Paper No. ___
`Filed: June 14, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_____________________________
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`MODERNA THERAPEUTICS, INC.,
`Petitioner,
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`v.
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`PROTIVA BIOTHERAPEUTICS, INC.,
`Patent Owner.
`_____________________________
`
`Case IPR2018-00739
`Patent No. 9,364,435
`_____________________________
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`
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`PATENT OWNER’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
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`TABLE OF CONTENTS
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`III.THE ENTIRE PETITION IS BASED ON A FLAWED LEGAL
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`VI.THE PETITION FAILS TO IDENTIFY THE GROUNDS OF
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`I.INTRODUCTION ................................................................................................ 1
`II.OVERVIEW OF THE ’435 PATENT AND THE PRIOR ART .......................... 6
`THEORY .................................................................................................... 13
`IV.CLAIM CONSTRUCTION ............................................................................. 15
`V.LEVEL OF ORDINARY SKILL IN THE ART ................................................ 18
`CHALLENGE WITH PARTICULARITY ................................................. 19
`VII.GROUND 1 FAILS ........................................................................................ 22
`A.
`The petition fails to address the claimed invention as a whole .......... 22
`B.
`Petitioner’s reliance on Peterson is misplaced .................................. 25
`C. Motivation to combine and reasonable expectation of success
`are nonexistent .................................................................................. 27
`D.
`patent ................................................................................................ 29
`VIII.GROUND 2 FAILS....................................................................................... 33
`A.
`Ahmad .............................................................................................. 34
`B.
`nonsensical ....................................................................................... 35
`IX.GROUND 3 FAILS ......................................................................................... 37
`A.
`anticipation by the ’554 publication .................................................. 39
`Petitioner relies on the inapposite legal framework of Peterson ........ 43
`B.
`C.
`’554 publication or a reasonable expectation of success .................... 44
`X.CONCLUSION ................................................................................................. 45
`XI.APPENDIX ..................................................................................................... 47
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`Petitioner mischaracterizes the unexpected results of the ’435
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`Petitioner fails to assess the full scope and content of Lin and
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`The asserted motivation to combine is conclusory and
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`The petition materials lack any cogent analysis supporting
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`Petitioner provides no discussion of a motivation to modify the
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`-i-
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`I.
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`INTRODUCTION
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`The Board should not institute inter partes review of claims 1-20 of U.S.
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`Patent No. 9,364,435 (“the ’435 patent”) because Moderna Therapeutics, Inc.
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`(“Petitioner”) fails to show that it has a reasonable likelihood of prevailing.
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`The ’435 patent protects an important technological advance in the emerging
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`field of gene delivery systems. It covers novel nucleic-acid lipid particle
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`formulation that can be used, for instance, to treat cancer, liver disease, and viral
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`infections, as set forth in the challenged claims.
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`Before the ’435 patent, the trend was to use particles with “low levels of
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`cationic lipid.” EX1001, 2:52-56. That prevailing wisdom was understandable.
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`Cationic liposome complexes were understood to “elicit considerable toxic side
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`effects.” Id. High levels of cationic lipid were also known to result in in vivo
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`aggregation, immunogenicity, and rapid clearance of these particles from
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`circulation. The prior art that Petitioner cites only confirms the community’s
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`aversion to the toxicity and poor in vivo efficacy associated with formulations with
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`a high level of cationic lipid. Those concerns were so entrenched in the community
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`that even Petitioner’s expert acknowledges as much in his own publications. See
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`EX2006 at 125; see also EX1018 at 8 (citing EX2006).
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`Another prior art trend was to incorporate higher than the claimed levels of
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`conjugated lipids to stabilize the particle so that the therapeutic payload could
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`-1-
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`reach the target cells. Failing to do so was understood to cause the particles to
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`degrade or undergo dissolution before reaching their targets, resulting in little more
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`than a wasted effort.
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`The inventors solved these problems by requiring cationic lipids at “50 mol
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`% to 85 mol %,” non-cationic lipids at “13 mol % to 49.5 mol %,” and conjugated
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`lipids at “0.5 mol % to 2 mol %.” This specific combination, it turns out, is
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`surprisingly effective, stable following systemic (in vivo) administration, and does
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`not elicit the feared toxic effects associated with formulations having a high level
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`of cationic lipid. Given the innovation protected by the ’435 patent, the petition is a
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`poorly conceived challenge. It seeks troubling shortcuts to the legally mandated
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`obviousness analysis and fails to coherently identify the specific invalidity theories
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`it asks the Board to review in this matter.
