`
`Paper No. ___
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`Filed: November 13, 2019
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`ARBUTUS BIOPHARMA CORPORATION,
`Patent Owner.
`
`_____________________________
`
`Case IPR2019-00554
`Patent No. 8,058,069
`_____________________________
`
`
`PATENT OWNER’S RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
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`
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`

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`
`TABLE OF CONTENTS
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`Page
`Introduction ...................................................................................................... 1 
`I. 
`Overview of the ʼ069 Patent and the Prior Art ................................................ 7 
`II. 
`Procedural History ........................................................................................... 8 
`III. 
`IV.  Claim Construction—Nucleic Acid-Lipid Particle ......................................... 9 
`V.  Obviousness in view of Overlapping Ranges Fails (Grounds 1 & 3) ........... 11 
`A.  No Affirmative Teaching of an Overlapping Phospholipid
`Range Defeats Petitioner’s Obviousness Theory Based on
`Overlapping Ranges ............................................................................ 12 
`i. 
`Ground 1 – The ’196 PCT and the ’189 Publication do
`not disclose the recited phospholipid concentration range. ...... 14 
`Ground 3 – The ’554 Publication also does not disclose
`or suggest the recited phospholipid concentration range. ......... 16 
`Formulating Nucleic Acid-Lipid Particles Was Not a Matter of
`Routine Optimization .......................................................................... 19 
`The Broad Ranges of the Prior Art do not Support Routine
`Optimization ........................................................................................ 25 
`Petitioner Does not Explain Selecting the Claimed Composition
`from the Prior Art Ranges ................................................................... 27 
`i. 
`Claim as a Whole/Interaction of Components .......................... 28 
`ii. 
`Cationic Lipids Were Known to be Toxic ................................ 29 
`VI.  Unexpected Results Further Rebut any Prima Facie Obviousness .............. 31 
`A. 
`The ʼ069 Patent Reports Extensive Testing of Numerous
`Formulations within the Claimed Range ............................................. 33 
`Post-Filing Publications Provide Testing Data for a Broad
`Range of Lipids and Cargo Molecules ................................................ 37 
`
`ii. 
`
`B. 
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`C. 
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`D. 
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`B. 
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`-i-
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`C. 
`
`B. 
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`C. 
`
`D. 
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`Petitioner Fails to Present Any Meaningful Critique to Patent
`Owner’s Evidence Supporting Patentability ....................................... 42 
`VII.  Additional Objective Indicia of Non-Obviousness Further Rebut any
`Prima Facie Obviousness ............................................................................... 44 
`A. 
`Long-Felt Need – the delivery problem was not solved for over
`20 years ................................................................................................ 45 
`Failure of Others – those in the art failed to formulate nucleic
`acid-lipid particles suitable for systemic delivery ............................... 47 
`Skepticism – those in the art questioned the safety of the
`SNALP as a suitable delivery platform ............................................... 48 
`Commercial Success – the claimed nucleic acid-lipid particle is
`the first FDA approved siRNA drug ................................................... 49 
`VIII.  Anticipation in View of Overlapping Ranges Fails (Grounds 1 and 3) ........ 50 
`A.  No Affirmative Teaching of a Phospholipid Range Defeats
`Petitioner’s Anticipation Theory ......................................................... 50 
`Ranges in the Art are Not Sufficiently Specific to Anticipate the
`Claimed Ranges ................................................................................... 51 
`a. 
`Ground I—Neither the ’196 PCT nor the ’189
`Publication Anticipate the Remaining Claimed Ranges ........... 52 
`Ground 3—The ’554 Publication is Not Anticipatory ............. 54 
`b. 
`IX.  Ground 2 Fails ............................................................................................... 55 
`A. 
`Lin and Ahmad Do Not Supply the Missing Motivation for
`Ground 2 .............................................................................................. 57 
`Petitioner Ignores Content of Lin and Ahmad that Undermines
`its Obviousness Assertions .................................................................. 59 
`The Dependent Claims are Neither Obvious Nor Anticipated ...................... 60 
`A. 
