent Owner
`___________
`
`
`Case No. IPR2018-00739
`U.S. Patent No. 9,364,435
`
`___________
`
`
`PETITIONER’S OPPOSITION TO PATENT OWNER’S
`CONTINGENT MOTION TO AMEND
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`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`10655266
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`Case No. IPR2018-00739
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`TABLE OF CONTENTS
`
`I.
`II.
`
`Page
`INTRODUCTION ........................................................................................ 1
`THE TERM “SERUM STABILE” AND THE LIMITATION OF
`RESISTING NUCLEASE DEGRADATION DO NOT RENDER
`THE CLAIMS PATENTABLE.................................................................... 3
`A. The Addition of the Term “Serum-Stable” Is Technically
`Deficient ................................................................................................ 3
`B. The Limitation of Resisting Degradation Does Not
`Differentiate the Prior Art ..................................................................... 7
`III. THE NARROWED CLAIMED CONCENTRATIONS OF LIPID
`COMPONENTS REMAIN OBVIOUS BY A PREPONDERANCE
`OF THE EVIDENCE ................................................................................... 8
`A. Overlap with the Prior Art Ranges Is Even More
`Pronounced ........................................................................................... 8
`B. Test Data Does Not Demonstrate Unexpected Results
`Commensurate with the Scope of the Claims ....................................... 9
`IV. THE PROPOSED SUBSTITUTE CLAIMS LACK WRITTEN
`DESCRIPTION SUPPORT ........................................................................ 10
`A. The Written Description in the ’435 Patent Describes siRNA
`Payloads .............................................................................................. 10
`B. A POSITA Would Not Consider Patentee To Be In
`Possession of Nucleic-Acid Lipid Particles with a mRNA
`Payload ................................................................................................ 14
`C. The Board Has Found Comparable Disclosures Lacking .................. 16
`THE PROPOSED SUBSTITUTE CLAIMS LACK ENABLEMENT ..... 18
`V.
`VI. CONCLUSION ........................................................................................... 20
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`TABLE OF AUTHORITIES
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` Page(s)
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`Cases
`AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc.,
`759 F.3d 1285 (Fed. Cir. 2014) .......................................................................... 11
`Aqua Prods., Inc. v. Matal,
`872 F.3d 1290 (Fed. Cir. 2017) ............................................................................ 6
`Ariad Pharms., Inc. v. Eli Lilly and Co.,
`598 F.3d 1336 (Fed. Cir. 2010) (en banc) .......................................................... 11
`Catalina Marketing Int’l, Inc. v. CoolSavings.com, Inc.,
`289 F.3d 801 (Fed. Cir. 2002) .............................................................................. 3
`In re Clemens,
`622 F.2d 1029 (C.C.P.A. 1980) ............................................................................ 9
`E.I. DuPont de Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) .............................................................................. 8
`Nat’l Recovery Tech., Inc. v. Magnetic Separation Sys., Inc.,
`166 F.3d 1190 (Fed. Cir. 1999) .......................................................................... 18
`Symantec Corp. v. Comput. Assocs. Int’l, Inc.,
`522 F.3d 1279 (Fed. Cir. 2008) ............................................................................ 3
`Rules
`37 C.F.R. § 42.121 ............................................................................................... 2, 10
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`LIST OF EXHIBITS RELIED UPON IN THE REPLY AND THE OPPOSITION TO AMEND
`
`
`References
`
`U.S. Patent No. 9,364,435
`International Publication No. WO 2005/007196
`U.S. Publication No. US2006/0134189
`U.S. Publication No. US2006/0240554
`Lin, Alison J. et al., Three-Dimensional Imaging of Lipid Gene-
`Carriers: Membrane Charge Density Controls Universal
`Transfection Behavior in Lamellar Cationic Liposome-DNA
`Complexes, 84 BIOPHYSICAL JOURNAL, 3307–16 (2003) (“Lin”)
`Ahmad, Ayesha et al., New multivalent cationic lipids reveal bell
`curve for transfection efficiency versus membrane charge density:
`lipid-DNA complexes for gene delivery, 7 J GENE MED 739–48
`(2005) (“Ahmad”)
`Declaration of Dr. Andrew S. Janoff
`Gao, Xiang et al., Nonviral Gene Delivery: What We Know and
