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`Paper No. ___
`Filed: April 17, 2019
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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 IPR2018-00739
`Patent No. 9,364,435
`_____________________________
`
`PATENT OWNER’S SUR-REPLY
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`
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`TABLE OF CONTENTS
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`I.
`II.
`III.
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`B.
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`B.
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`Page
`INTRODUCTION .......................................................................................... 1
`CLAIM CONSTRUCTION ........................................................................... 3
`IT IS NOW UNDISPUTED THAT L054 DOES NOT
`ANTICIPATE THE CHALLENGED CLAIMS ............................................ 7
`IV. THERE IS NO RATIONALE/MOTIVATION SUPPORTING
`OBVIOUSNESS ........................................................................................... 12
`A.
`Formulating Nucleic Acid-Lipid Particles Was Not a
`Matter of Routine Optimization ......................................................... 14
`Petitioner’s New Picking and Choosing Argument
`Should be Rejected ............................................................................. 17
`V. UNEXPECTED RESULTS FURTHER REBUT ANY PRIMA
`FACIE OBVIOUSNESS .............................................................................. 18
`A.
`The ’435 Patent Reports Extensive Testing of Numerous
`Formulations Within the Claimed Range ........................................... 20
`Post-Filing Publications Provide Testing Data for a
`Broad Range of Lipids and Cargo Molecules (including
`both siRNA and mRNA) .................................................................... 23
`Petitioner Remaining Arguments are Unavailing .............................. 27
`C.
`VI. PETITIONER’S FALSE NARRATIVE OF NON-TOXIC
`CATIONIC LIPIDS SHOULD BE REJECTED .......................................... 27
`VII. LIN/AHMAD DO NOT SUPPLY THE MISSING
`MOTIVATION FOR GROUND 2 ............................................................... 31
`VIII. OBJECTIVE INDICIA CONFIRM PATENTABILITY OF
`CLAIMS ....................................................................................................... 34
`IX. DEPENDENT CLAIMS ............................................................................... 35
`X.
`CONCLUSION ............................................................................................. 36
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`I.
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`INTRODUCTION
`This sur-reply is filed in response to Petitioner’s Reply filed March 22,
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`2019. See EX2056.
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`The Reply illustrates precisely why attorney argument should be accorded
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`no weight, and why such argument cannot take the place of evidence in the record.
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`Much of the Reply relies on attacking arguments Patent Owner never made,
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`mischaracterizing the deposition testimony of Patent Owner’s expert, and flatly
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`ignoring detrimental testimony from Petitioner’s own expert. Beyond that, the
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`Reply attempts to weave false narratives about non-toxic cationic lipids and
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`inoperable formulations that not only lack a shred of supporting evidence, but are
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`contradicted by Petitioner’s own publications.
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`In the end, Petitioner’s unpatentability challenges lack supporting evidence,
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`and the Reply fails to show otherwise. Petitioner’s sole remaining anticipation
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`challenge fails in that neither the L054, nor any other composition in the ’554
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`publication, represents particles (as opposed to starting ingredients) having a lipid
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`composition required by the challenged claims—nor does the L054 composition or
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`any other composition disclosed in the ʼ554 patent encapsulate nucleic acid in the
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`particle so as to protect the nucleic acid from enzymatic degradation.
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`Regarding Petitioner’s obviousness assertions, Patent Owner previously
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`pointed out those challenges fail for being premised on the false notion that
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`overlapping lipid ranges in the prior art alone necessarily render the ’435 patent
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`claims obvious. The Reply perpetuates this erroneous argument, now citing to E.I.
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`duPont de Nemours & Co. v. Synvina C.V., 904 F.3d 996 (Fed. Cir. 2018). But
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`duPont, like all other overlapping range cases, is based the specific rationale of
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`“routine optimization”—rather than obviating the need for the critical aspects of an
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`obviousness inquiry (e.g., motivation, reasonable expectation of success). Id. at
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`1006. Petitioner has never established that formulating nucleic acid-lipid particles
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`as claimed would have been a matter of routine optimization (or any other
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`obviousness rationale). Here, the evidence is overwhelming — achieving the
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`nucleic acid-lipid particles of the ’435 patent was not a matter of routine
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`optimization.
