`
`
`
`Paper No. ___
`Filed: April 29, 2019
`
`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 PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`

`

`
`
`TABLE OF CONTENTS
`
`I. 
`II. 
`
`ii. 
`
`iii. 
`
`iv. 
`
`Page
`Introduction ...................................................................................................... 1 
`The General Plastic Factors as well as Petitioner’s Abuse of Inter
`Partes Review Petitions Warrant Denial of Institution ................................... 3 
`A. 
`Each of General Plastic Factors Support Discretionary Denial ........... 4 
`i. 
`Factor 1 supports denial because Petitioner previously
`filed a petition directed against similar claims in a related
`patent ........................................................................................... 4 
`Factor 2 supports denial because at the time of filing the
`petition for the ’739 IPR, Petitioner knew of the prior art
`asserted in the instant petition ..................................................... 6 
`Factor 3 supports denial because Petitioner benefited
`from Patent Owner’s briefings and the institution
`decision in the ’739 IPR .............................................................. 6 
`Factors 4 and 5 support denial because there is no
`justification for the 10 month delay in filing the instant
`petition ........................................................................................ 7 
`Factor 6 supports denial because the finite resources of
`the Board should not be used to entertain Petitioner’s
`attempt at re-litigating the issues of the ’739 IPR ...................... 8 
`Factor 7 and its considerations under 35 U.S.C.
`§316(a)(11) also support denial .................................................. 8 
`Petitioner’s Conduct is an Abuse of the Inter Partes Review
`Process and Patent Owner Harassment ................................................. 9 
`i. 
`Petitioner largely ignores the issues raised and evidence
`presented in the ’739 IPR ............................................................ 9 
`The instant petition was filed to harass Patent Owner .............. 11 
`ii. 
`III.  Overview of the ʼ069 Patent and the Prior Art .............................................. 13 
`
`v. 
`
`vi. 
`
`B. 
`
`-i-
`
`

`

`B. 
`
`C. 
`
`B. 
`
`B. 
`
`
`IV.  Claim Construction ........................................................................................ 15 
`V.  Grounds 1-3: Prior Art Does Not Disclose the Claimed Phospholipid
`Range. ............................................................................................................ 17 
`A.  Grounds 1 & 2 – The ’196 PCT and the ’189 Publication do not
`teach the recited phospholipid concentration range. ........................... 18 
`Ground 3 – The ’554 Publication also does not teach the recited
`phospholipid concentration range. ...................................................... 19 
`Petitioner engages in illogical calculations and improper
`hindsight to arrive at purported ranges. ............................................... 19 
`VI.  There is No Rationale/Motivation Supporting Obviousness ......................... 23 
`A. 
`Formulating Nucleic Acid-Lipid Particles Was Not a Matter of
`Routine Optimization .......................................................................... 26 
`Lin and Ahmad Do Not Supply the Missing Motivation for
`Ground 2 .............................................................................................. 29 
`VII.  Unexpected Results Further Rebut any Prima Facie Obviousness .............. 32 
`A. 
`The ʼ069 Patent Reports Extensive Testing of Numerous
`Formulations within the Claimed Range ............................................. 34 
`Post-Filing Publications Provide Testing Data for a Broad
`Range of Lipids and Cargo Molecules (including both siRNA
`and mRNA) ......................................................................................... 37 
`VIII.  Petitioner Fails to Make the Requisite Assessment of Objective
`Indicia of Non-Obviousness .......................................................................... 42 
`A. 
`Long-Felt Need – the delivery problem was not solved for over
`20 years ................................................................................................ 43 
`Failure of Others – despite the motivation alleged by Petitioner,
`those in the art failed to formulate nucleic acid-lipid particles
`suitable for systemic delivery .............................................................. 45 
`Skepticism – those in the art questioned the safety of the
`SNALP as a suitable delivery platform ............................................... 46 
`
`C. 
`
`B. 
`
`-ii-
`
`