`What Is Next, 9 AAPS JOURNAL Article 9, pp. E92-E104 ( 2007)
`(“Gao”)
`Bennett, Michael J. et al., Cholesterol Enhances Cationic Liposome-
`Mediated DNA Transfection of Human Respiratory Epithelial Cells,
`15 Bioscience Reports, pp. 47-53 (1995) (“Bennett”)
`Heyes, James et al., Cationic lipid saturation influences
`intracellular delivery of encapsulated nucleic acids, 107 JOURNAL
`OF CONTROLLED RELEASE 276–87 (2005) (“Heyes”)
`U.S. Patent No. 5,753,613
`U.S. Patent No. 7,939,505
`U.S. Publication No. US2007/0042031
`U.S. Publication No. US2006/0008910
`Excerpts from ’069 Patent File History
`’435 Patent File History
`U.S. Patent No. 5,264,618
`Curriculum Vitae of Dr. Andrew S. Janoff
`Deposition Transcript of David H. Thompson – Volume 1 (February
`4, 2019)
`Deposition Transcript of David H. Thompson – Volume 2 (February
`5, 2019)
`
`iii
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`
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`Exhibit
`No.
`1001
`1002
`1003
`1004
`1005
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`1006
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`1007
`1008
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`1009
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`1010
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`1011
`1012
`1013
`1014
`1015
`1016
`1017
`1018
`1019
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`1020
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`Exhibit
`No.
`1021
`1022
`1023
`1024
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`1025
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`
`
`References
`
`Reply Declaration of Dr. Andrew S. Janoff
`Janoff Declaration for Opposition to Motion to Amend
`Patent Owner Response in IPR2018-00739
`Kauffman, et al. Optimization of Lipid Nanoparticle Formulations
`for mRNA Delivery in Vivo with Fractional Factorial and Definitive
`Screening Designs, Nano Letters (2015) (“Kauffman”)
`Decision on Appeal, Appeal No. 2016-008388 (P.T.A.B. July 18,
`2018)
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`I.
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`INTRODUCTION
`As outlined in the Petition, the issued claims of the ’435 patent are over-broad,
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`covering disparate nucleic acid payloads, any of a host of potential lipid components,
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`and wide ranges for lipid component concentrations for nucleic acid-lipid particles.
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`As written, these claims overlap with the prior art, including the Patent Owner’s own
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`prior disclosures, rendering them prima facie obvious. The set of substitute claims
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`presented in Patent Owner’s Contingent Motion to Amend (“MTA”) do not remedy
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`the invalidity issues raised.1 The proposed substitute claims purport to add
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`“limitations” to the preamble, are based upon mischaracterizations of the knowledge
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`in the art, and lack written description support and an enabling disclosure for the
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`different nucleic acid payloads recited therein.
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`First, the substitute claims add the term “serum-stable” to the preamble, but
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`this window dressing is without effect because the preamble is non-limiting. See
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`MTA, 3. The substitute claims also add the limitation “wherein the particle is
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`formulated such that that the nucleic acid is not substantially degraded after exposure
`
`of the particle to a nuclease at 37ºC for 20 minutes” to the body of the claims. See
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`id. But this limitation does not differentiate over the prior art, given that serum-stable
`
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`1 Patent Owner does not propose changes to dependent claims 2-20. The proposed
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`amendments do nothing to address that the additional limitations present in these
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`claims are disclosed in the prior art.
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`particles that resist nuclease degradation are disclosed in the prior art already of
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`record.
