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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
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`
`Moderna Therapeutics, Inc.
`
`Petitioner
`
`v.
`
`Protiva Biotherapeutics, Inc.
`
`Patent Owner
`___________
`
`
`Case No. IPR2019-00554
`U.S. Patent No. 8,058,069
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`___________
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`
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`PETITIONER’S REPLY TO PROTIVA’S RESPONSE
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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
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`10809121
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`Case No. IPR2019-00554
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` U.S. Patent No. 8,058,069
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`TABLE OF CONTENTS
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`I.
`II.
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`V.
`
`C.
`
`Page
`INTRODUCTION ........................................................................................ 1
`PROTIVA’S EXPERT HAS MINIMAL EXPERIENCE WITH
`CATIONIC LIPIDS ...................................................................................... 2
`III. CLAIM CONSTRUCTION ......................................................................... 3
`IV. THE INSTITUTED GROUNDS .................................................................. 4
`A. An Overlapping Phospholipid Range Is Disclosed ............................ 5
`B.
`The Same Four Lipid-Component Carrier Particles Are
`Disclosed ............................................................................................ 6
`Routine Optimization Of Lipid-Carrier Particles ............................... 7
`(1) OPTIMIZATION OF THE CATIONIC LIPID .................................. 11
`(2) OPTIMIZATION OF THE CONJUGATED LIPID ............................ 18
`(3) OPTIMIZATION OF THE CHOLESTEROL .................................... 20
`(4) OPTIMIZATION OF THE PHOSPHOLIPID .................................... 21
`D. Dependent Claims ............................................................................ 22
`SECONDARY CONSIDERATIONS CANNOT OVERCOME
`PETITIONER’S OBVIOUSNESS SHOWING ......................................... 24
`A.
`The Test Data Is Not Commensurate With Claim Scope ................ 24
`B.
`Test Data Does Not Show Unexpected Results ............................... 25
`C.
`Other Secondary Considerations Lack The Required
`Nexus Or Are Attributable To The Prior Art ................................... 27
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`TABLE OF AUTHORITIES
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` Page(s)
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`Cases
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) .......................................................... 7, 11, 12, 13
`In re Baxter-Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ............................................................................ 27
`Genentech, Inc. v. Hospira, Inc.,
`946 F.3d 1333 (Fed. Cir. 2020) ........................................................................ 4, 5
`IXI IP, LLC v. Samsung Elecs. Co., Ltd.,
`903 F.3d 1257 (Fed. Cir. 2018) ............................................................................ 5
`In re Kulling,
`897 F.2d 1147 (Fed. Cir. 1990) .......................................................................... 24
`Tokai Corp. v. Easton Enters., Inc.,
`632 F.3d 1358 (Fed. Cir. 2011) .......................................................................... 24
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) .......................................................................... 24
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`LIST OF EXHIBITS RELIED UPON IN THE REPLY
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`
`
`Exhibit
`No.
`1020
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`1021
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`1022
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`1023
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`1024
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`1025
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`1026
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`1027
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`References
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`Declaration of Thomas J. Anchordoquy, Ph.D. iso Petitioner's Reply
`to Protiva’s Response (“Anchodoquy”)
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`Curriculum Vitae of Thomas J. Anchordoquy
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`Final Written Decision in IPR2018-00739, Paper 51, Entered
`September 11, 2019
`
`Onpattro Labeling, Application No. 210922Orig1s000
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`Ian MacLachlin, Liposomal Formulations for Nucleic Acid Delivery
`(2007)
`
`Deposition of David H. Thompson, Ph.D. taken January 15, 2020
`
`Akinc et. al., Onpattro story and clinical translation of
`nanomedicines containing nucleic acid-based drugs, Nature
`Nanotechnology, Vol. 14, Dec. 2019, pp. 1084-1087
`
`Zimmerman et. al., RNAi-mediated gene silencing in non-human
`primates, 2006 Nature Publishing Group
`
`1028
`
`U.S. Patent No. 7,799,565 issued to MacLachlan, Sept. 21, 2010
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`I.