`Claim 8 ................................................................................................ 60 
`B. 
`Claim 14 .............................................................................................. 61 
`
`B. 
`
`B. 
`
`X. 
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`-ii-
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`C. 
`Claim 15 .............................................................................................. 61 
`Claim 16 .............................................................................................. 62 
`D. 
`Claim 17 .............................................................................................. 62 
`E. 
`Claim 18 .............................................................................................. 63 
`F. 
`Claim 20 .............................................................................................. 63 
`G. 
`Claim 21 .............................................................................................. 64 
`H. 
`Claim 22 .............................................................................................. 64 
`I. 
`XI.  Conclusion ..................................................................................................... 65 
`XII.  Certificate of Compliance .............................................................................. 66 
`XIII.  Appendix – List of Exhibits ........................................................................... 67 
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`-iii-
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`I.
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`INTRODUCTION
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`The nucleic acid-lipid particles claimed by the ’069 patent have achieved
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`tremendous recognition in the field of genetic therapy. The ’069 patent is now
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`listed in FDA’s Orange Book as protecting the patisiran—tradename “Onpattro”—
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`commercial product. EX2025. Patisiran received regulatory approval in the U.S.
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`and Europe and has been designated by the FDA as a “first-in-class” drug.
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`EX2024. The therapeutic potential of genetic therapy has been appreciated for
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`over 25 years, but effectively delivering nucleic acids to target cells without
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`eliciting vehicle-related toxicity prevented realization of this potential. E.g.,
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`EX2016, 38, 42; EX2018, 11. By 2008, the industry-wide failure to identify a
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`solution to the delivery problem resulted in waning confidence. EX2019, 2, 10;
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`EX2018, 11; EX2023, 291-292.
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`The nucleic acid-lipid particle formulations of the ’069 patent met a long-felt
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`need for compositions that could safely and effectively deliver nucleic acids to
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`patient target cells. The combination of effectiveness and low toxicity that
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`characterizes the claimed compositions surprised many in the field, and finally
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`solved the delivery problem that hindered the field for decades.
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`The petition is a poorly conceived challenge, relying on erroneous legal
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`analysis in each of the under-developed obviousness (Grounds 1-3) and
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`anticipation (Ground 1 and 3) challenges.
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`-1-
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`Petitioner’s obviousness challenges are based solely on the theory that
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`alleged overlapping ranges create a presumption or prima facie case of
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`obviousness under the legal framework in In re Peterson, 315 F.3d 1325 (Fed. Cir.
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`2003) and E.I. duPont de Nemours & Co. v. Synvina C.V. 904 F.3d 996 (Fed. Cir.
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`2018). E.g., Pet. 31-32, 33, 39, 40, 49, 54, 56, 58, 59; Paper 8, Decision on
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`Institution (“DI”), 25-27, 36-37. Petitioner’s theory fails for numerous reasons.
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`First, Petitioner has failed to set forth evidence of prior art ranges that
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`overlap with the claimed ranges, and therefore, the prior art and lack of evidence
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`on which it relies cannot be the basis for establishing a prima facie case of
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`obviousness. Peterson and duPont are inapposite here where the proposition is
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`that “[a] prima facie case of obviousness typically exists when the ranges of a
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`claimed composition overlap with ranges disclosed in the prior art.” Peterson,
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`315 F.3d at 1329 (emphasis added). Neither case dictates nor even loosely implies
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`the existence of such presumption when the prior art fails to actually disclose any
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`ranges overlapping with those claimed. For example, the prior art presented by
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`Petitioner fails to disclose any concentration range for a phospholipid
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`component—much less one that overlaps with the claimed invention. As such,
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`Petitioner has failed to provide any evidence supporting its arguments of prima
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`facie obviousness under the framework of Peterson and duPont. To hold
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`Petitioner’s lack of evidence sufficient to show a prima facie case of obviousness
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`-2-
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`
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`would require a series of unwarranted and unsupported assumptions—a marked
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`departure from the framework of these cases. This is particularly pertinent here as
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`Petitioner’s arguments rest solely on its putative “prima facie” case, as though that
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`alone meets its ultimate burden of proof. This reliance underscores the
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`deficiencies in the Petition, including not only its failure to address the claimed
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`subject matter as a whole (i.e., the claimed particle formulation), as mandated by
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`statute, but also the lack of any meaningful discussion of motivation to combine or
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`reasonable expectation of success.