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`Second, the substitute claims recite a narrower range for certain lipid
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`concentrations. MTA, 3 (decreasing cationic lipid from 50-85 mol% to 50-75 mol%
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`and increasing the non-cationic lipid concentration accordingly). The cited prior art
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`references overlap with the lower end of the claimed ranges for cationic lipid
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`(disclosing up to 60 mol%). This amendment thus does not add any further
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`differentiation vis-à-vis the prior art and actually increases the overlap with the prior
`
`art. Instead, it is apparently geared toward more closely aligning the claims with
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`testing that the Patent Owner relies upon as evidence of unexpected results. MTA,
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`16. Even with these amendments, however, the testing still only covers a small
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`portion of the scope of the claims and is thus deficient.
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`For these two reasons, the amended claims “do[] not respond to a ground of
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`unpatentability involved in the trial” as they must. See 37 C.F.R. § 42.121(a)(2)(i).
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`This is a sufficient basis for the Board to deny the MTA in full.
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`In addition, the substitute claims broadly cover any nucleic acid payload—
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`despite wide variations in potential nucleic acids and without support for anything
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`but siRNA. This over-breadth goes to the heart of the dispute between the parties.
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`Petitioner is an mRNA company, while Patent Owner (and its predecessors) have
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`traditionally focused on siRNA. Patent Owner’s attempt to extend its disclosures to
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`cover other nucleic acid payloads is improper and ignores the admitted variability in
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`the art. Importantly, the Board has recognized this exact issue and rejected similar
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`assertions regarding the scope of these disclosures for other patents belonging to
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`Patent Owner. See Section IV.C infra. The same reasoning applies here, and the
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`substitute claims are thus invalid for lacking written description and enablement.
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`II.
`
`THE TERM “SERUM STABILE” AND THE LIMITATION OF RESISTING
`NUCLEASE DEGRADATION DO NOT RENDER THE CLAIMS PATENTABLE
`THE ADDITION OF THE TERM “SERUM-STABLE” IS TECHNICALLY
`DEFICIENT
`Patent Owner’s amended claims are technically deficient. Amended claim 21
`
`A.
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`adds the term “serum-stable” to the preamble, but not to the body of the claim. MTA,
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`4. “[I]t is assumed that the preamble language … merely provides context for the
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`claims, absent any indication to the contrary in the claims, the specification or the
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`prosecution history.” Symantec Corp. v. Comput. Assocs. Int’l, Inc., 522 F.3d 1279,
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`1289 (Fed. Cir. 2008). A term that appears only in the preamble is not considered
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`limiting unless it is incorporated into the body of the claim to give it “life, meaning,
`
`and vitality.” Catalina Marketing Int’l, Inc. v. CoolSavings.com, Inc., 289 F.3d 801,
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`808 (Fed. Cir. 2002). The addition of the limitation regarding resisting nuclease
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`degradation does not require the particle to be “serum stable” as such resistance can
`
`be tested in vitro using a nuclease. EX1020 (Thompson), 368:2-18 (“… it's testable
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`with a purified single nuclease” in vitro). Thus, like the applicant in Catalina
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`Marketing, Patent Owner neither “rel[ied] on th[e] phrase to define its invention”
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`nor is “the phrase essential to understand limitations or terms in the claim body.” Id.
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`at 810. A POSITA would therefore not consider the term “serum-stable” limiting in
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`the claims. Ex. 2022, (“Janoff”), ¶53.
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`Even if found limiting, the cited prior art references disclose serum-stable
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`particles at greater than 50 mol% cationic lipid. Each of the three primary references
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`disclose the desire for serum-stable particles. EX1002, [0002] (“serum-stable
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`nucleic acid-lipid particles”), [0015-0016], [0120], [0134]; EX1003, [0182]
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`(“serum-stable nucleic acid-lipid particles”), [0191], [0217]; MTA, 15 (“… the ’554
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`publication stresses that serum-stability is a critical property of in vivo
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`formulations.” (citing EX1004, [0014], [0015], [0158])); Janoff, ¶54. Each of the
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`references also disclose that the cationic lipid concentrations can be up to 60 mol%.