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`Petitioner builds its obviousness argument of Ground 1 on a misapplication
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`and over-reading of In re Peterson. 315 F.3d 1325 (Fed. Cir. 2003). Petitioner
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`relies on Peterson to argue for a prima facie case of obviousness on a per-
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`limitation basis for what it contends are overlapping ranges of individual claim
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`elements. Having invoked Peterson, Petitioner rests on its putative “prima facie”
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`case as though that alone meets its obligation to justify institution, rather than
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`present the requisite obviousness analysis.
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`-2-
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`For starters, Petitioner fails to perform its obviousness analysis on the claim
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`as a whole, repeatedly arguing that each “limitation is prima facie obvious.” Of
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`course, obviousness must be performed on the full combination of a claim and not
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`merely on a per-limitation basis. This is a fundamental, and indeed fatal, defect of
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`the petition.
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`Moreover, it is well-established that, before a conclusion of obviousness is
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`reached based on the presence of elements in the prior art, a petitioner must
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`evaluate whether there is a motivation to combine those disclosures with a
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`reasonable expectation of success. These critical elements of the obviousness
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`analysis are missing from the petition.
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`Petitioner also attempts to side-step its legal obligation to make such
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`showings by invoking prima facie obviousness of claim limitations. As a threshold
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`matter, the concept of a prima facie obviousness showing is a “burden-shifting
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`framework [that] does not apply in the adjudicatory context of an IPR.” In re
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`Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1375 (Fed. Cir. 2016). Petitioner’s
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`attempt to cut corners by invoking this inapposite analytic substitute is another
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`fatal flaw in the petition.
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`Beyond that, Petitioner’s misguided effort to shoehorn the facts here into the
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`holding of Peterson is the type of misuse of precedent that the Federal Circuit has
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`already criticized. Genetics Institute v. Novartis Vaccines, 655 F.3d 1291, 1306
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`(Fed. Cir. 2011) (criticizing “attempts to shoehorn the facts of this case into our
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`holding in Peterson”). In Genetics Institute, the Federal Circuit stated that Peterson
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`does not apply to broad prior art ranges that would encompass a “very large
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`number of possible distinct compositions.” Id. Here, the number of permutations
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`encompassed by the broad ranges of each component is very large. Petitioner has
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`not even attempted to show that the permutations in the prior art are more like
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`those in Peterson than those in Genetics Institute.
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`The Federal Circuit further explained that the rationale of Peterson is limited
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`to the observation that typically scientists will be motivated to identify an optimal
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`value within a range. Id. But, there is no substitute for an actual motivation
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`analysis on the facts of a particular case and thus the Genetics Institute court
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`rejected the challenger’s reliance on Peterson. Id.
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`There are numerous complex considerations in trying to devise a lipid-
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`nucleic acid composition—as the prior art repeatedly reminds those of skill in the
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`art—such as safety, efficacy and avoidance of particle aggregation. But the Petition
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`fails to perform the required motivation analysis, much less does it establish a
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`reasonable expectation of success.
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`Ground 2 is a weak attempt to backfill Ground 1. It adds “Lin and/or
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`Ahmad” to the prior art relied upon in Ground 1. It is not clear how many
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`independent obviousness theories are supposed to be encompassed within Ground
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`2, although it appears to implicate five references in an unstated variety of
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`combinations. Regardless, the petition only addresses claim element 1(b)1 and
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`claim 4 instead of a systematic analysis of the claims as a whole. And Petitioner
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`inexplicably addresses motivation to combine without even including a section
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`showing it can satisfy the requisite reasonable expectation of success test.
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`On the substance, Ground 2 fails, for example, to establish that ordinarily
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`skilled artisans would select formulations with a high level of cationic lipid when
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`cobbling together the disparate teachings of the many references that are included
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`in this ground, such that they would reach the claimed “50 mol % to 85 mol %”
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`range. Petitioner states that Ahmad builds on Lin and encourages the heavy use of
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`cationic lipids. Not so. Ahmad flatly teaches against selecting such a high level of
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`cationic lipid by specifically stating that “[m]inimizing the amount of cationic lipid
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`is desirable to reduce cost as well as potential toxic effects of the cationic lipid.”