`

`D. 
`
`Commercial Success – The Claimed Nucleic Acid-Lipid
`Particle is the First FDA Approved siRNA Drug ............................... 47 
`IX.  Conclusion ..................................................................................................... 48 
`X. 
`Certificate of Compliance .............................................................................. 50 
`XI.  Appendix – List of Exhibits ........................................................................... 51 
`
`
`
`-iii-
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`

`

`
`
`I.
`
`INTRODUCTION
`
`The Board should not institute inter partes review of claims 1-22 of U.S.
`
`Patent No. 8,058,069 (the ’069 patent) because Moderna Therapeutics, Inc.
`
`(“Moderna” or “Petitioner”) fails to show that it has a reasonable likelihood of
`
`prevailing.
`
`The nucleic acid-lipid particles claimed by the ’069 patent have achieved
`
`tremendous recognition in the field of genetic therapy. The ’069 patent is now
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`listed in the FDA’s Orange Book as protecting the patisiran commercial product—
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`tradename “Onpattro.” EX2025. Patisiran received regulatory approval in the
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`U.S. and Europe and has been designated by the FDA as a “first-in-class” drug.
`
`EX2023; EX2024.
`
`As an initial matter, the petition (2-3) cites to Petitioner’s pending challenge
`
`(IPR2018-00739) of Patent Owner’s related U.S. Patent No. 9,364,435, but fails to
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`appreciate that its serial attacks actually weigh against institution here. Petitioner
`
`asserts similarities between the cases, but does not explain why it sat on the present
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`challenge for 10 months while using prior Board decisions and Patent Owner’s
`
`briefing as a roadmap for drafting the current petition. Despite this advantage,
`
`Petitioner ignores the evidence presented in the ’739 IPR directly pertinent to
`
`numerous issues presented here—evidence that should have been addressed but
`
`was not. Infra Sections VII-VIII. This includes, inter alia, extensive experimental
`
`-1-
`
`

`

`
`
`testing evidence demonstrating criticality of the lipid ranges claimed here, and
`
`extensive objective indicia supporting nonobviousness (e.g., failure, skepticism,
`
`and commercial success). E.g., ʼ739 IPR, Paper 24, 21-28, 53-61. Petitioner was
`
`required to address this evidence to show a reasonable likelihood of success on the
`
`merits. E.g., Praxair Distribution, Inc. v. Mallinckrodt Hospital Products,
`
`IPR2016-00777, Paper 10, 9.
`
`The present challenges also fail on the merits for numerous reasons. First,
`
`each ground of challenge rests on the false notion that overlapping lipid ranges in
`
`the prior art either anticipate or render the ’069 patent claims “prima facie”
`
`obvious. Pet. 1-3, 33, 38, 56. As a threshold matter, there can be no such “prima
`
`facie” case here because Petitioner fails to identify prior art disclosure of the
`
`claimed lipid ranges in the first place.
`
`Independent claim 1 recites four components at different concentrations,
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`including phospholipid “from 4 mol % to 10 mol % of the total lipid.” The petition
`
`fails to show any disclosed phospholipid range in the cited art, let alone
`
`phospholipid ranges that overlap with those recited in independent claim 1. Thus,
`
`despite staking its entire case on allegations of prior art disclosure of the lipid
`
`constituent ranges recited in the challenged claims, Petitioner does not (as it
`
`cannot) substantiate this charge. Each ground of challenge fails for at least this
`
`reason.
`
`-2-
`
`