`
`EX1002, [0088], EX1003, [0152], EX1004, [0116]; Janoff, ¶54. In addition, ’189
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`publication specifically discloses a series of in vivo experiments detailing efficacy
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`of the 2:40 formulation. EX1003, [0351]-[0391]. The ’554 publication goes even
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`further detailing a series of in vivo experiments with formulations having cationic
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`lipid concentrations of 48-52 mol%. Ex. 1004, [0408], Table IV (L077, L069, L080,
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`L082, L083, L060, L061, and L051 at 48-52 mol% cationic lipid); Fig. 29 (efficacy
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`of formulations in vivo). A POSITA would understand these disclosures in the
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`context of the prior art references to disclose serum-stable particles at greater than
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`50 mol% cationic lipid. Janoff, ¶54.
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`Patent Owner erroneously concludes that the ’196 PCT limits the cationic
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`lipid mol% to 5-15 for systemic use for all embodiments. MTA, 14. The ’196 PCT
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`states that “for systemic delivery, the cationic lipid may comprise from about 5
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`mol% to about 15 mol%.” EX1001, [0088]. But, this range limitation is permissive
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`for good reason—it may be appropriate for certain cationic lipids (e.g., non-ionizable
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`cationic lipids), but unnecessary for other substantially non-toxic cationic lipids
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`(e.g., ionizable cationic lipids like DLinDMA). Janoff, ¶55.
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`It was well-known in the prior art that toxicity in nucleic acid-lipid particles
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`is largely a function of such particles having a net positive charge. EX1002, [0015]
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`(an overall neutral charge are preferred), EX1003, [0219] (same); EX1010, 277
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`(SNALPs developed with “low surface charge required for systemic delivery”);
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`Janoff, ¶56. The potential impact of the amount of cationic lipid on the net charge of
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`resulting particles depends, inter alia, on whether the cationic lipid carries a positive
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`charge at physiological pH. Id., ¶56. To address potential toxicity issues, years
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`before the '435 patent, ionizable cationic lipids had been developed whose charge
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`was low or essentially neutral at physiological pH of 7.4. Id., ¶57; Ex. 1003 [0223]
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`(using DLinDMA); Ex. 1010, 280 (same), Fig. 1 (showing substantially neutral
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`charge at pH 7.4). Because of the low charge of such cationic lipids at physiological
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`pH, higher concentrations of cationic lipid can be used while maintaining a neutral
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`charge in the resulting particles. Janoff, ¶57; Ex. 1003, [0351-0391] (various in vivo
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`testing for 2:40 formulation using DLinDMA), [0076], [0151] (resulting particles
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`“substantially non-toxic”). Patent Owner’s expert admits that the class of lipids
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`which includes DLinDMA was known not to have significant toxicity concerns:
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`“[t]he data that -- that I’ve seen for this -- that I’ve reviewed for this class of cationic
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`lipids has -- in vivo has not suggested that there are significant toxicity concerns.”
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`EX1020, 266:18-267:20; see also id., 267:22-268:15 (DLinDMA “known that it had
`
`a low toxicity profile ….”). Patent Owner’s assertions ignore these well-known facts.
`
`The ’189 publication is instructive. It contains the exact same permissive
`
`language regarding a 5-15 mol% range of cationic lipid for systemic use found in
`
`the ’196 PCT. EX1003, [0152]. The ’189 publication describes systemic use in in
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`vivo testing using a 2:40 formulation (well above 5-15 mol% range) using the
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`ionizable cationic lipid DLinDMA. Id., [0351-0391]. Of note, the MTA completely
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`fails to address the disclosures in the ’189 publication and can be denied on that basis
`
`alone. See Aqua Prods., Inc. v. Matal, 872 F.3d 1290, 1306 (Fed. Cir. 2017) (“any
`
`proposed amendment must seek to … propose a substitute for a challenged claim …
`
`by responding to an instituted ground of unpatentability.”).