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`EX1006 at 745. No matter how confused, truncated or complicated the petition, it
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`1 Claim element 1(b), as recited in the claim language, is directed to the level of
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`cationic lipid. Petitioner refers to this feature as claim element 1(C). To avoid
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`confusion, Protiva will refer to claim elements consistent with their labeling in the
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`claim.
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`cannot get around this prior art fear of high levels of cationic lipid in formulations
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`for therapeutic use in vivo.
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`Ground 3 appears to be a partially formed after-thought. Petitioner argues
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`for “anticipation and/or obviousness” based on the ’554 publication. The
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`anticipation analysis fails because it never establishes that the relied on
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`compositions comprise nucleic acid-lipid particles, as opposed to some other type
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`of composition, let alone that these compositions are formulated for in vivo use.
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`Petitioner picks and chooses from disparate teachings of the ’554 publication and
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`fails to establish that the reference discloses “a conjugated lipid that inhibits
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`aggregation of particles” as required by the challenged claims (i.e., claim element
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`1(d)).
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`Ground 3 does not work any better as an obviousness argument. Once again,
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`Petitioner totally excludes the requisite reasonable expectation of success analysis
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`and improperly relies on the inapposite prima facie approach of Peterson as a
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`substitute for articulating a motivation to combine.
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`For all these reasons, institution should be denied.
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`II. OVERVIEW OF THE ’435 PATENT AND THE PRIOR ART
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`The ’435 patent discloses the “surprising discovery” that nucleic acid-lipid
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`particle formulations with a high level of cationic lipid and a remarkably low level
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`of conjugated lipid exhibited 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, 5:55-6:2; see also id., 11:28-37 (defining the inventive formulations as
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`“extremely useful for systemic applications”). Reflective of this discovery, the
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`’435 patent claims nucleic acid-lipid particle formulations with a high level of
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`cationic lipid (50–85 mol %) and an unconventionally low level of conjugated lipid
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`(0.5–2 mol %).
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`For example, independent claim 1 recites:
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`A nucleic acid-lipid particle comprising:
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`(a) a nucleic acid;
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`(b) a cationic lipid comprising from 50 mol % to 85 mol % of the total
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`lipid present in the particle;
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`(c) a non-cationic lipid comprising from 13 mol % to 49.5 mol % of the
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`total lipid present in the particle; and
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`(d) a conjugated lipid that inhibits aggregation of particles comprising
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`from 0.5 mol % to 2 mol % of the total lipid present in the particle.
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`The prior art instructed precisely the opposite of what is disclosed and
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`claimed in the ’435 patent. While overlooked in the petition, the prior art at the
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`time of invention (including all references cited by Petitioner) instructed that
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`formulations with a high level of cationic lipid were toxic and poorly tolerated in
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`vivo and had little to no in vivo transfection efficiency. E.g., EX1002 ¶6. Moreover,
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`the prior art instructs that the level of cationic lipid should be minimized, as high
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`levels were deemed unsuitable for in vivo transfection. EX1006 at 745.
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`Additionally, where conjugated lipids were utilized, the art instructed much higher
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`levels as compared to those claimed. EX1008 at E97.
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`The ’196 PCT (EX1002) is the primary reference relied upon in Grounds 1
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`and 2. However, the ’196 PCT, if anything, teaches away from in vivo use (i.e.,
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`systemic applications) of its disclosed cationic liposome complexes — warning of
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`toxic side effects and rapid clearance (i.e., low efficacy).
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`Cationic liposome complexes, however, are large, poorly defined systems
`that are not suited for systemic applications2 and can elicit considerable
`toxic side effects … Tam, et al, Gene Ther. 7: 1867 (2000). As large,
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`positively charged aggregates, lipoplexes are rapidly cleared when
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`administered in vivo, with highest expression levels observed in first-pass
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`organs, particularly the lungs (Huang, et al., Nature Biotechnology 15:
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`620 (1997); ….
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`EX1002 ¶6.3
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`2 Systemic application refers to delivery of a composition into the circulation of
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`a subject (e.g., injection into the tail vein of a mouse).