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`To the extent any prima facie case of obviousness was established by
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`identification of overlapping lipid ranges in the art, that case is rebutted by the
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`extensive experimental data in the ’435 patent and numerous post-filing
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`publications, including Petitioner’s own publications. As explained previously, and
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`as corroborated throughout the literature at the time (and unrebutted by Petitioner),
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`high-level cationic lipid formulations (e.g., 50-85% cationic lipid) were expected
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`to have poor in vivo activity and elicit increased toxicity and immunogenicity
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`relative to lower-level cationic lipid formulations. EX1005, 3315; EX1006, 745;
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`EX1008, E96; EX2007, 30:34-41.
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`Patent Owner, however, found that the claimed formulations surprisingly
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`impart increased activity of the encapsulated nucleic acid and improved tolerability
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`of the formulations in vivo, resulting in a significant increase in the therapeutic
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`index. EX1015, 38-39, 68-69. Moreover, the claimed formulations are stable in
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`circulation and are substantially non-toxic when administered to mammals. These
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`surprising results are different in kind, not merely degree. The Reply fails to
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`demonstrate otherwise.
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`As such, when all the evidence of record is weighed and considered,
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`Petitioner has failed to meet its burden of demonstrating unpatentability by a
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`preponderance of the evidence, and the challenges in the Petition should be
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`rejected and the claims of the ’435 patent found not unpatentable.
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`II. CLAIM CONSTRUCTION
`Petitioner now abandons the construction of the term “nucleic acid-lipid
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`particle” that was proffered in the Petition and rejected in the Institution Decision
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`(e.g., Pet. 24; Decision 10-11). The Reply (3) instead provides a single conclusory
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`sentence stating that the Board’s preliminary construction of this term “is
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`appropriate.”1 EX1021, ¶13. Petitioner offers no argument or analysis as to why
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`1 This represents the third different construction for this term advanced by
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`Petitioner.
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`this construction is appropriate (e.g., reasonable in view of the specification), and
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`provides no meaningful response to the evidence presented in the Response (e.g.,
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`11-13).
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`As explained in the Response (11-12), the “preliminary construction” puts
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`misplaced reliance on limited discussion of a different term (“lipid particle”), does
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`not account for pertinent disclosure elsewhere in the specification, and is
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`unreasonably broad.
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`As explained by Dr. Thompson, a “nucleic acid-lipid particle” (as opposed
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`to a “lipid particle”) does include a nucleic acid encapsulated in the particle so as
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`to protect the nucleic acid from enzymatic degradation. Response, 11-12; EX2009,
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`¶¶38-40, 44-45. Such an interpretation is supported throughout the specification of
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`the ʼ435 patent. E.g., EX1001, 11:51-54 (“nucleic acids, when present in the lipid
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`particles of the present invention, are resistant in aqueous solution to degradation
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`with a nuclease”) (emphasis added); see also id., Examples and Tables (e.g.,
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`Tables 2, 4, 6, 7) all reporting high encapsulation; 11:20-22 (equating
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`encapsulation with resistance to nuclease degradation); cf. 68:56-58 (“For vehicle
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`controls, empty particles with identical lipid composition were formed in the
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`absence of siRNA.”). Petitioner does not dispute this interpretation in its Reply or
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`elsewhere—nor can it.2
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`The Reply (4-5) is largely spent attacking a strawman, incorrectly stating
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`that Patent Owner proposed importing various “SNALP” and “in vivo” limitations
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`into the claims. But it was Petitioner’s expert who repeatedly testified during
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`cross-examination that the patent defines the claimed nucleic acid-lipid particles as
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`SNALPs. E.g., EX2028, 118:19-119:4 (“...we’re defining them in this invention as
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`SNALPs and what they comprise of.... So that would seem to me to be a
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`definition.”), 120:5-6 (“It’s a definition in the context of this patent.”), 121:14-25
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`(“So it’s pretty clear that we’re talking about lipid particles of the invention, and
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`it’s pretty clear we’re talking about SNALPs...”).