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`Second, regardless of whether the framework of duPont and Peterson even
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`applies as a threshold matter, Petitioner’s obviousness challenges still lack
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`motivation to combine with reasonable expectation of success. As the Federal
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`Circuit has explained, every obviousness challenge requires motivation to combine
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`with an expectation of success. In re Stepan Co., 868 F.3d 1342, 1346 n.1 (Fed.
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`Cir. 2017). The Federal Circuit has explained that even if prima facie obviousness
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`is established, it is overcome with a showing that routine optimization does not
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`apply. duPont, 904 F.3d at 1006 (“disclosure of very broad ranges may not invite
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`routine optimization”)(citing Genetics Inst., LLC v. Novartis Vaccines &
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`Diagnostics, Inc., 655 F.3d 1291, 1306 (Fed. Cir. 2011). The framework of
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`duPont and Peterson is no exception and is predicated specifically on a routine
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`optimization rationale.
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`-3-
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`Here, routine optimization is not applicable—rebutting any argument of
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`prima facie obviousness. This issue was previously litigated in Moderna, Inc. et
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`al. v. Arbutus Biopharma Corp., IPR2018-00739 (“the ’739 IPR”) in the context of
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`the same person of ordinary skill in the art (“POSITA”), at the same relevant time,
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`viewing the same specification as the challenged ’069 patent. E.g., POPR, 23-29;
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`EX2033, 36:5-13. Here, like in the ’739 IPR, Petitioner and its expert expressly
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`embrace the complexity of the technology, emphasize unpredictability, and
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`disavow the notion that arriving at the claimed subject matter would have been a
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`matter of simple optimization. E.g., EX2033, 42:7-10 (“If the range is immense,
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`there would be undue experimentation, I believe, to find a combination or a range
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`that behaved in a desirable light.”), 60:5-16 (ranges narrower than those in the
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`cited art are “immense” and “would require undue experimentation, not simple
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`optimization.”), 19:25-20:15. Accordingly, routine optimization (and by
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`extension, the framework of Peterson and duPont) is not a viable rationale in view
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`of the broad ranges cited in the art, as well as expert testimony and extensive
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`literature indicating that developing nucleic acid lipid at the time simply was not
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`considered a routine matter of optimizing variables.
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`Third, even if Petitioner is credited with some showing of obviousness,
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`unexpected results overcome any such presumption. Extensive experimental
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`testing demonstrates the claimed nucleic acid-lipid particles are surprisingly non-
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`-4-
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`toxic, non-immunogenic, and more potent and efficacious than prior art
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`compositions. These unexpected results are different in kind and are supported by
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`data from both the ’069 patent and post-filing publications that test many different
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`formulations, with many different combinations of lipid components, gene targets,
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`nucleic acid payloads, and methods of production. The petition materials provide
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`no meaningful analysis of the full scope of experimental data presented in the ’069
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`patent and ignore the post-filing publications entirely.
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`Fourth, additional objective indicia further rebut any case of obviousness.
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`Indeed, the uncontested record demonstrates a long-felt need, failure of others,
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`skepticism in the industry, and commercial success—each of which supports the
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`non-obviousness of the claimed invention.