`
`INTRODUCTION
`The Board ordered an IPR over the’069 patent with respect to grounds 1-3 for
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`claims 1-22. In response, Patent Owner Protiva relies upon the mistaken premises
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`that (1) the prior art references do not teach overlapping ranges for the phospholipid
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`component (Response, 12-18) and (2) the disclosed ranges are too broad to support
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`routine optimization (id., 19-30). Both are demonstrably false. First, Protiva’s expert
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`admits that the cited references disclose an overlapping phospholipid range and
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`actual prior art testing demonstrating phospholipid concentrations overlapping with
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`the claimed range. Second, Protiva’s own prior test data confirms the regular practice
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`in the field of optimizing lipid concentrations and provides a starting point for such
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`routine optimization.
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`Protiva relies heavily on its expert’s belief that all the “cationic lipids should
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`be minimized” because of toxicity concerns. Response, 29. This oversimplification
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`evinces Protiva’s expert’s inexperience with lipid carrier particles. It was well
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`known years before the ’069 patent that ionizable cationic lipids can be used in high
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`amounts to create particles that are substantially non-toxic. See, e.g., EX1004,
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`[0151].
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`Faced with prior disclosures of particle formulations with overlapping ranges
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`for all claimed lipid components rendering the claims prima facie obvious, Protiva
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`seeks to cloud the matter as much as possible. For example, Protiva points to the
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`therapeutic Patisiran (tradename—Onpattro) as alleged support for secondary
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`considerations of non-obviousness, but fails to inform the Board that the actual
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`commercial product does not use the claimed lipid ranges. Protiva cannot rebut
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`Petitioner’s obviousness showing by ignoring express disclosures in the prior art,
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`denying comparable
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`teachings,
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`importing
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`limitations
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`into
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`the claims,
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`mischaracterizing test data, and making demonstrably false assertions.
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`II.
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`PROTIVA’S EXPERT HAS MINIMAL EXPERIENCE WITH
`CATIONIC LIPIDS
`Protiva’s expert, Dr. Thompson, researches carrier molecules using polymers,
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`not lipids. EX2005, 21:9-25 (“…we make stabilized nucleic acid particles, but
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`they’re not lipid particles. We make them out of polymers.”). His experience with
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`SNALPs is limited to using them as benchmarks in research. Id., 46:3-10, 49:11-17.
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`He admits that he has not worked with ionizable cationic lipids, like DLinDMA,
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`used in the ’069 patent. Id., 74:20-75:13. In its Final Determination in the related
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`’435 patent IPR, the Board repeatedly discounted Dr. Thompson’s opinions: “…we
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`find Dr. Thompson’s opinion…is speculative and thus, not accorded weight.”
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`EX1022, 24. Here, Dr. Thompson’s opinions are again unsupported and counter to
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`the prevailing wisdom in the field.
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`As an example, Dr. Thompson identifies Onpattro as a commercial
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`embodiment of the ’069 patent. EX2031, ¶¶117-118, 134-136. He relies on a 2014
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`patent for the alleged lipid formulation (EX2012) instead of the 2018 FDA approved
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`label for the product (EX1023). The FDA label, however, shows that a different
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`formulation is actually used that does not practice the claims. Anchordoquy,1 ¶¶139-
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`142.
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`III. CLAIM CONSTRUCTION
`The Board’s prior construction of “nucleic acid-lipid particle” as “a particle
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`that comprises a nucleic acid and lipids, in which the nucleic acid may be
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`encapsulated in the lipid portion of the particle” from the ’435 patent IPR is
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`appropriate and Petitioner agrees therewith. EX1008, ¶88; Anchordoquy, ¶¶27-29.
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`Dr. Anchordoquy agrees with Dr. Janoff that a POSITA would adopt this
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`construction using the appropriate standard in light of the intrinsic record. Id., citing
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`EX1001, 11:4-12.