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`The Reply (4) attempts to whitewash Dr. Janoff’s testimony in this regard
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`with a heavily edited quotation from the transcript—that is, edited to remove
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`counsel’s improper coaching objection and Dr. Janoff’s unequivocal affirmance of
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`2 Dr. Janoff embraced this interpretation during cross-examination. EX2028,
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`195:20-22 (“...what [the ’435 patent] says is when nucleic acids are present in the
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`lipid particles, they’re resistant to a degradation.”); see also id., 194:3-195:22,
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`198:4-22, 199:10-18.
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`defining the claimed particles as SNALPs (highlighted below). The more complete
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`quotation is shown here:
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`EX2028, 119:5-17; see also id., 119:23-121:25 (confirming at least 3 more times
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`his position that the specification defines lipid particles as SNALPs); Response,
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`12; EX2028, 16:13-25.
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`As stated in the Response (12-13), a reasonable reading of the ’435 patent
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`supports Dr. Janoff’s position in that there is no meaningful distinction between
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`descriptions of a “lipid particle” containing a nucleic acid (nucleic acid-lipid
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`particle) and particle characteristics that confer serum stability.3 Nothing in the
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`Reply demonstrates otherwise.
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`III.
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`IT IS NOW UNDISPUTED THAT L054 DOES NOT ANTICIPATE
`THE CHALLENGED CLAIMS
`The L054 formulation fails to anticipate the challenged claims for several
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`reasons.4 The Reply attempts to sidestep these points, but does not directly address,
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`let alone rebut, them.
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`First, the Petition cites the L054 formulation of Table 4, but that is a lipid
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`mixture for making particles—not itself a particle (See, e.g., claim 1 directed to a
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`“nucleic acid-lipid particle”). Dr. Thompson explained the erroneous nature of
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`3 During prosecution of the parent application leading to U.S. Patent No. 8,058,069
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`(ʼ069 patent), Patent Owner described the claimed “nucleic acid-lipid particle” as
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`“SNALP formulations advantageously impart increased activity of the
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`encapsulated nucleic acid (e.g., an interfering RNA such as siRNA) and improved
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`tolerability of the formulations in vivo.” EX1015, 38 (emphasis original). See
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`Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015).
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`4 Petitioner appears to have abandoned its anticipation arguments that disclosure of
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`the prior art ranges are sufficiently specific to anticipate. E.g., Pet. 38 (1(d)), 39
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`(1(e)), 43 (Claim 7); EX1007, ¶¶116-117, 124.
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`simply assuming resulting complexes have the same composition as the starting
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`lipid mixture. E.g., EX2009, ¶110 (citing EX2012; EX2013).
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`The Reply (13) makes the conclusory assertion that listing only starting
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`formulations, and not the particle composition, was “accepted practice in the
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`field.” This dubious assertion misses the point.5 The claims are directed to a
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`“nucleic acid-lipid particle.” The ’554 publication does not disclose lipid
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`compositions of resulting particles, nor does it disclose sufficient detail to
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`reasonably assume the resulting particles fall within the scope of claim 1. E.g.,
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`Response, 40-43. Petitioner disputes none of this, and the anticipation challenge
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`fails for this reason alone.
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`The Reply (14) mischaracterizes Patent Owner’s argument as an unfounded
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`assumption of one-directional variation. As a threshold matter, it is not Patent
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`5 The Reply (13-14) attempts to pivot to a discussion of the ’435 patent, which is a
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`different document (with different disclosure) irrelevant to the deficient content of
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`the ’554 publication. In contrast to the ’554 publication, the ’435 patent discloses
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`detailed descriptions of particle production methods and extensive characterization
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`of finished particles. E.g., EX1001, 57:60-60:59, Tables 2, 4, 6, 7, 76:26-48;
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`68:58-69:5 (describing typical variation in lipid composition); EX1019, 168:7-
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`172:14.