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`3 Tam explains that administering cationic liposome complexes results in liver
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`damage and systemic tissue damage. EX2004 at 1869. Huang explains that
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`unwanted aggregation of cationic lipids essentially eliminates in vivo transfection
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`Ground 2 further relies on Lin (EX1005), which explains that “[c]ationic
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`liposomes (CLs) are used worldwide as gene vectors (carriers) in nonviral clinical
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`applications of gene delivery, albeit with unacceptably low transfection
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`efficiencies.” EX1005 at 3307 (emphasis added).
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`Petitioner also cites to Gao (EX1008). E.g., Pet. 34, 37, 38. Gao identifies
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`severe toxicity effects and concludes that the cationic lipoplex formulations were
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`unsuitable for use in humans:
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`Detailed toxicological studies … revealed that the cationic lipid
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`contributes significantly to the toxicity observed. Similar toxic effects
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`are also noticeable in systemic gene delivery via the tail vein with other
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`types of cationic lipids. Symptoms include acute pulmonary hypotension,
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`induction of inflammatory cytokines, tissue infiltration of neutrophils in
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`lungs, decrease in white cell counts, and in some cases tissue injury in
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`liver and spleen. In humans, various degrees of adverse inflammatory
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`reactions, including flulike symptoms with fever and airway
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`inflammation, were noted among subjects who received aerosolized
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`GL67 liposomes alone or lipoplexes. These early clinical data suggest
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`that these lipoplex formulations are inadequate for use in humans.
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`efficiency. EX2005 at 621 (“These problems … severely limit the intravenous
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`application of cationic liposome/ DNA complexes.”).
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`EX1008 at E96 (emphasis added). Gao further explains that “most [cationic lipids]
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`do not perform well in the presence of serum, and only a few are active in vivo.”
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`Id.
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`Once administered in vivo, lipoplexes tend to interact with negatively
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`charged blood components and form large aggregates that could be
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`absorbed onto the surface of circulating red blood cells, trapped in a thick
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`mucus layer, or embolized in microvasculatures, preventing them from
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`reaching the intended target cells in the distal location. Some even
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`undergo dissolution after they are introduced to the blood circulation.
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`Id. (emphasis added).
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`Petitioner also cites to Heyes (EX1010). Pet. 8, 25. Heyes analyzed various
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`lipid particle formulations and observed that “particles with a more pronounced
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`positive charge are more likely to interact with small amounts of negatively
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`charged, unencapsulated nucleic acid present in SNALP preparations, thereby
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`increasing the chance of particle aggregation.” EX1010 at 284-85.
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`Given the difficulties involving cationic lipids, the prior art uniformly taught
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`using a low level of of cationic lipid. Minimizing the level of cationic lipid was
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`critically emphasized for in vivo applications, where toxicity, systemic
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`aggregation, and low transfection efficiency were of particular concern.
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`The ’196 PCT indicated that, when formulating lipid particles, “[p]referred
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`embodiments are charge-neutralized.” EX1002 ¶14. The ’196 PCT further instructs
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`that “for systemic delivery, the cationic lipid may comprise about 5% to about
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`15% of the total lipid present in said particle.” Id. ¶88 (emphasis added).
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`Ground 2 of the Petition relies upon Ahmad (EX1006). Ahmad tested
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`formulations in vitro, finding that a low level of cationic lipid was critically
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`important:
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`A relatively low lipid/DNA charge ratio, therefore, can be considered
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`optimal since it allows for achievement of maximum TE with the least
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`amount of cationic lipid … Minimizing the amount of cationic lipid is
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`desirable to reduce cost as well as potential toxic effects of the cationic
`lipid.
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`EX1006 at 745 (emphasis added). Indeed, minimizing the level of cationic lipid for
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`in vivo applications was one of the key conclusions. Id. at 747 (“This ability to use
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`fewer cationic molecules for high TE is important for cost reduction and possibly
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`in vivo toxicity of cationic components.”).
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`The ’554 publication (EX1004), asserted in Ground 3, similarly instructs
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`that “[t]he complexes are preferably charge-neutralized.” EX1004 ¶135.