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`To avoid prior art, Protiva seeks to import limitations arguing that the claims
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`“necessarily including a nucleic acid encapsulated in the lipid portion of the
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`particle,2 thereby protecting it from enzymatic degradation.” Response, 9. The Board
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`soundly rejected this argument previously. EX1022, 11-13 (“Dr. Thompson attempts
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`to shoehorn the statement that nucleic acids….”). Moreover, it conflicts with the
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`’069 patent’s disclosure of “…delivery of associated or encapsulated therapeutic
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`agents….” EX1001, 6:20-23. Encapsulation is just one means of preventing
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`1 Petitioner’s prior expert, Dr. Janoff, passed away in December 2019 and Dr.
`Anchordoquy has thus been engaged.
`2 All emphasis added unless otherwise noted.
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`degradation. Anchordoquy, ¶¶29-35. Other options include chemical modification
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`of the payload to resist degradation. EX1001, 44:33-35 (chemical modification); see
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`also EX1005, ¶20 (“…use of chemically-modified siNA … [has] increased
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`resistance to nuclease degradation….”).
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`Protiva also attempts to narrow the term to exclude lipoplexes addressed in
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`Lin (EX1006) and Ahmad (EX1007). Response, 5; EX2031, ¶111. But a POSITA
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`would understand that lipoplex and liposomal structures existed at the time of the
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`’069 patent that can meet the claim limitations. Anchordoquy, ¶¶36-41, 87-91.
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`Indeed, the ’189 publication, also directed at SNALPs, specifically identifies
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`liposomes and lipoplexes as “…alternative lipid-based carrier systems suitable for
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`use with the present [SNALP] invention….” EX1004, [0149].
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`IV. THE INSTITUTED GROUNDS
`Protiva relies on arguments directed at the claimed range for the phospholipid
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`and cholesterol components. Response, 14, 17. Protiva fails, however, to
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`demonstrate “that there is something special or critical about the claimed range” for
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`these components. Genentech, Inc. v. Hospira, Inc., 946 F.3d 1333, 1341 (Fed. Cir.
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`2020). For example, there is no evidence that 11mol% phospholipid or 41mol%
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`cholesterol, as opposed to points in the claimed ranges, would have any impact on
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`the particle efficacy. Anchordoquy, ¶43.
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`A. AN OVERLAPPING PHOSPHOLIPID RANGE IS DISCLOSED
`Even if the phospholipid range is considered, the Board’s initial
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`determination that EXS1003-1005 disclose overlapping ranges for each lipid
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`component is correct. Initial Determination (“ID”), 16-18, 22-24, 34-37;
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`Anchordoquy, ¶¶44-50. Protiva does not dispute that each reference discloses a
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`non-cationic/neutral lipid range of 5-90mol% (see EX1003, [0091], EX1004,
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`[0152]; EX1005, [0313]) or that a phospholipid is one of the disclosed species of
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`non-cationic/neutral lipids (EX1003, [0089]; EX1004, [0159]; EX1005, [0455]).
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`During prosecution, the patentee admitted that the same disclosures in Protiva’s
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`prior ’910 publication (EX1015, ¶85) provides a phospholipid range of 5-90mol%
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`confirming that a POSITA would be put on notice of an overlapping phospholipid
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`range. EX1016, 5-6.
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`Protiva argues that there is no “express disclosure of a phospholipid range”
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`(Response, 6; EX2031, ¶39)3—that is irrelevant. The applicable legal standard is
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`what a “POSITA reading [the reference] would understand.” See IXI IP, LLC v.
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`Samsung Elecs. Co., Ltd., 903 F.3d 1257, 1264-1265 (Fed. Cir. 2018) (rejecting
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`arguments based upon lack of an “express disclosure”). At deposition, Protiva’s
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`expert agreed that a POSITA would understand from the above disclosures that a
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`3 The Board in the ’435 patent IPR similarly focused on the lack of a “specific range
`for the amount of phospholipid.” EX1022, 31.