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`Owner’s burden to prove the composition of the L054 particle when that
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`composition is not provided in the reference. Petitioner fails to establish the ’554
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`publication’s particles would have a lipid composition within the scope of claim 1.
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`See 35 U.S.C. § 316(e). Beyond that, the ’554 publication provides only cryptic
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`description of its production methods, and what scant detail is provided more
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`reasonably predicts different incorporation efficiencies for different lipid
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`components, thereby resulting in particles with lipid ratios well outside the claimed
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`ranges. E.g., EX2009, ¶113 (“The predictable result of using cholesterol-based
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`detergents is less cholesterol in the finished particles than in the starting
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`materials.”), ¶115; EX1020, 226:7-11 (“If we have lower cholesterol, that
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`conjugate lipid concentration is going up, not down.”); EX2028, 157:12-158:16
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`(Dr. Janoff describing failure to recover cholesterol in a particle altering the
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`amount of the remaining components); EX1020, 223:14-21 (explaining that the
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`cationic lipid would be expected outside the claimed range).6 The Reply offers no
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`meaningful rebuttal.
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`6 The Reply (14) mischaracterizes Dr. Thompson’s testimony as somehow
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`supporting Petitioner’s argument, where he actually expressly rejected it. See
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`EX1020, 224:6-21, 223:14-21 (“...very likely that these particles are outside the
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`(continued...)
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`Second, there is no evidence that L054-derived lipid particles encapsulate
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`nucleic acid as required by the ’435 patent (i.e., encapsulated in the particle so as
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`to protect the nucleic acid from enzymatic degradation). See Section II; see also
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`EX2028, 199:10-18, 198:4-17, 194:3-21. The ’554 publication makes no assertion
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`that L054 encapsulates nucleic acid in the particle as specifically required by the
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`’435 patent, or in any capacity at all, let alone verify such encapsulation with any
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`evidence.
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`The Reply (14-15) again attempts to sidestep the encapsulation issue and
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`avoid detrimental testimony of its own expert. Instead, the Reply offers only the
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`cryptic assertion that the ’554 publication “discusses encapsulation.” None of the
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`citations to the ’554 publication discuss L054 encapsulation. See Reply, 14-15
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`(citing EX1004, ¶11 (background discussing different particles), ¶136 (not
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`addressing L054), ¶317 (not addressing L054, encapsulation only as a possibility),
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`¶400 (no mention of encapsulation)).
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`And Petitioner offers no explanation as to how “encapsulation” would be
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`understood in the context of the ’554 publication. This is critically pertinent in
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`(...continued from previous page)
`range [for cationic lipid].”), 226:13-23 (“I’m not taking the bait on that one. The
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`point is clear.”).
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`view of Dr. Janoff’s repeated testimony (and publications) that encapsulation
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`means very different things in different contexts. Compare EX2028, 137:16-
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`138:16 (“[Encapsulation] has many different meanings...”), 147:18-22
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`(“[Encapsulation is] a fungible term. It means different things to different people in
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`different contexts.”), 146:22-147:1, and EX2007, 4:11-19, with EX2028, 199:10-
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`18, 198:4-22, 194:3-21, and 195:12-22. There is no evidence or argument that
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`L054 (or any other particle produced using the compositions disclosed by the ’554
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`publication) encapsulates nucleic acid in the particle so as to protect the nucleic
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`acid from enzymatic degradation.7
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`Accordingly, Petitioner fails to establish that L054 (or any other composition
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`in the ’554 publication) 1) includes particles having a lipid composition required
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`by the challenged claims; or 2) encapsulates nucleic acid so as to protect the
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`nucleic acid from enzymatic degradation.