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`[T]he formulated particles formed in the present invention are preferably
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`neutral or negatively-charged at physiological pH. For in vivo
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`applications, neutral particles are advantageous, while for in vitro
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`applications the particles are more preferably negatively charged. This
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`provides the further advantage of reduced aggregation over the
`positively-charged liposome formulations in which a biologically active
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`molecule can be encapsulated in cationic lipids.
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`EX1004 ¶462 (emphasis added).
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`Even Petitioner’s own expert, Dr. Janoff, articulated the same principle of
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`using a low level of cationic lipid in his own publications. EX2006 at 125
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`(“Another advantage of DODAP is that a larger change in surface charge is
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`ultimately possible without including so much positively charged lipid that
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`liposome destabilization occurs or non-specific interaction with cells occurs before
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`enzymatic cleavage or endocytosis.”) (emphasis added).
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`Where conjugated lipids were utilized to stabilize the liposome, the prior art
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`instructed that much higher levels (relative to that claimed in the ’435 patent) were
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`required to stabilize the lipid particle following systemic (in vivo) application and
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`to prevent aggregation of particles. EX1008 at E97.
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`In sum, Petitioner’s own cited references indicate that a POSITA would
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`have expected nucleic acid-lipid particle formulations with a high level of cationic
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`lipid to be too toxic for in vivo applications. Further, a POSITA would have
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`understood that positively charged particles trigger aggregation and subsequent
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`immune responses, resulting in little to no in vivo transfection efficiency. Yet,
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`contrary to these expectations, the claimed formulations uniformly withstood
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`rigorous in vivo tests that established stability following systemic (in vivo)
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`administration, suitability for mammals with no considerable toxicity, and
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`transfection efficiencies that were competitive, and in many cases superior, to
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`conventional formulations.
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`III. THE ENTIRE PETITION IS BASED ON A FLAWED LEGAL
`THEORY
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`It is well-established that the concept of “prima facie” obviousness, and the
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`corresponding burden-shifting framework, represent an ex parte prosecution
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`procedural tool that does not apply in inter partes reviews. Yet, the entire petition
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`is constructed on the misplaced notion that mere identification of an overlap in
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`range establishes “prima facie” obviousness so as to shift the burden to Protiva.
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`To start, none of the grounds of challenge offers any meaningful discussion
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`of motivation to combine. In fact, motivation to combine is simply unaddressed in
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`Grounds 1 and 3. Similarly, discussion of whether there would be any reasonable
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`expectation of success in the proposed combination is virtually non-existent
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`throughout the petition. As such, each of the grounds can be denied both for being
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`based on a flawed legal theory and for a correspondingly deficient challenge.
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`Remarkably, the petition asserts at least thirty-three times that it has
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`established “prima facie” obviousness of a claim limitation. Petitioner cites to
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`Peterson, repeatedly throughout the Petition for the proposition that “[e]ven a
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`slight overlap in range establishes a prima facie case of obviousness.” E.g., Pet. 2,
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`3, 34, 39, 40, 41, 43, 44, 54, 55, 56, 57, 59, 60 (citing 315 F.3d at 1329). Each of
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`the grounds of challenge is predicated on the misapprehension that invoking
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`Peterson obviates the need for a complete analysis under section 103. Rather than
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`assessing the full scope and content of the prior art or providing a corroborated
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`analysis of any motivation to combine, Petitioner simply regurgitates the same
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`quotation from Peterson.
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`It is well-recognized that the burdens of proof for establishing obviousness
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`differ between prosecution and an adjudicatory setting, and that the burden-shifting
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`framework of “prima facie” obviousness does not apply in an inter partes review:
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`In an inter partes review, the burden of persuasion is on the petitioner to
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`prove ‘unpatentability by a preponderance of the evidence,’ 35 U.S.C. §
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`316(e), and that burden never shifts to the patentee. … We have noted
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`that “a burden-shifting framework makes sense in the prosecution
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`context,” … [H]owever, that burden-shifting framework does not apply
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`in the adjudicatory context of an IPR.
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`Magnum Oil Tools, 829 F.3d at 1375.