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`In Ground 2, Petitioner relies on Lin and Ahmad for the conjured notion that
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`it would be obvious “to increase the cationic lipid to the 50%-65% range in order
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`to potentially increase the transfection.” Pet. 50. Lin and Ahmad are irrelevant for
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`Petitioner’s purposes. Lin and Ahmad are directed to lipoplexes—a fundamentally
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`different class of particles that are expressly differentiated by the ’069 patent from
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`the claimed “nucleic acid-lipid particle.” EX1001, 2:12-18, 3:3-10. Even
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`Petitioner’s own expert testified that lipoplexes are outside the scope of the
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`challenged claims. EX2001, 122:1-24. Further, Petitioner never once articulates a
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`motivation as to why a POSITA would increase the concentration of cationic
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`-5-
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`lipids. All Petitioner offers is a series of assertions that such modification “could”
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`increase transfection efficiency. See Pet. 49 (“may increase...”), 50 (“...potentially
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`increase...”), (“...could impact...”). Such assertions have never been sufficient to
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`demonstrate obviousness. Notwithstanding Petitioner’s misrepresentation of Lin
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`and Ahmad, Ground 2 inherits all the defects of Ground 1 and thus also fails for
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`those same reasons.
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`Finally, Petitioner’s half-baked anticipation challenges are dead on arrival.
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`The anticipation theory relies on the conclusory assertion that the prior art
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`“disclosures are sufficiently specific to anticipate the claimed range.” Pet. 33.
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`Missing from Petitioner’s analysis is any explanation as to how prior art
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`disclosures can be “sufficiently specific” to anticipate the claimed phospholipid
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`range, when, in fact, the prior art does not disclose any phospholipid range.1 As to
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`the other lipid components, the cited ranges at best partially overlap with the
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`claimed range. Missing again is any explanation as to how the disclosures are
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`“sufficiently specific” to establish anticipation.
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`1 Even the Board’s Institution Decision acknowledges that the cited references
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`lack express disclosure of a phospholipid range and require a series of
`
`assumptions. DI, 23-25, 36-37
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`-6-
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`For these reasons, and those explained in further detail herein, Petitioner
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`fails to meet its burden of demonstrating the unpatentability of the claims, and each
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`Ground under the Petition should be rejected.
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`II. OVERVIEW OF THE ʼ069 PATENT AND THE PRIOR ART
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`The ’069 patent is directed to the surprising discovery that nucleic acid-lipid
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`particle formulations with high levels of cationic lipids and low levels of
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`conjugated lipids exhibit favorable in vivo transfection efficiencies as well as
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`“improved tolerability of the formulations in vivo, resulting in a significant
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`increase in the therapeutic index [a measure of dosage relative to toxic effect] as
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`compared to nucleic acid-lipid particle compositions previously described.”
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`EX1001, 5:55-58; id., 5:58-6:3; 11:26-32 (defining the inventive formulations as
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`“extremely useful for systemic applications”); see also EX2031, ¶¶25-28. The
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`’069 patent claims nucleic acid-lipid particle formulations with high levels of
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`cationic lipids (50–65 mol%) and low levels of conjugated lipids (0.5–2 mol%)—
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`as well as specific levels of cholesterol/derivative (30-40 mol%) and phospholipid
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`(4-10 mol%).
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`Prior art taught against the invention claimed by the ’069 patent. Largely
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`ignored by the petition, prior art at the time of invention (including all references
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`cited by Petitioner) instructed that formulations with a high level of cationic lipid
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`were toxic and poorly tolerated in vivo and had little to no in vivo transfection
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`-7-
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`efficiency. E.g., EX1003, ¶6; EX1006, 3315; EX2009, 30:34-41; EX2031, ¶¶80-
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`88. Moreover, the prior art instructs that the level of cationic lipid should be
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`minimized, as high levels were deemed unsuitable for in vivo transfection.
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`EX1007, 745. Additionally, where conjugated lipids were utilized, the art
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`instructed much higher levels as compared to those claimed. EX1009, 5; EX2031,
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`¶¶77-78.