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`phospholipid range is disclosed. EX1025, 167:10-22 (“…this is a range that is of
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`composition 5mol% and 90mol% of any number of different phospholipids that are
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`recited here.”).
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`B.
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`THE SAME FOUR LIPID-COMPONENT CARRIER PARTICLES ARE
`DISCLOSED
`Carrier particles comprising the exact same four lipid components in the
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`’069 patent claims (i.e., cationic lipid, phospholipid, cholesterol, and conjugated
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`lipid) are expressly disclosed in the working examples of each prior art reference.
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`EX1004, [0369]; EX1003, [0223]; EX1005, Table IV (L051, L053, L054, L069,
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`L077, L080, L082, L083, L109), Anchordoquy, ¶¶51-55. Protiva’s expert admits
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`that such working examples would help inform a POSITA. EX1025, 110:1-8. Yet,
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`Protiva completely ignores these working examples in arguing that the Petition
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`only addresses “the individual lipid components” as opposed to the particles as a
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`whole. Response, 27; EX2031, ¶73.
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`For example, the ’189 publication discloses effective transfection using the
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`closest prior art—a carrier particle with the formulation 40/10/48/2 (cationic
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`lipid/phospholipid/cholesterol/conjugated lipid) (“2:40 formulation”) that uses the
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`same basic species for each lipid component4 to carry the same nucleic acid
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`4 DPPC is used instead of DSPC in the ’069 patent testing, but Protiva’s expert
`acknowledges that the two phospholipids would behave similarly. EX2031, ¶102;
`EX2005, 158:20-159:4 (“I don't think it's going to have that much of an impact.”).
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`payload as tested in the ’069 patent. Compare, e.g., EX1004 (Examples 13-17)
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`with EX1001 (Examples 2-3); Anchordoquy, ¶¶51-55. This reference thus
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`expressly spells out the lipid components combined as in the ’069 patent claims.
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`EX1025, 115:7-21 (Protiva’s expert admitting same four-lipid component particle
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`described).5
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`C. ROUTINE OPTIMIZATION OF LIPID-CARRIER PARTICLES
`As the Board noted, “it has long been recognized that where the general
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`conditions of a claim are disclosed in the prior art, it is not inventive to discover
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`the optimum or workable ranges by routine experimentation.” ID, 24 citing E.I.
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`DuPont de Nemours & Co. v. Synvina C.V., 904 F.3d 996, 1006 (Fed. Cir. 2018)
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`(internal quotations omitted). “[W]here the general conditions of a claim are
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`disclosed in the prior art, it is not inventive to discover the optimum or workable
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`ranges by routine experimentation.” In re Applied Materials, Inc., 692 F.3d 1289,
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`1295 (Fed. Cir. 2012). The Board’s determination that “in view of the high level of
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`ordinary skill in the art…optimization of the ranges of components to achieve the
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`claimed composition would be the ‘normal desire of scientists or artisans to
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`improve upon what is already generally known’” (ID, 25) is correct. Given the
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`defined efficacious prior art systems discussed above (e.g., the 2:40 formulation in
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`5 Protiva also argues that “the prior art is not limited to a formulation requiring a
`phospholipid.” Response, 26; EX2031, ¶41. There is no such legal requirement.
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`EX1004), a POSITA would have used the general conditions of such systems as a
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`starting point and been motivated to optimize the lipid formulations therein.
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`EX1008, ¶108; Anchordoquy, ¶¶56-69.
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`The intrinsic record establishes that such optimization is routine once the
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`general conditions of the system have been defined. Id. The ’069 patent states that
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`“[i]t will be readily apparent to one of skill in the art that depending on the
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`intended use of the particles, the proportions of the components can be varied….”
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`EX1001, 49:62-65. Similarly, during prosecution, the examiner concluded that
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`“MacLachlan [’910 publication]…teaches that the proportions of the components
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`can be varied by those of skill in the art. Thus, by routine experimentation towards
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`optimization, one of skill in the art could arrive at the instantly claimed
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`proportions.” EX1016, 6 (emphasis added). As Protiva’s expert admitted: “[y]ou're
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`trying to vary different proportions to see where the best in vivo performance, the
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`best tolerance of ranges are identified.” EX1025, 83:19-84:17, 84:3-11 (optimizing
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`phospholipid), 85:3-21 (optimizing cationic lipid).