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`Regarding the ’554 publication, Patent Owner ignores the full disclosures in
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`the reference and contradicts the express experimental results. The identified L054
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`formulation was used in in vitro testing and contained the cationic lipid, DMOBA.
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`Patent Owner asserts that DMOBA is too toxic for systemic use at a higher cationic
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`lipid concentrations. MTA, 16. Patent Owner ignores the disclosure in the ’554
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`publication that 52 mol% DMOBA showed in vivo efficacy. EX1004, Table IV
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`(L060 formulation); [0408] (testing); Fig. 29 (results); Janoff, ¶59. Patent Owner’s
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`mantra that cationic lipids must be minimized due to toxicity in vivo is inconsistent
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`with the state of the art.
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`B.
`
`THE LIMITATION OF RESISTING DEGRADATION DOES NOT
`DIFFERENTIATE THE PRIOR ART
`Testing for resistance to nuclease degradation by exposure to nucleases for 20
`
`min at 37°C was commonplace. A POSITA would have been aware of such testing,
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`especially given the express disclosures in Patent Owner’s prior disclosures. Janoff,
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`¶60. Patent Owner erroneously states that the prior art “does not disclose nucleic
`
`acid-lipid particles formulated for systemic use that can withstand nuclease exposure
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`for 20 min at 37°C.” MTA at 17. Each of the three primary references disclose
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`nucleic acid-lipid particles that can also withstand nuclease exposure and Patent
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`Owner’s prior disclosures disclose these exact parameters. EX1002, cl.2 [0011] (“…
`
`the nucleic acid in the nucleic acid-lipid particle is resistant in aqueous solution to
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`degradation by a nuclease.”), [0085], [0174], [0204] (stability tested at 37 degrees
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`for 30 minutes); EX1003, cl. 31 (“… the nucleic acid in said nucleic acid-lipid
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`particle is not substantially degraded after exposure of said particle to a nuclease at
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`37° C. for 20 minutes.”), [0013] (nuclease resistance for “at least 30, 45, or 60
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`minutes” at 37°C), [0076], [0151], [0248]; Ex. 1004, [0020], [0210], [0261], [0268]
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`(“… chemically modified nucleotides present in the single stranded siRNA
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`molecules of the invention are preferably resistant to nuclease degradation ….”),
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`[0299], [0514], [0522-0523]. A POSITA would have been aware of the test
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`procedures disclosed in this limitation. Janoff, ¶60.
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`Patent Owner points to an irrelevant paragraph in an unrelated reference for
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`the ’196 PCT (EX1008 (Goa)) and fails to address the ’189 publication at all. MTA,
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`18. Regarding the ’554 publication, Patent Owner ignores the disclosure that testing
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`was done on modified nucleic acid constructs, for example with a construct
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`containing siRNA, to show “nuclease stability for systemic administration in vivo
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`….” EX1004, [0578]; MTA, 18.
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`III. THE NARROWED CLAIMED CONCENTRATIONS OF LIPID COMPONENTS
`REMAIN OBVIOUS BY A PREPONDERANCE OF THE EVIDENCE
`A. OVERLAP WITH THE PRIOR ART RANGES IS EVEN MORE
`PRONOUNCED
`Patent Owner does not argue that the proposed substitute claims change the
`
`analysis with regards to the prior art. See MTA, 16. The prior art discloses
`
`concentration of cationic lipids that overlap an even greater proportion of the ranges
`
`in the substitute claims. E.I. DuPont de Nemours & Co. v. Synvina C.V., 904 F.3d
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`996, 1006-08 (Fed. Cir. 2018) (overlap in ranges establishes prima facie case of
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`obviousness). Instead, Patent Owner argues that the substitute claims more closely
`
`align with testing of the claimed particles. MTA, 16 (“the data … is nearly co-
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`extensive with the claimed range”). This is legally insufficient and the testing is
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`anything but coextensive with the substitute claims.
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`B.