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`7 Petitioner fails to inform the Board that the ’554 publication takes a
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`fundamentally different approach and relies on nuclease-resistant RNA constructs.
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`EX1004, ¶¶522, 523, 578. The reliance on such modified RNA indicates particle
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`construction that fails to prevent nuclease exposure.
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`IV. THERE IS NO RATIONALE/MOTIVATION SUPPORTING
`OBVIOUSNESS
`Patent Owner previously pointed out that the obviousness challenges of at
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`least Grounds 1 and 3 in the Petition fail to identify any particular motivation or
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`rationale to combine components specifically in the proportions required by the
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`claims (or any discussion of reasonable expectation of success). POPR, 27-28, 44;
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`Response, 18-20, 46-47. Rather, those challenges rest on the false notion that
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`overlapping lipid ranges in the prior art alone necessarily render the ’435 patent
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`claims obvious. The Reply (10-11) perpetuates this erroneous argument, now
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`citing to duPont.
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`Petitioner, however, fails to acknowledge that none of duPont, Peterson, or
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`any other overlapping range case stands for the proposition that an overlapping
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`range in the prior art obviates the requirements for motivation to combine and
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`reasonable expectation of success in an obviousness challenge. Instead, the Federal
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`Circuit has explained that overlapping ranges, without evidence to the contrary,
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`may invoke a rebuttable presumption of obviousness under the specific rationale of
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`“routine optimization.” See, e.g., In re Stepan Co., 868 F.3d 1342, 1346 n.1 (Fed.
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`Cir. 2017) (explaining no matter what the obviousness theory “there must be a
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`motivation to make the combination and a reasonable expectation that such a
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`combination would be successful.”); In re Peterson, 315 F.3d 1325, 1330 n.1 (Fed.
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`Cir. 2003) (“[Overlapping] ranges that are not especially broad invite routine
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`experimentation to discover optimum values, rather than require nonobvious
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`invention”); duPont, 904 F.3d at 1006 (“The legal principle at issue in this case is
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`old....it is not inventive to discover the optimum or workable ranges by routine
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`experimentation.”); Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc.,
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`655 F.3d 1291, 1306 (Fed. Cir. 2011) (“Simply put, the typical desire of scientists
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`to find an optimum value within a narrow disclosed range does not apply to the
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`facts in this case.”). 8
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`This distinction is important because “routine optimization” simply does not
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`apply here. In fact, Petitioner has never established that formulating nucleic acid-
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`lipid particles as claimed would have been a matter of routine optimization (or any
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`8 At institution, the Board suggested the Petition may be based on a theory of
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`routine optimization. Decision, 23. That is not so clear. Petitioner carefully avoids
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`assertions of routine experimentation and, as discussed below, actually embraces
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`the complexity of the technology when pivoting to experimental data supporting
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`the criticality of the claimed lipid ranges. But this exposes an internal contradiction
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`in Petitioner’s case and Petitioner cannot have it both ways. In re Applied
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`Materials, Inc., 692 F.3d 1289, 1298 (Fed. Cir. 2012) (Explaining that in the
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`context of overlapping ranges evidence that variables interact in an unpredictable
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`or unexpected way support nonobvious.).
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`other obviousness rationale).9 The obviousness challenges fail for at least that
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`reason alone. See, e.g., Stepan, 868 F.3d at 1346, 1346 n.1 (rejecting obviousness
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`in view of overlapping ranges because “[m]issing from the Board’s analysis is an
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`explanation as to why it would have been routine optimization to arrive at the
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`claimed invention.”).
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`Even if Petitioner’s obviousness challenges are deemed to include a sub
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`silentio rationale of routine optimization, such a theory has been addressed
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`directly, lacks any supporting evidence, and has been thoroughly rebutted. As
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`explained in detail below, the evidence is overwhelming — achieving the nucleic
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`acid-lipid particles of the ’435 patent was not a matter of routine optimization.