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`Yet, contrary to these teachings, the claimed formulations uniformly
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`withstood rigorous in vivo tests that established stability following systemic (in
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`vivo) administration, suitability for mammals with no considerable toxicity, and
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`transfection efficiencies superior to conventional formulations. E.g., EX2031,
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`¶¶89-112.
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`III. PROCEDURAL HISTORY
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`Petitioner challenges the ’069 patent in the instant proceeding and has
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`previously challenged another patent from this patent family, U.S. Patent No.
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`9,364,435 (“the ’435 patent”), a continuation of the ’069 patent, in the ’739 IPR.
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`The independent claim in the ’069 patent contains a similar limitation to a range of
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`phospholipids as claim 7 of the ’435 patent, and, is in fact, narrower. The Board
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`issued a Final Written Decision in the ’739 IPR (’739 IPR, Paper 51, “FWD”) on
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`September 11, 2019, after institution of the instant proceeding, in which it was
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`determined that claim 7 was patentable. FWD, 51.
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`-8-
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`IV. CLAIM CONSTRUCTION—NUCLEIC ACID-LIPID PARTICLE
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`No claim construction is necessary in order to determine that the Petition
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`fails. Vivid Techs., Inc. v. American Science & Eng’g, Inc., 200 F.3d 795, 803
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`(Fed. Cir. 1999)(“only those terms need be construed that are in controversy, and
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`only to the extent necessary to resolve the controversy.”). That being said,
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`Petitioner’s proffered construction of “nucleic acid-lipid particle” is incorrect.
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`Claim terms are not construed in the abstract but are construed as to how
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`they would be understood by a POSITA when read in light of the specification and
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`the prosecution history. Fenner Investments, Ltd. V. Cellco Partnership, 778 F.3d
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`1320, 1323 (Fed. Cir. 2015). As such, the term “nucleic acid-lipid particle” should
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`be construed as necessarily including a nucleic acid encapsulated in the lipid
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`portion of the particle, thereby protecting it from enzymatic degradation. This is
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`consistent with the disclosure of the specification, wherein “nucleic acids, when
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`present in the lipid particles of the present invention, are resistant in aqueous
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`solution to degradation with a nuclease.” EX1001, 11:42-55; see also id., 11:10-12;
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`EX2009, 4:15-19; EX2031, ¶¶32-33.
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`Moreover, during prosecution of the underlying application of the ’069
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`patent, applicants specifically touted encapsulation of the nucleic acid. EX1016,
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`38; EX2031, ¶34. Encapsulation was also argued extensively in the ’739 IPR.
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`Thus, prosecution history reinforces the teaching of the specification that the
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`-9-
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`
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`claimed nucleic acid-lipid particles necessarily require encapsulation of the nucleic
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`acid. Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015);
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`Aylus Networks, Inc. v. Apple Inc., 856 F.3d 1353, 1361 (Fed. Cir. 2017).
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`Petitioner does not offer its own claim construction analysis, but merely
`
`adopts the Board’s preliminary interpretation, notably determined under a different
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`claim construction standard, from the institution decision in the ʼ739 IPR. That
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`construction, however, is unduly broad as it relies on an incomplete reading of the
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`specification and would encompass an empty lipid particle. The portion of the
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`specification relied upon by the Board in its construction of “nucleic acid-lipid
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`particle” is directed at the term “lipid particle,” and not “nucleic acid-lipid particle”
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`as required by the claims. ’739 IPR, Paper 15, 10-11. That is, as disclosed in the
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`’069 specification, a “lipid particle” “may [include a nucleic acid] encapsulated in
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`the lipid portion of the particle, thereby protecting it from enzymatic degradation.”
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`EX1001, 11:4–12. A “nucleic acid-lipid particle,” however, does include a nucleic
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`acid encapsulated in the lipid portion of the particle, thereby protecting it from
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`enzymatic degradation.2 EX1001, 11:22-32, 11:51-55; EX2031, ¶¶35-37.