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`Consistent with Magnum Oil Tools, the Board has recognized that the
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`burden-shifting of Peterson is inapplicable to inter partes reviews. In Colas
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`Solutions, the Board noted the “dubious transferability of [the Peterson] principle
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`in the inter partes review setting.” Colas Solutions, Inc. v. Blacklidge Emulsions,
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`Inc., IPR2016-01032, Paper 40 at 27; see also E.I. Du Pont de Nemours v. Furanix
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`Tech., IPR2015-01838, Paper 43 at 15 (similar). In sum, applying Peterson as
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`proposed by the Petitioner would contravene the adjudicatory nature of the instant
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`forum.4
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`Petitioner’s improper burden shifting is further compounded by its distortion
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`of the holding in Peterson. Peterson never adopted a bright-line rule for
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`obviousness and, in fact, specifically took into consideration the state of the art,
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`differences between the claimed invention and the prior art, and the context of the
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`prior art disclosures—factors that Petitioner overlooks. Peterson. 315 F.3d at 1382-
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`83. Therefore the Board should reject Petitioner’s reliance on a misstated principle
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`that is inapplicable to inter partes reviews.
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`IV. CLAIM CONSTRUCTION
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`A claim subject to inter partes review receives the broadest reasonable
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`construction or interpretation in light of the specification of the patent in which it
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`appears. See 37 C.F.R. § 42.100(b). The terms identified in the petition do not
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`require construction in order to reach a decision denying institution. The
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`constructions proposed in the petition, however, should be rejected as being
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`unreasonably broad and largely detached from the ’435 patent specification.
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`4 The Federal Circuit recently explained that even in the ex parte context
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`establishing a prima facie case due to overlapping ranges still requires a motivation
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`to combine and a reasonable expectation of success. In re Stepan, 868 F.3d 1342,
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`1346 n.1, 1348 (Fed. Cir. 2017)
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`Petitioner contends that the term “nucleic acid-lipid particle” means “a
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`composition of lipids and a nucleic acid for delivering a nucleic acid to a target site
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`of interest.” Pet. 24. The petition makes only the conclusory assertion that the
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`proffered construction “is based on the disclosures provided in the ’435 patent,”
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`and identifies a single citation to the specification discussing a different term. Id.
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`(citing EX1001, 11:14-17 (addressing the term “lipid particle”)).5
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`But the claims of the ’435 patent recite the term “nucleic acid-lipid particle,”
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`not the term “lipid particle” that the petition construes. And Petitioner ignores that
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`the specification uses the term “nucleic acid-lipid particle” to refer to particles
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`specifically formulated for systemic (in vivo) administration and having the nucleic
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`acid component encapsulated within the lipid. For example:
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`As used herein, the term “SNALP” includes an SPLP, which is the term
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`used to refer to a nucleic acid-lipid particle comprising a nucleic acid
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`(e.g., a plasmid) encapsulated within the lipid. SNALP and SPLP are
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`extremely useful for systemic applications, as they can exhibit extended
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`circulation lifetimes following intravenous (i.v.) injection, they can
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`accumulate at distal sites (e.g., sites physically separated from the
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`5 Besides citing to a definition of a different term than the term recited in the
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`claims, the proffered construction in the petition is not reflective of the definition
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`the different term “lipid particle.” As such, it is entirely unclear how the proffered
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`construction “is based on the disclosures provided in the ’435 patent” as asserted.
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`administration site), and they can mediate expression of the transfected
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`gene or silencing of target gene expression at these distal sites.
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`EX1001, 11:31-42.
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`[T]he present invention provides stable nucleic acid-lipid particles
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`(SNALP) that advantageously impart increased activity of the
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`encapsulated nucleic acid (e.g., interfering RNA such as siRNA) and
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`improved tolerability of the formulations in vivo, resulting in a
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`significant increase in the therapeutic index as compared to nucleic acid-
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`lipid particle compositions previously described.
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`Id., 5:62-6:2; see also id., 6:25-30, 2:38-47, 13:38-49.