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`The prior art similarly establishes that “[i]t will be readily apparent to one of
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`skill in the art that the proportions of the components of the nucleic acid-lipid
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`particles may be varied.” EX1004, [0152]; EX1003, [0088] (“…the proportions of
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`the components are varied….”). This is further confirmed by the inventors'
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`publications at the time. EX1024, 251 (“…SNALP formation by ethanol dilution is
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`optimized by balancing ionic strength, cationic lipid, and PEG lipid content.”).
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`The testing in the ’069 patent illustrates just this type of optimization.
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`EX1001, Example 2 (Table 2) below:
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`As can be seen, the payload and lipid species are defined and the lipid proportions
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`and lipid:drug ratio are varied to optimize the formulation. Anchordoquy, ¶¶61-62.
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`As another example, Protiva’s ’910
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`publication discloses experiments with a
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`SNALP with a siRNA payload with a
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`cationic lipid concentration ranging from 5-
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`40mol%. EX1015, [0335]. As can be seen
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`from Figure 23, increasing concentrations of
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`DLinDMA were tested to determine optimal
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`knockdown levels. Anchordoquy, ¶63.
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`As another example, EX2014, 15-20
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`(Tables 1 and 2) illustrates in detail testing of formulations for a wide variety of
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`lipid percentages for each lipid component (e.g., a cationic lipid range of 20-
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`80mol%) to optimize formulations. See also id., 116-120 (discussing optimization
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`based on results); Anchordoquy, ¶64.
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`Protiva argues that the field involves complex technology and significant
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`unpredictability in particle formulation. Response, 12, 19-24; EX2031, ¶¶59-61.
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`This misses the point. The prior art defines an effective four-lipid carrier particle
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`system for the same payload and with substantively the same lipid species as used
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`in the ’069 patent, just with slight differences in lipid concentrations. EX1004
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`(Examples 13-17); Anchordoquy, ¶¶66-68. A POSITA would not start from
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`scratch, but use the general conditions of this proven systems as a starting point.
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`Applied Materials, 692 F.3d at 1295.6
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`(1) OPTIMIZATION OF THE CATIONIC LIPID
`Protiva’s focus on the cationic lipid concentration alone evincing a
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`fundamental misunderstanding of lipid carrier particles—what matters is the
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`amount of cationic lipid, not merely the concentration. Positively charged cationic
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`lipids are added to carrier particles offset the negatively charged nucleic acid
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`phosphate groups (the resulting ratio is called the “N/P ratio”). EX1008, ¶62;
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`EX1025, 111:2-24, 199:1-8, 112:11-16 (“one of the ways that you would increase
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`the charge neutralization [is] to increase the proportion of cationic lipid.”);
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`Anchordoquy, ¶¶70-72. The amount of cationic lipid depends not only on the
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`cationic lipid concentration, but also on the lipid:drug ratio.7 Id. For example, if
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`you double the cationic lipid concentration from 25 to 50mol%, but at the same
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`time halve the lipid:drug ratio, there is no net impact on the amount cationic lipid.
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`For the 2:40 formulation in EX1004, the N/P ratio was approximately 6. See
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`EX1004, [0350]-[0391]; Anchordoquy, ¶73. This N/P ratio is optimized for the
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`siRNA payload and the ionizable cationic lipid used, DLin-DMA. Id. The pKa of
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`6 Protiva’s argument that the Board’s determinations regarding obviousness in the
`’435 patent IPR obviate this issue are misplaced. Response, 4. While the Board
`found that Petitioner in that IPR had not carried its burden to demonstrate
`obviousness (see EX1022, 36-37), that decision is under appeal and involves
`different claims, facts and arguments than are at issue here.