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`2 During his deposition in the ’739 IPR, Dr. Janoff repeatedly testified that the
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`claimed particle should be defined as a SNALP. EX2001, 118:19-119:4, 119:9-17,
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`120:5-6, 121:14-25. Petitioner has never explained the contradiction between its
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`-10-
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`V. OBVIOUSNESS IN VIEW OF OVERLAPPING RANGES FAILS (GROUNDS 1 & 3)
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`Petitioner’s obviousness challenge rises and falls on its mere alleged
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`presumption of obviousness based only on the theory of overlapping ranges. E.g.,
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`Pet., 31-32, 54; DI, 25-26, 37 (citing Peterson and duPont). This obviousness
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`theory is both legally and factually wrong.
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`The Federal Circuit has explained that overlapping ranges, without evidence
`
`to the contrary, may invoke a presumption of obviousness when “routine
`
`optimization” is applicable. Routine optimization, however, is not applicable when
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`broad ranges need to be assessed. Peterson, 315 F.3d at 1330 n.1 (“[Overlapping]
`
`ranges that are not especially broad invite routine experimentation to discover
`
`optimum values, rather than require nonobvious invention”) (emphasis added);
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`duPont, 904 F.3d at 1006. The legal paradigms of “overlapping ranges” and
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`“routine experimentation” do not apply here. Genetics, 655 F.3d at 1306 (“Simply
`
`put, the typical desire of scientists to find an optimum value within a narrow
`
`disclosed range … does not apply to the facts in this case.”).
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`First, there can be no presumption of obviousness in view of overlapping
`
`ranges when the cited art simply does not disclose an overlapping range for a
`
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`expert’s testimony in the ’739 IPR and its conclusory statement that the Board’s
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`construction in the ’739 IPR “is appropriate.” EX2003, ¶13.
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`-11-
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`
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`claimed component. Neither Peterson nor duPont supports a presumption of
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`obviousness based on the hindsight-driven and selective picking and choosing of
`
`disclosures to contrive a range, as Petitioner attempts to do.
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`Second, “routine optimization” is not a viable rationale for arriving at the
`
`claimed subject matter. The testimony of both experts, contemporaneous
`
`literature, and industry recognition all illustrate that developing lipid particle
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`formulations for drug delivery was far from a simple or routine matter of
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`optimizing variables.
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`Furthermore, regardless of the obviousness theory, the petition fails to
`
`establish any motivation to combine and a reasonable expectation of success in
`
`doing so. It is clear that these requirements to prove a case of obviousness have
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`not been met.
`
`A. No Affirmative Teaching of an Overlapping Phospholipid Range
`Defeats Petitioner’s Obviousness Theory Based on Overlapping
`Ranges
`
`Under the relevant caselaw, a presumption of obviousness may apply when
`
`the prior art actually discloses overlapping ranges that are not especially broad.
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`Peterson, 315 F.3d at 1329-30. When, as here, the prior art fails to disclose any
`
`range for a claimed component (let alone ranges that overlap), there can be no
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`presumption of obviousness.
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`-12-
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`The petition cites to Peterson and duPont, though neither case supports a
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`presumption of obviousness when ranges are not disclosed but are instead
`
`contrived. In both those cases, the court found a prima facie case of obviousness
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`based on very close prior art expressly disclosing component ranges that
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`overlapped with ranges claimed. Peterson, 315 F.3d at 1329-32; duPont, 904 F.3d
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`at 1011-13. In neither instance did the court find a presumption of obviousness by
`
`making a series of assumptions or inferences to arrive at a range not affirmatively
`
`disclosed. Peterson, 315 F.3d at 1329-32; duPont, 904 F.3d at 1011-13.