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`A.
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`Formulating Nucleic Acid-Lipid Particles Was Not a Matter of
`Routine Optimization
`At the time of invention, formulating nucleic acid-lipid particles was not a
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`matter of routine optimization. Dr. Thompson addressed this issue directly.
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`EX1020, 403: 22-25 (“Q. In the 2008 timeframe, was developing nucleic acid-lipid
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`particles considered a routine matter of optimizing variables? A. No.”); EX2009,
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`9 Dr. Janoff’s declaration includes only a single conclusory sentence regarding
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`determining an “optimal proportion” of cationic lipid, one component of the
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`formulation. EX1007, ¶110; see also 37 C.F.R. § 42.65(a).
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`¶58 (“The effects of making changes to the proportion of other components in the
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`lipid particle would be unpredictable...”), ¶60 (“Making safe and effective nucleic
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`acid-lipid particle formulations was not simply a matter of ‘varying the proportion’
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`of cationic lipid in prior art formulations …”); see also id., ¶¶57-59, 136; EX1019,
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`32:3, 31:22-23 (“Change solvent, change additives, change lots of different
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`variables”), 32:9, 41:4-6 (“plenty of places to go wrong”), 43:9-10, 178:17-18,
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`180:6; EX1020, 404:11-18 (“As I stated multiple times in my deposition, these are
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`multicomponent systems and varying one component at a time was not a viable
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`strategy.”).
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`Petitioner and its expert actually embrace the complexity of formulating
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`nucleic acid-lipid particles, repeatedly arguing unpredictability in adjusting lipid
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`proportions. Reply, 15-16; Pet. 8-9 (“The structure of lipoplexes is influenced by
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`multiple factors.... Transfection efficacy is complex because ‘[a] large number of
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`parameters are involved.”); EX1007 ¶¶65-68 (same), ¶73 (“[A] POSITA would
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`have had no way of knowing if lipid combination at any given proportion would
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`have resulted in formulations of superior therapeutic index to other
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`formulations.”). During deposition, Dr. Janoff repeatedly emphasized the
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`complexity of the field of art at the time. EX2028, 144:18-145:1 (“We’re in deep
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`waters, and what you think are simple questions belie — and I don’t mean to be
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`pejorative — belie an ignorance of the field that you’re questioning me in”), 57:19
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`(“it’s a very technical area”), 58:22-59:1 (“we’re in deep water here talking about
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`very technical issues), 61:9-11 (“You’re asking me a very, very, very technical
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`question...”), 63:5-11 (“we’re in technical deep waters”), 68:12 (“we’re in deep
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`technical territory here”); see also EX1021, ¶25 (discussing “the complicated
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`nature of what affects transfection efficiencies”). A highly technical and
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`unpredictable state of the art is the very antithesis of routine optimization.
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`Prior art cited in the Petition corroborates the expert testimony that forming
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`functioning lipid particles at the time was far from routine, but instead was a
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`function of multiple parameters whose interactions were poorly understood, with
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`limited guidance existing. See, e.g., EX1006, 740 (“...the lack of mechanistic
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`understanding of gene delivery by CL-DNA complexes is due to the large number
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`of parameters involved.”), (“[I]n comparative studies, typically only one or two
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`data points per lipid are evaluated, allowing the ideal lipid composition (the ratio
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`of neutral to cationic lipid) or cationic lipid/DNA ratio to be overlooked.”); see
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`also EX1021, ¶25; EX1008, E99 (“[It is] essential for us to identify the critical
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`parameters limiting gene delivery in the current systems.”).