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`As discussed above, the prior art taught that high-level cationic lipid
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`formulations were toxic and poorly suited for systemic (in vivo) application,
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`whereas the ’435 patent is directed to nucleic acid-lipid particle compositions
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`having a high level of cationic lipid while formulated for systemic (in vivo)
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`application. Moreover, the specification draws a distinction between lipid particle
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`formations having encapsulated nucleic acids and liposome complexes
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`(“lipoplexes”) forming a heterogeneous aggregate. See e.g., EX1001, 2:56-65.6
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`6 A number of the cited references, including Lin and Ahmad, are undeniably
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`directed to such liposome complexes. See EX1005, Title (“Three-Dimensional
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`Imaging of Lipid Gene-Carriers: Membrane Charge Density Controls Universal
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`Transfection Behavior in Lamellar Cationic Liposome-DNA Complexes”)
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`-17-
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`

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`V. LEVEL OF ORDINARY SKILL IN THE ART
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`Petitioner’s proposed level of ordinary skill should be rejected to the extent
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`that Petitioner equates the level of ordinary skill with knowledge possessed by the
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`inventors themselves. Pet. 5-6. It is well-settled that an “invention must be
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`evaluated not through the eyes of the inventor, who may have been of exceptional
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`skill, but as by one of ‘ordinary skill.’” Interconnect Planning Corp. v. Feil, 774
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`F.2d 1132, 1138 (Fed. Cir. 1985) (citing Stewart-Warner Corp. v. City of Pontiac,
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`Michigan, 767 F.2d 1563, 1570 (Fed. Cir. 1985)). Further, while Petitioner
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`identifies a POSITA as having an M.D., the petition is missing any discussion of
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`therapeutic considerations, such as toxicity, in vivo aggregation, and overall
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`systemic tolerance. As such, Petitioner’s proffered definition of a POSITA (and
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`any corresponding argument) appears tainted by the inventor’s own knowledge and
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`detached from the actual concerns of those of ordinary skill in the art at the time of
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`invention.
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`(emphasis added), Abstract; see also EX1006, Title (“New multivalent cationic
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`lipids reveal bell curve for transfection efficiency versus membrane charge density:
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`lipid–DNA complexes for gene delivery) (emphasis added), 739.
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`-18-
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`

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`VI. THE PETITION FAILS TO IDENTIFY THE GROUNDS OF
`CHALLENGE WITH PARTICULARITY
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`The Board should deny the petition because it does not present any of the
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`three grounds of challenge with the requisite degree of particularity. See, e.g., Pet.
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`5. All three grounds include various alternate legal theories and/or different
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`permutations and combinations of the “cited references.” In some instances, the
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`stated grounds are so convoluted that it is unclear what basis of review Petitioner is
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`requesting.
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`This is particularly problematic with respect to Ground 2—i.e., “Claims 1-20
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`are obvious in view of patent owner’s prior disclosures in light of Lin and/or
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`Ahmad.” Pet. 5. First, it is unclear what the petition envisions as the “patent
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`owner’s prior disclosures.” In one section of the petition, three different references
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`are identified as “patent owner’s prior disclosures”—i.e., the ’196 PCT, the ’189
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`publication, and the ’910 publication. Id. at 24-25. Yet, in another section, the ’196
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`PCT and the ’189 publication are mentioned in the discussion of Ground 2 (Pet.
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`48), and then in the motivation to combine section only the ’196 PCT is discussed.
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`Pet. 48-51. Second, it is altogether unclear which claims are challenged in Ground
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`2. The petition states Ground 2 is directed to claims 1-20, yet only element 1(b)
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`-19-
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`

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`(directed to the level of cationic lipid) and claim 4 are specifically addressed. Pet.
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`49-50.7
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`Grounds 1 and 3 suffer similar shortcomings. Ground 1 is presented as
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`alleged obviousness in view of “the ’196 PCT and ’189 publication” (Pet. 5, 48),
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`but provides no meaningful discussion of the ’189 publication.8 Ground 3 is
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`presented as alternate legal theories of anticipation or obviousness, with different
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`theories applied to different claims and the theories of obviousness varying
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`between prima facie obvious in view of overlapping range (Pet. 51, 56) and
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`obvious to try (Pet. 56).
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`The AIA statute and the corresponding Board rules require that the petition
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`“identif[y], in writing and with particularity, each claim challenged, the grounds
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`on which the challenge to each claim is based, and the evidence that supports the
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`grounds for the challenge to each claim.” 35 U.S.C. § 312(a)(3) (emphasis added);
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`see also 37 C.F.R. § 42.104(b).
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`7 Assuming the identified “patent owner’s prior disclosures” is referrin