`

`
`
`Beyond the missing limitations discussed above, the obviousness challenges
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`also fail because Petitioner does not identify any particular motivation or rationale
`
`to combine components specifically in the proportions required by the claims (or a
`
`reasonable expectation of success). For Grounds 1 and 3, Petitioner argues for
`
`prima facie obviousness on a per-limitation basis for what it contends are
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`overlapping ranges of individual claim elements. E.g., Pet. 2, 33, 35 (citing In re
`
`Peterson, 315 F.3d 1325 (Fed. Cir. 2003) and E.I. du Pont de Nemours & Co. v.
`
`Synvina C.V., 904 F.3d 996 (Fed. Cir. 2018).
`
`But those cases, like all other overlapping range cases, are based on the
`
`specific rationale of “routine optimization”— none obviated the need for critical
`
`aspects of an obviousness inquiry. Petitioner here does not assert, let alone
`
`establish, that formulating nucleic acid-lipid particles as claimed would have been
`
`a matter of routine optimization. Petitioner, in fact, embraces complexity and
`
`unpredictability throughout the petition materials, which only underscores the fact
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`that “routine optimization” is not a viable rationale for arriving at the claimed
`
`subject matter.
`
`Accordingly, institution of inter partes review should be denied.
`
`II. THE GENERAL PLASTIC FACTORS AS WELL AS PETITIONER’S ABUSE OF
`INTER PARTES REVIEW PETITIONS WARRANT DENIAL OF INSTITUTION
`
`Institution of an inter partes review is discretionary. See 35 U.S.C. § 314(a);
`
`see also Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1367 (Fed. Cir. 2016).
`
`-3-
`
`

`

`
`
`Here, denial of institution is warranted in view of the factors set forth in General
`
`Plastic, and Petitioner’s delaying tactics and abuse of the inter partes review
`
`process to harass Patent Owner. General Plastic Industrial Co. v. Canon
`
`Kabushiki Kaisha, IPR2016-01357, Paper 19, 9-10 (precedential as to §II.B.4.i).
`
`A. Each of General Plastic Factors Support Discretionary Denial
`
`General Plastic set forth seven non-exclusive factors to determine whether
`
`discretionary denial is appropriate. Id. Each factor supports denial of institution.
`
`i. Factor 1 supports denial because Petitioner previously filed
`a petition directed against similar claims in a related patent
`
`
`
`The first General Plastic factor is “whether the same petitioner previously
`
`filed a petition directed to the same claims of the same patent.” On March 5, 2018,
`
`over ten months before the filing of the instant petition, Petitioner filed a petition
`
`against U.S. Patent No. 9,364,435 (“the ʼ435 patent”) in IPR2018-00739 (ʼ739
`
`IPR). The ’435 patent is a continuation of the ’069 patent challenged in the instant
`
`proceeding. The two patents have similar, although not identical claims.
`
`
`
`Petitioner challenges the ’069 patent using the same grounds and same prior
`
`art used in its challenge of the ’435 patent in the ’739 IPR. Specifically, both the
`
`instant petition and the ’739 IPR assert three grounds. Pet. 5; ’739 IPR, Paper 2, 5.
`
`Ground 1 argues both anticipation and obviousness based on the ’196 PCT and the
`
`’189 publication. Next, Ground 2 alleges obviousness and attempts to tack on Lin
`
`-4-
`
`

`

`
`
`and Ahmad to the references of Ground 1. Lastly, Ground 3 again alleges both
`
`anticipation and obviousness, but does so based on the ’554 publication.
`
`The General Plastic factors were articulated in the context of denying a
`
`follow-on petition filed on the same patent. However, the Board has held on
`
`multiple occasions that the logic underlying the General Plastic factors are
`
`applicable in other contexts. See NetApp, Inc. v. Realtime Data LLC, IPR2017-
`
`01195, Paper 9, 10 (Oct. 12, 2017) (applying the General Plastic factors where
`
`different petitioners filed petitions on the same patent). That is, the General
`
`Plastic factors are meant to address scenarios that are “unfair to patent owners and
`
`[] an inefficient use of the inter partes review process.” General Plastic, Paper 19,
`
`16-17; see also August 2018 Trial Practice Guide Update at 10 (“The General
`
`Plastic factors are also not exclusive and are not intended to represent all situations
`
`where it may be appropriate to deny a petition”); Becton, Dickinson and Company,
`
`v. B. Braun Melsungen AG, IPR2017-01586, Paper 8, 22-28 (exercising discretion
`
`to deny institution where the same prior art and same arguments were presented
`
`during prosecution of the parent application). Here, Petitioner is challenging a
`
`closely related patent with similar claims using the same prior art and the same
`
`grounds. Thus, the first factor favors denial.
`
`-5-
`
`