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`The evidence also illustrates recognition in the industry that developing lipid
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`particle formulations for drug delivery was not a simple or routine matter of
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`optimizing variables. EX2011, 38 (“[P]hysical delivery of the drugs to diseased
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`cells is extremely challenging.”); EX2012, 7248 (“The intrinsic complexity of any
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`such gene delivery vehicle can be expected to present continued challenges ...”);
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`EX2014, 11 (“The major hurdle right now is delivery, delivery, delivery.”);
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`EX2016, 7 (“What’s interesting about what we do is that the drug isn’t the
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`problem. It’s the delivery of it.”); EX2015, 2; EX2011, 42; EX2016, 1; EX2023,
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`291-292 (“[Delivery] proved to be a substantially harder problem than we
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`anticipated...”), (“All of those tear-your-hair-out days were worth it to get to
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`today”).
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`Accordingly, “routine optimization” is not a viable rationale for arriving at
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`the claimed subject matter.
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`B.
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`Petitioner’s New Picking and Choosing Argument Should be
`Rejected
`The Reply (8-10) now argues that low PEG-lipid amounts were “known in
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`the art” and that “the amount of conjugated lipid (e.g., PEG) could be minimized.”
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`Reply, 9 (emphasis added). Such assertions have never been sufficient to support
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`obviousness. PersonalWeb Techs., LLC v. Apple, Inc., 848 F.3d 987 (Fed. Cir.
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`2017) (“reasoning...that [references] could be combined...is not enough: it does not
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`imply a motivation”) (emphasis in original).
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`Similarly, the Reply (9, 11) newly argues high cationic/low PEG was
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`“known” and then leaps to the conclusion that one would pick and choose from
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`various different formulations (from the ’189 patent and ’554 publication) to arrive
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`at the claim. As a threshold matter, this untimely new combination/theory was not
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`presented in the petition. Even if considered, the argument is factually incorrect
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`and entirely conclusory. None of the cited formulations are within the claimed
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`ranges—the “2:40” composition is well outside the claim, and the newly cited ’554
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`publication formulations (like L054) are merely a listing of starting ingredients
`
`(see discussion above) and are outside the claimed ranges. Furthermore, the Reply
`
`(11) cites to Dr. Janoff (EX1021, ¶22), which merely cites back to his previous
`
`erroneous and conclusory testimony. Cf. EX2009, ¶¶61-62; EX1020, 404:5-18;
`
`Section IV.A. While it is not Patent Owner’s burden to prove no motivation, one
`
`would more logically expect increased conjugated lipid (i.e., at or above the more
`
`typical 5-10%) to accompany a hypothetically increased cationic lipid. Response,
`
`14, 20; EX2009, ¶¶61-62. The Reply does not rebut this point.
`
`V. UNEXPECTED RESULTS FURTHER REBUT ANY PRIMA FACIE
`OBVIOUSNESS
`As explained above, to the extent any prima facie case of obviousness in
`
`view of overlapping ranges was ever established in the first place, it is rebutted by
`
`uncontroverted evidence that developing nucleic acid-lipid particles as claimed
`
`was not a matter of routine optimization of lipid variables. The Federal Circuit has
`
`explained in Peterson and elsewhere, one may also overcome a prima facie case of
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`obviousness “by showing that the claimed range achieves unexpected results.” 315
`
`F.3d 1325, 1330-1331. Any such prima facie case here is even further overcome
`
`- 18 -
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`
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`
`
`by the extensive experimental data in the ’435 patent and post-filing publications
`
`showing unexpected results.
`
`The Reply (15-16) argues that the test data is not commensurate with the
`
`scope of the claims because only a “small portion” of formulations were tested.
`
`But neither Petitioner nor Dr. Janoff specify what “portion” of formulations were
`
`believed to have been tested. Nor does the Reply provide any analysis as to why
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`this portion is too “small” to overcome the prima facie obviousness challenge of
`
`the Petition. In addition, the Reply (16-19) only addresses a subset of the test data
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`disclosed in the ʼ435 patent, largely ignoring the post-filing data provided and
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`discussed in the Response (59-61). See EX2046; EX2055, 44:19-45:9 (Dr. Janoff
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`referring to only the data in the ʼ435 patent), 70:18-73:4, 75:25-77:7 (admitting he
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`did not consider Petitioner’s own publications reporting testing of claimed
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`formulations).