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`TEST DATA DOES NOT DEMONSTRATE UNEXPECTED RESULTS
`COMMENSURATE WITH THE SCOPE OF THE CLAIMS
`It is well-settled that “unexpected results” must be demonstrated for the entire
`
`claimed range to support patentability. In re Clemens, 622 F.2d 1029, 1035
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`(C.C.P.A. 1980) (“In order to establish unexpected results for a claimed invention,
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`objective evidence of non-obviousness must be commensurate in scope with the
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`claims which the evidence is offered to support.”). First, the cited test data is
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`anything but coextensive with the claimed range—claim 21 covers any payload and
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`any lipid components to make nucleic-acid lipid particles using any formulation
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`process. Janoff, ¶63. Patent Owner points to testing of only siRNA payloads with a
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`limited number of exemplar lipid components and with limited formulation
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`processes. Id. Patent Owner’s expert admits that changes to the payload, identity of
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`lipid components, or production techniques can all impact the particle properties and
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`resulting efficacy. EX1020, 231:23-232:10 (“does the composition affect transition-
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`pardon me, transfection performance. And the answer is yes.”), EX1019, 29:7-15
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`(payload “one of a host of factors that can impact--performance.”), 36:8-37:4 (same),
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`182:12-20 (physical properties of particles is dependent on the lipid composition and
`
`its ratios); EX1020, 393:21-394:24 (“… it’s a different molecule [cationic lipid]. So
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`you would expect that it may have different behavior.”), EX1019, 53:9-54:9 (same);
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`id., 59:22-60:7 (phospholipid identity impacts efficacy); id., 156:18-157:4 (“… the
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`conjugate lipid can impact the particle performance. That’s what the data show.”);
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`EX1020, 259:20-260:18 (production technique impacts efficacy: “[s]o you can look
`
`at different compositions, pray that those nominal concentrations actually are
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`reflective in the particle. But it ultimately at the end of the day, it’s how those are
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`formulated.”).
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`Second, contrary to Patent Owner’s assertions, Patent Owner’s expert
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`admitted that the test data did not show the claimed formulations outperforming the
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`prior art 2:40 formulation. EX1019, 183:22-184:13 (“[s]ome are better, some are
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`similar.”).
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`Third, Patent Owner cites to later testing that confirms that the 1:57
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`formulation is ineffective with various cationic lipids. EX2017, Fig. 2; EX2018,
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`Figs. 1-3; Janoff, ¶65. A fact that Patent Owner’s expert confirmed: cationic lipids
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`using 1:57 formulation “have similar knockdown levels as--as PBS.” EX1020,
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`401:6-21; see also id., 393:21:394:24 (1:57 formulation with DLin morph shows no
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`efficacy). Given these deficiencies, the test data does not demonstrate unexpected
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`results commensurate with the scope of the claims.
`
`IV. THE PROPOSED SUBSTITUTE CLAIMS LACK WRITTEN DESCRIPTION
`SUPPORT
`THE WRITTEN DESCRIPTION IN THE ’435 PATENT DESCRIBES SIRNA
`PAYLOADS
`Patent Owner fails to identify adequate written description support for the
`
`A.
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`substitute claims as required by 37 C.F.R. § 42.121(b). To satisfy section 112’s
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`written description requirement, the specification must “convey[] to those skilled in
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`the art that the inventor had possession of the claimed subject matter as of the filing
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`date,” i.e., “that the inventor actually invented the invention claimed.” Ariad
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`Pharms., Inc. v. Eli Lilly and Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc).
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`If a claim scope encompasses a genus of chemical molecules, the specification must
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`disclose sufficient “representative number of species falling within the scope of the
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`genus or structural features common to the members of the genus so that [a POSITA]
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`can visualize or recognize the members of the genus.” AbbVie Deutschland GmbH
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`& Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir. 2014) (internal
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`quotes removed). Indeed, “merely drawing a fence around a perceived genus is not
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`a description of the genus.” Id. at 1300. Here, all Patent Owner did was to draw a
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`large fence around myriad disparate “nucleic acid” payloads (e.g., mRNA), while
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`describing only siRNA.