`7 N/P ratios are not listed in the ’069 patent, but a POSITA can calculate the ratio by
`using the lipid:drug ratio and the lipid component molar ratios. Anchordoquy, ¶72.
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`DLinDMA is 6.7. EX1011, 281. At that pKa, one-sixth of the cationic molecules
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`possess a positive charge at physiological pH (i.e., 7.4). Anchordoquy, ¶¶86-87.
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`An N/P ratio of 6 thus fully neutralizes the negative charge on the nucleic acids in
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`serum. See EX1004, [0062] (goal to neutralize 90% of the negative charges);
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`EX1027, 3 (2006 publication from inventors using N/P ratio of 6 with DLinDMA).
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`Consistent with this testing in the ’189 publication, in Example 3 of the ’069
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`patent, the 1:57 formulation (Group 11) on which Protiva relies has exactly the
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`same relative amount of cationic lipid (N/P of 6) as the prior art 2:40 type
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`formulation (Group 12)—and also as the 2:40 formulations used in the ’189
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`publication. Anchordoquy, ¶¶73-76. A POSITA would expect in such similar
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`systems that cationic lipid amounts at similar N/P ratios would behave similarly.
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`Id. Having a consistent optimized N/P ratio provides further motivation to increase
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`the cationic lipid concentration while decreasing the lipid:drug ratio accordingly
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`and a basis for expecting the resulting particles to be effective at the higher
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`cationic lipid concentration.8 Id.
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`Even if one focuses on only the cationic lipid concentration, the prior still
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`demonstrates that a range of 50-65mol% would have been obvious. It is undisputed
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`that each prior art reference discloses a cationic lipid range of 2-60mol%,
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`8 One potential benefit of increasing the cationic lipid concentration while decreasing
`the lipid:drug ratio (with a constant N/P ratio) is a net decrease in the amount of
`helper lipids. Anchordoquy, ¶77.
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`substantially overlapping with the claimed range. See EX1003 [0088]; EX1004,
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`[0152]; EX1005 [0313]. Additionally, each reference discloses a narrower range of
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`40-50mol% that also overlaps. Id. A POSITA would have understood from these
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`disclosures potential cationic lipid concentration ranges (including the 50-60mol%
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`portion) for safe, effective lipid-carrier particles. Anchordoquy, ¶¶52-54.
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`Moreover, a POSITA would have known that an excess of positive charge
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`promotes endosomal release of the payload once a target is reached. EX1008, ¶62;
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`EX1024, 230 (“Cationic lipids also function by providing the liposome with a net
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`positive charge, which in turn enables binding of the NA complex to anionic cell
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`surface molecules.”). Protiva’s expert himself admits to evaluating ranges of
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`cationic lipid concentrations in titration-like experiments that “were quite high”
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`prior to the ’069 patent. EX1025, 41:2-16; see also 87:18-88:6 (using 50-65mol%
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`cationic lipid was obvious for in vitro use).
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`The Protiva’s prior art disclosures also illustrate a trend toward using higher
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`cationic lipid concentrations. The ’196 PCT (2003) discloses testing SNALPs with
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`siRNA in a four-lipid system with lipid percentages of 15/20/55/10 (cationic
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`lipid/phospholipid/ cholesterol/conjugated lipid). EX1003, [0232]. Protiva’s U.S.
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`Patent No. 7,799,565 (mid-2004) discloses testing SNALPs with siRNA in a four-
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`lipid component system with lipid percentages of 30/20/48/2. EX1028, 52:54-
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`53:17. Protiva’s ’189 publication (late 2004) discloses testing SNALPs with
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`Case No. IPR2019-00554
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`siRNA in a four-lipid component system with lipid percentages of 40/10/48/2.