`
`Lacking any meaningful analysis, the Reply fails to acknowledge that the
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`present case is nothing like previous instances where testing was rejected as not
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`commensurate. See, e.g., Peterson, 315 F.3d at 1331 (unexpected results not
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`commensurate where only two data points were tested, and only one data point
`
`produced unexpected results); duPont, 904 F.3d at 996 (only a single data point
`
`was tested); In re Greenfield, 571 F.2d 1185, 1189 (Fed. Cir. 1978) (testing only
`
`one species in a large genus).
`
`- 19 -
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`
`
`
`
`Here, the ’435 patent presents testing on dozens of different formulations
`
`falling within the scope of claim 1. Publications following the ’435 patent
`
`(including Petitioner’s own publications) tested dozens more formulations within
`
`the scope of claim 1, finding those formulations efficacious and well-tolerated.
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`Genetics Inst., 655 F.3d at 1307 (“[W]e have held that evidence of unexpected
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`results may be used to rebut a case of prima facie obviousness even if that
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`evidence was obtained after the patent’s filing or issue date….”).
`
`As addressed in more detail below, the extensive scope of the experimental
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`testing conducted—and essentially ignored in the Reply—included many different
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`formulations, with many different combinations of different lipid components,
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`gene targets, nucleic acid payloads and methods of production. See EX2046
`
`(summary of exemplary formulations tested and within the scope of the ’435 patent
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`claims). Such testing is more than sufficient to rebut any prima facie case of
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`obviousness.
`
`A. The ’435 Patent Reports Extensive Testing of Numerous
`Formulations Within the Claimed Range
`The ’435 patent specification provides experimental data for numerous
`
`formulations within the scope of claim 1 supporting the unexpected degree of
`
`tolerability and efficacy of the claimed compositions. The Reply and Dr. Janoff’s
`
`opinions appear to be based on a misconception of the testing actually presented in
`
`the ’435 patent. EX2055, 39:16-40:5, 66:8-67:3.
`
`- 20 -
`
`
`
`
`
`For instance, Example 3 in the ’435 patent specification report that each of
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`the tested formulations falling within the scope of claim 1 (Groups 11, 13, 14)
`
`demonstrated potent silencing activity in vivo. The 1:57 formulations were
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`substantially more effective at silencing the expression of a target gene as
`
`compared to all other nucleic acid-lipid particle formulations tested. E.g., EX1001,
`
`72:20-23, Table 4.
`
`Example 4 demonstrates that 1:57 formulations were 10 times more
`
`efficacious as compared to a nucleic acid-lipid particle formulation previously
`
`described (“2:30 SNALP”) in mediating target
`
`gene silencing in vivo at a 10-fold lower dose.
`
`E.g., id., 73:64-67, Figure 3 (annotated shown -
`
`left); see also EX1016, 39.
`
`Example 5 describes testing of seven additional formulations within the
`
`scope of claim 1. EX1001, 74:1-53, Table 6 (Groups 2-8), Figure 4. Those
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`formulations included combinations of different conjugated lipids (PEG2000 and
`
`PEG5000), cationic lipids (DLinDMA and DODMA), phospholipids (DPPC and
`
`DPPE), and cholesterol/derivative (cholesterol and cholestanol). As disclosed in
`
`Example 5 and illustrated in Fig. 4, each of those formulations demonstrated potent
`
`silencing activity in vivo.
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`- 21 -
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`
`
`
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`Example 6 describes testing of fourteen additional formulations within the
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`scope of claim 1. EX1001, 74:60-75:49, Table 2 (Groups 2-15), Figure 5. Each of
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`the tested formulations demonstrated potent silencing activity in vivo.
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`Examples 7 and 8 describe testing of tolerability and efficacy using “1:57”
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`SNALPs prepared by various different manufacturing processes. Id., 75:41-80:45.
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`The tested SNALPs were well-tolerated and efficac
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