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`In gene therapy, a variety of nucleic acid payloads can be used, e.g., siRNA
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`or mRNA. Janoff, ¶66; EX1001, 10:26-67. The sizes of these different nucleotides
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`can vary dramatically. Janoff, ¶66. An siRNA is typically around 20-23 bases in
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`length. Id.; EX1019, 37:24-38:9 (“20 to 23 is kind of the standard dogma”). An
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`mRNA tends to be about a thousand bases in length. Janoff, ¶66; see also EX1019,
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`38:10-15 (mRNA “several hundred” bases in length). In addition, nucleic acid-lipid
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`particles can serve different functions based upon their payload. Janoff, ¶67. For
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`example, they may be used to enhance gene expression using an mRNA payload or
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`they may be used to promote gene silencing using siRNA. Id. A POSITA would
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`have been well aware that switching between payloads can impact particle dynamics.
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`Id.; EX1019, 35:12-36:4 (“… the size of the cargo, for example, will have a huge
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`impact ….”).
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`The proposed substitute claims broadly cover any “nucleic acid” payload
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`(claim 21) or a list of disparate nucleic acids, including “mRNA” (claim 22). For
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`written description support, Patent Owner points only to generic references to
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`“nucleic acids” or “nucleic acid-lipid particles” in the “earlier-filed specifications.”
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`MTA, 6. For claim 22, Patent Owner cites to similar generic disclosures and a broad
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`definition of “nucleic acid.” EX2041, [0070]. The more detailed disclosures in these
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`earlier references regarding particle formulation relate to siRNA. Janoff, ¶68.
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`Similarly, the ’435 patent specification broadly defines the term “nucleic
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`acid” to be interchangeably used with mRNA encoded by a gene, and an interfering
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`RNA molecule. EX1001, 10:16-57. The ’435 patent broadly references using a
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`“nucleic acid” payload with the disclosed SNALPs. E.g., id., Abstract. Like the
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`earlier references, all the more detailed disclosures in the ’435 patent relate to
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`siRNA. Janoff, ¶69.
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`For example, in the Background of the Invention section, the ’435 patent
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`describes using siRNA for gene silencing. EX1001, 1:39-51. Indeed, the last
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`paragraph of the section confirms the purpose of the invention is “downregulating
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`the expression of genes of interest to treat or prevent diseases and disorders such as
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`cancer and atherosclerosis.” Id., 3:2-4. This is not a function of mRNA. Janoff, ¶70.
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`In the Brief Summary of the Invention section, the ’435 patent identifies
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`SNALPs containing “one or more interfering RNA molecules such as siRNA,
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`aiRNA, and/or miRNA” as the focus of the invention. EX1001, 3:32-37. Further,
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`both the described preferred embodiments in this section are described as containing
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`siRNA. Id., 3:47-67.
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`In the Detailed Description of the Invention section, again, all the examples
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`are of siRNA payloads. E.g., id., 5:62-2:2. In the definitions section, “therapeutically
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`effective amount” is described as “… inhibition of expression of a target sequence
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`….” Id., 7:55-60. This effect is associated with interfering RNA, not mRNA. Again,
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`the SNALP payloads are all described as being interfering RNA. Id., 11:23-46.
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`In the Description of the Embodiments section, the preferred embodiments
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`are described as having an siRNA payload: “in preferred embodiments, the active
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`agent or therapeutic agent comprises an siRNA.” Id., 14:62-17:47.
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`In the section of the specification describing the “Active Agent,” the
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`specification states: “[t]he siRNA component of the nucleic acid-lipid particles of
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`the present invention is capable of silencing the expression of a target gene of
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`interest.” Id., 28:57-59. The specification then describes in detail the selection of the
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`siRNA sequence (id., 30:1-32:27), generating the siRNA sequence (id., 32:28-
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`33:45), modifying the siRNA sequence (id., 33:46-35:67), and targets of siRNA for
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`silencing (id., 36:1-40:36). The specification goes on to briefly describe alternative
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`silencing options (aiRNA, miRNA, and Antisense Oligonucleotides, and
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`Ribozymes). Id., 40:37-45:31. mRNA is not discussed or disclosed as an example of
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`an Active Agent in this portion of the specification.