`
`In contrast to Peterson and duPont, independent claim 1 of the ’069 patent
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`recites four components at different concentrations, including a range for
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`phospholipid “from 4 mol % to 10 mol % of the total lipid.” Petitioner claims the
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`cited prior art references explicitly disclose a 0-19% or a 0-19.5% phospholipid
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`range, but it is indisputable that none of these references disclose any such range,
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`nor any range for phospholipids specifically. E.g., EX1008, ¶118 (citing EX1003,
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`¶¶89, 91; EX1004, ¶¶152, 159) compare with FWD, 31-32, 35-37. The Board in
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`its Institution Decision did not dispute that the cited refences lacked affirmative
`
`disclosure of a phospholipid range, but instead instituted on the basis that a
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`phospholipid range could be contrived through “reasonable inferences.” DI, 23, 36;
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`EX2031, ¶¶38-39.
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`-13-
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`Petitioner cites no authority that the presumption of obviousness under
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`Peterson and duPont would allow a “reasonable inference” to be satisfied by
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`selective, hindsight-driven picking and choosing, and especially not when dealing
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`with the broad ranges at issue. Peterson, 315 F.3d at 1330 n.1; duPont, F.3d at
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`1011 n.15 (in distinguishing Genetics, noting that the “case [in duPont] presents
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`‘not especially broad’ ranges of temperature and pressure.”). Put simply,
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`Petitioner attempts to shoehorn the present facts into a legal framework that simply
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`does not apply and Petitioner has not shown the claims are obvious.
`
`i. Ground 1 – The ’196 PCT and the ’189 Publication do not
`disclose the recited phospholipid concentration range.
`
`Neither the ’196 PCT nor the ’189 publication provide affirmative disclosure
`
`of any phospholipid range, let alone a phospholipid range that overlaps with the
`
`claimed range. See FWD, 31-32, 35-37. Petitioner relies on the disclosure of a
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`range for non-cationic lipid from 20% to about 85% of the total lipid present in the
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`particle. EX1008, ¶118 (citing EX1003, ¶¶89, 91; EX1004, ¶¶152, 159). The ’196
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`PCT disclosure is not limited to phospholipids; rather, phospholipids are merely an
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`example of a noncationic lipid component. EX2031, ¶¶40-41.
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`Similarly, ’189 publication states that the non-cationic lipid “typically
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`comprises from about 5 mol % to about 90 mol %, from about 10 mol % to about
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`85 mol %, from about 20 mol % to about 80 mol %, from about 30 mol% to about
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`70 mol %, from about 40 mol % to about 60 mol % or about 48 mol% of the total
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`-14-
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`lipid present in the particle,” also failing to expressly teach a phospholipid range,
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`or a range close to the claimed 4-10% range. EX1004, ¶152; EX2031, ¶42.
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`Petitioner’s reliance on the ’618 patent does not cure the above deficiencies.
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`It is also irrelevant in term of Petitioner’s overlapping ranges theory for
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`obviousness. The ’618 patent discloses a nucleic acid lipid complex with 56%
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`cationic lipid, 14% phospholipid, and 30% cholesterol. Pet. 38 (citing EX1017,
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`34:54-35:23). The disclosure of 14% phospholipid does not result in any
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`“reasonable inference” of a phospholipid range of 4-10%—it is indisputably
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`outside of the claimed range and there is no teaching to lower the percent
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`phospholipid in this formulation. EX2031, ¶43. Furthermore, claim 1 of the ’069
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`has a clear limitation including a conjugated lipid that would make up 0.5-2 mol%
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`of the formulation, not similarly present in the ’618 patent. To believe Petitioner’s
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`theory in light of these apparent holes would require impermissible hindsight. In re
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`Arkley, 455 F.2d 586, 587-88 (C.C.P.A. 1972); In re Ruschig, 379 F.2d 990, 995
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`(C.C.P.A. 1967)) (“Working backward from [the invention], that is by hindsight, it
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`is all very clear what route one would travel through the forest of the specification
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`to arrive at it.”); Orexo AB v. Actavis Elizabeth LLC, 903 F.3d 1265, 1271 (Fed.