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`EX1004, [0351]-[0385]. Over time, there is thus a consistent increase in cationic
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`lipid concentrations used:
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`Anchordoquy, ¶¶78-80; see also EX1025, 136:20-137:21 (Protiva expert admitting
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`POSITA would consider trend toward higher concentrations), 142:14-143:3
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`(50mol% cationic lipid was “one of many possible avenues to explore….”). This
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`understanding is confirmed by Protiva’s ’910 publication which, as discussed
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`above, discloses testing varying the cationic lipid concentration from 5-40mol%
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`and illustrating better performance at higher concentrations. EX1015, [0335], Fig.
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`23.9 These disclosures would further motivate a POSITA, using the 2:40
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`formulation as a starting point, to create particles with a cationic lipid in the
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`9 Protiva incorrectly asserts “the 2:30 SNALP formulation contains the greatest
`amount of cationic lipid of all the SNALP formulations prepared and tested” in the
`’910 publication. Response, 35.
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`claimed range with a reasonable expectation of success. Anchordoquy, ¶¶81-82.
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`Protiva’s argument that all cationic lipids are toxic also misses the point.
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`Response, 7; EX2031, ¶¶80-88. First, Protiva again improperly equates the cationic
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`lipid concentration with the amount of cationic lipid. Anchordoquy, ¶¶83-84.
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`Second, a POSITA would have been aware that toxicity in lipid particles is largely
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`a function of having a net positive charge in serum (i.e., at physiological pH). Id.;
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`EX1025, 62:22-63:14 (Protiva’s expert admitting to need to shield charge of
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`cationic lipid). To address potential toxicity issues, years before the ’069 patent
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`priority date, ionizable cationic lipids had been developed whose charge was low at
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`physiological pH, but became strongly cationic in the acidified environment of the
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`endosome. Anchordoquy, ¶¶85-88; EX1004 [0223] (using ionizable lipid
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`DLinDMA); EX1011, 280 (same), Fig. 1 (substantially neutral charge at pH 7.4);
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`EX1009, 6 (“Cationic lipids that are charged only at mildly acidic but not at neutral
`
`pH … may also be a potential solution to the toxicity issues ….”); EX1005, [0462]
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`(same); EX1025, 239-240 (same); EX2021, 173 (neutral particles at physiological
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`pH preferred). This understanding still holds true today: “…such positively
`
`charged systems induce pronounced toxicity in vivo due to immune
`
`activation…[t]o circumvent this problem, we developed ionizable cationic
`
`lipids….” EX1026, 1085.
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`Consistent with this reasoning, the examples in both the ’069 patent and the
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`prior art demonstrate the use of high cationic lipid concentrations to achieve an
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` U.S. Patent No. 8,058,069
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`optimal N/P ratio of 6 in substantially non-toxic particles. EX1004 [0351-0391] (in
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`vivo testing using DLinDMA), [0076, 0151] (particles “substantially non-toxic”);
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`EX1025, 123:16-124:10 (Protiva’s expert admitting ’189 data indicates no
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`toxicity); 133:20-134:4 (formulation effective and safe); EX1001, Example 3,
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`Table 4 (Groups 11-12).
`
`Protiva’s expert admits that cationic lipids are designed to be non-toxic.
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`EX2005, 64:15-65:14 (“Because they’re toxic. They are--they tend to be, unless
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`designed properly….”) (emphasis added); EX2006, 260:11-18. He also admits that
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`the class of cationic lipids which includes DLinDMA used in the ’189 publication
`
`was known not to have significant toxicity concerns: “[t]he data that…I’ve reviewed
`
`for this class of cationic lipids has--in vivo has not suggested that there are
`
`significant toxicity concerns.” Id., 266:18-267:20; see also id., 267:22-268:15
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`(“known that [DLinDMA] had a low toxicity profile….”).
`
`Protiva points to accumulation in the plasma and immunogenicity as
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`alternative sources of toxicity. Response, 29-30; EX2031, ¶86. Protiva has
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`confirmed, however, the lack of such toxicity issues for the 2:40 formulation:
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`“[t]here was no evidence for complement activation, delayed coagulation, pro-
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`inflammatory cytokine production…or changes in hematology
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`parameters…toxicities that have been observed previously with treatments using
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`related approaches.”10 EX1027, 3; Anchordoquy, ¶¶94-95.