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`The specification then describes preparation of lipid particles with an siRNA
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`payload (id., 57:60-61:22) and administration of lipid particles with an siRNA
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`payload (id., 61:24-66:31). No such description is provided regarding mRNA. The
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`specification then provides eleven “examples” of experiments involving SNALPs
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`with siRNA payloads, and none as mRNA payloads. Id., 68:18-86:44. All of the
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`Figures 1-22 concern testing of siRNA payloads. Id., 4:26-5:49. No experiments or
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`figures detailing testing of an mRNA payload are described. EX1019 98:18-20;
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`Janoff, ¶75.
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`B.
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`A POSITA WOULD NOT CONSIDER PATENTEE TO BE IN
`POSSESSION OF NUCLEIC-ACID LIPID PARTICLES WITH A MRNA
`PAYLOAD
`A POSITA would not consider the inventors of the ’435 patent to be in
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`possession of a nucleic-acid lipid particles with an mRNA payload. Janoff, ¶76. A
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`POSITA would not have expected the described formulations and production
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`techniques optimized for siRNA to perform similarly for mRNA. Id. Indeed, Patent
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`Owner’s expert argues in a related IPR involving the ’127 patent that a “POSITA
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`would understand that mRNA is typically larger than siRNA, and the size of the
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`payload would be expected to affect the physical properties of a particle.” EX1023,
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`39-40. Patent Owner’s own expert also testified that he cannot “speculat[e]” on the
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`“optimization parameters” for the mRNA payloads based on the parameters that
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`were most effective for siRNA. EX1019, 43:6-10 (“Q. And do you think that they
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`would also, the same optimize -- optimization parameters would still be optimized
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`for the new mRNA cargo? A. That's speculation. I couldn't -- I can't go there. I don't
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`... I can't predict that one.”), 49:7-10.
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`The insufficiency of such disclosures is confirmed by current research post-
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`dating the ’435 patent, which confirms that siRNA lipid nucleic acid particles
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`(“LNPs”) are poor predictors of mRNA LNP percentages for optimization. EX1024
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`(“Kaufman”). Kaufman confirms “differences in optimized formulation parameter
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`design spaces [of LNPs] for siRNA and mRNA.” Id., Abstract. Kauffman identified
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`that optimized parameters for siRNA, were not optimized for mRNA. For example,
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`Kauffman for mRNA determined an “optimized formulation C-35 [that] had the
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`following formulation parameters: 10:1 C12-200:mRNA weight ratio with 35%
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`C12-200, 16% DOPE, 46.5% cholesterol, and 2.5% C14- PEG2000 molar
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`composition.” Id., D. For siRNA, formulations with 50% C12-200, 10% DOPE,
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`38.5% cholesterol, and 1.5% C14- PEG2000 worked as well. Id. These findings are
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`consistent with the variation in LNP performance with different nucleic acid
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`payloads that a POSITA would have expected at the time of the ’435 patent. Janoff,
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`¶77.
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`C.
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`THE BOARD HAS FOUND COMPARABLE DISCLOSURES LACKING
`The Board has already determined that disclosures comparable to those found
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`in the ’435 patent do not encompass mRNA payloads. On July 18, 2018, the Board
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`issued its decision in Appeal 2016-008388 regarding U.S. Patent Application
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`13/800,501, “involving claims to a method of delivery of messenger RNA for in vivo
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`production of protein.” EX1025, 1. The claims recited, among other limitations, “a
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`composition comprising an mRNA … [and a] liposome [which] comprises one or
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`more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based
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`lipids and one or more PEG-modified lipids ….” Id., 2. The cited prior art included
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`MacLachlan et al., US 2006/0008910, published Jan. 12, 2006 (EX1014), which t
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