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`Cir. 2018) (“It is inappropriate to use the template provided by the inventor, to
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`render the inventor’s contribution obvious.”)
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`-15-
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`Petitioner’s assumptions further illustrate impermissible hindsight.
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`Petitioner sets the amount of cationic lipid at 60%, with the only provided reason
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`being that it is at the high end of the disclosed range. Pet 39. Notably, Dr. Janoff
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`does not provide a reason for its selection. This unexplained, unsupported
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`assumption inappropriately serves as the linchpin for the remainder of Petitioner’s
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`analysis. EX2031, ¶¶44-50.
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`Accordingly, as the ’196 PCT and ’189 publication fail to disclose any range
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`for phospholipid, much less an overlapping range, Ground 1 necessarily fails.
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`ii. Ground 3 – The ’554 Publication also does not disclose or
`suggest the recited phospholipid concentration range.
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`As with Ground 1, the petition (Pet. 58) alleges “explicit disclosure of
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`encompassing ranges” for the phospholipid concentration range recited in the
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`challenged claims. The ’554 publication, however, does not discuss concentration
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`ranges for phospholipids. See Pet. 57-58 (failing to identify any teaching in the
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`asserted prior art regarding phospholipid concentrations); see also FWD, 35-37.
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`As already discussed, there can be no presumption of obviousness under Peterson
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`and duPont when there is no overlapping range in the cited reference, such as here,
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`where a range is contrived through a series of assumptions. Certainly, there is no
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`presumption of obviousness when those assumptions are illogical, unsupported by
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`the references, and clearly driven by improper hindsight.
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`Petitioner relies on the disclosure of a range for non-cationic lipid from
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`about 20% to about 85% of the total lipid present in the particle. Pet. 57. Like the
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`’196 PCT and the ’189 publication, the disclosure of the ’554 publication is not
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`limited to phospholipids; rather, phospholipids are merely an example of a
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`noncationic lipid component that may be used. Specifically, the non-cationic lipid
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`may be a neutral uncharged, zwitterionic, or anionic lipids that are capable of
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`producing a stable complex. EX1008, ¶157 (citing EX1005, ¶¶313, 315, 455). In
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`addition, the disclosed non-cationic lipid ranges are not close to the claimed 4-10%
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`range. EX2031, ¶¶51-52.
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`Petitioner’s reliance on the L106 formulation of Table 4 as including
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`cholesterol at 30% does not cure the above deficiencies. Pet. 57. The L106
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`formulation contains 67% DMOBA (cationic lipid), 30% cholesterol, and 3%
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`2KPEG-Cholesterol, but does not contain any phospholipid. EX1005, Table 4.
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`Petitioner does not explain why a POSITA would look to the L106 formulation in
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`formulating particles containing a phospholipid. In addition, both cationic and
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`conjugated lipid amounts are outside the claimed ranges, and Petitioner does not
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`explain the relevance of such a formulation to the claimed particles. EX2031, ¶53.
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`The Board in its Institution Decision also cites to L054, which “includes the
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`cationic lipid DMOBA, cholesterol, the phospholipid DSPC, and the [] PEG-n-
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`DMG in a molar ratio of 50/20/28/2.” DI, 36 (citing EX1005, Table 4). Again, a
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`-17-
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`POSITA would not understand a single formulation as defining a range for the
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`lipid components making up that formulation. Neither the Board or Dr. Janoff
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`explain how a single formulation having 28% phospholipid suggests a
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`phospholipid range of 0-20%. Moreover, the percentage of phospholipid is 28%,
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`well above the claimed range of 4-10%. EX2031, ¶54.
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`
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`Similar to Ground 1, Petitioner attempts to contrive a range for the
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`phospholipid from the ’554 publication, however its analysis is based on
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`unwarranted and unreasonable assumptions. Petitioner sets the amount of cationi