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` U.S. Patent No. 8,058,069
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`Lin and Ahmad (EXS1006-1007) provide further support that a POSITA
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`would have been motivated to employ greater amounts of cationic lipid.
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`Anchordoquy, ¶¶89-91. The testing therein establishes that for certain cationic
`
`lipids, increasing the N/P ratio by elevating the cationic lipid concentrations above
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`50mol% enhanced transfection efficiency. EX1008, ¶¶102-106.
`
`Protiva’s arguments that Lin and Ahmad are irrelevant are misplaced. First,
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`as discussed above, the claims of the ’069 patent are not limited to non-lipoplex
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`particles. Second, in this field, it was common to look at prior research regarding
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`various types of lipid carrier particles. Anchordoquy, ¶¶36-41. Both of the
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`Protiva’s prior art disclosures cite to prior work done on liposomes and lipoplexes.
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`EX1003, [0132], [0175]; EX1004, [0203], [0156] (incorporating ’618 patent
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`directed to lipoplexes).
`
`Protiva’s argument that Ahmad teaches away from increasing the cationic
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`lipid concentration (Response, 59) is also misplaced. Ahmad specifically noted that
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`in vitro, the tested cationic lipid amounts showed “no toxic effects on the cells as
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`judged by cell morphology and the amount of total cellular protein.” EX1006, 745-
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`10 Protiva also points to Moderna publications stating that toxicity issues with
`modern cationic lipids can be further minimized. Response, 29-30. That cationic
`lipids may be further improved does not negate their use at tolerable levels at the
`time of the ’069 patent.
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`46. In addition, Ahmad utilized multivalent cationic lipids to achieve very high
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` U.S. Patent No. 8,058,069
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`charge densities in order to test their hypothesis, and it was known by a POSITA
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`that such extreme charge densities with multivalent cationic lipids were typically
`
`not suitable for in vivo use due to their toxicity. Anchordoquy, ¶92.
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`Protiva also mischaracterizes Ahmad as reaching “saturation” at 50mol%
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`cationic lipid. Response, 58. Ahmad shows no such thing. As can be seen, the
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`monovalent cationic lipids do not level off until about 80mol% (EX1007, Fig. 3):
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`Anchordoquy, ¶93.
`(2) OPTIMIZATION OF THE CONJUGATED LIPID
`A second lipid typically optimized is the conjugated lipid, e.g., PEG. See
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`
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`EX1001, 68:35-48; Anchordoquy, ¶¶96-98. A POSITA would have been motivated
`
`to add PEG to carrier particles to provide a neutral, hydrophilic coating to the
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`particle’s exterior and thus prevent aggregation. EX1008, ¶64; EX1025, 58:1-13. In
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`the art, there is a known “PEG dilemma”—including enough PEG to stabilize the
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` U.S. Patent No. 8,058,069
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`particle, but not so much that the particle is unable to engage the target in vivo.
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`EX2005, 145:9-23 (“…another factor which is referred to in the literature as the PEG
`
`dilemma.”). In other words, it was known that the amount of conjugated lipid should
`
`be minimized to allow the nucleic acid payload to interact with the target. EX1024,
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`241. Consistent with this understanding, the ’189 publication discloses a low
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`concentration for the conjugated lipid that overlaps with the claimed range. EX1004,
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`[0152] (2mol%).
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`The formulations tested in the cited prior art similarly have low amounts of
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`PEG coupled with high cationic lipid concentrations. EX1004 [0351-0391] (2:40
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`formulation in the ’189 patent showing in vivo efficacy with 2mol% PEG); EX1005,
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`Table IV (L077, L069, L080, L082, L083, L060, L061, and L051 showed efficacy
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`in vivo with 2-3mol% PEG). While these specific formulations vary slightly from
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`the claimed ranges, they establish that a POSITA would have been motivated to use
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`PEG in low amounts coupled with high levels of cationic lipid with a reasonable
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`likelihood of su
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