`

`
`
`ii.
`
`Factor 2 supports denial because at the time of filing the
`petition for the ’739 IPR, Petitioner knew of the prior art
`asserted in the instant petition
`
`The second General Plastic factor is “whether at the time of filing of the
`
`first petition the petitioner knew of the prior art asserted in the second petition or
`
`should have known of it.” As detailed above, the ʼ739 IPR and the instant petition
`
`rely on the same prior art asserted in the same manner. Indisputably, Petitioner
`
`was aware of the asserted prior art at the time of filing the first petition. There is
`
`no reason Petitioner could not have filed the instant petition when it filed the
`
`petition in the ʼ739 IPR over a year ago. The second factor strongly favors denial.
`
`iii. Factor 3 supports denial because Petitioner benefited from
`Patent Owner’s briefings and the institution decision in the
`’739 IPR
`
`The third General Plastic factor is “whether at the time of filing of the
`
`second petition the petitioner already received the patent owner’s preliminary
`
`response to the first petition or received the Board’s decision on whether to
`
`institute review in the first petition.” In crafting the instant petition, Petitioner
`
`admittedly looked to Patent Owner’s preliminary response, the institution decision,
`
`as well as Patent Owner’s full response in the ʼ739 IPR. Pet. 1-2.
`
`Institution of the instant petition would essentially grant Petitioner a second
`
`bite at the apple in an attempt to remedy its missteps in the ʼ739 IPR. The third
`
`factor weighs in favor of denial.
`
`-6-
`
`

`

`
`
`iv.
`
`Factors 4 and 5 support denial because there is no
`justification for the 10 month delay in filing the instant
`petition
`
`The fourth and fifth General Plastic factors are “the length of time that
`
`elapsed between the time the petitioner learned of the prior art asserted in the
`
`second petition and the filing of the second petition,” and “whether the petitioner
`
`provides adequate explanation for the time elapsed between the filings of multiple
`
`petitions directed to the same claims of the same patent.” That is, the fourth and
`
`fifth factors assess whether there is any justification for Petitioner’s delay in filing
`
`the instant proceeding. There is none.
`
`The exact same prior art is asserted in both petitions, and at least 10 months
`
`elapsed from when Petitioner learned of the prior art asserted in the instant
`
`petition. Petitioner acknowledges that the Board instituted inter partes review of
`
`the ʼ435 patent, “the direct descendent” of the ʼ069 patent. Pet. 1. Despite this
`
`acknowledgment, Petitioner provides no explanation for the 10 month delay in
`
`filing the instant petition. E.g., Edwards Lifesciences Corp. v. Boston Sci. Scimed,
`
`Inc., IPR2017-01301, Paper 7, 10 (a delay of just over four months to file the
`
`second petition was found to support non-institution); Alere, Inc. v. Rembrandt
`
`Diagnostics, LP, IPR2017-01130, Paper 10, 9-10 (petitioner’s failure to explain its
`
`delay in filing the second petition supported non-institution). The fourth and fifth
`
`factors both favor denial.
`
`-7-
`
`

`

`
`
`v.
`
`Factor 6 supports denial because the finite resources of the
`Board should not be used to entertain Petitioner’s attempt
`at re-litigating the issues of the ’739 IPR
`
`The sixth General Plastic factor concerns the finite resources of the Board.
`
`Here, given the overlap in subject matter and prior art, it clearly would have been
`
`more cost effective and efficient for the Board to address any challenge of the ʼ069
`
`patent at the same time as the ʼ435 patent. Conducting two nearly identical
`
`proceedings in a staggered manner would be a significant waste of the Board’s
`
`finite resources. General Plastic, Paper 19, 21 (“[M]ultiple, staggered petition
`
`filings, such as those here, are an inefficient use of the inter partes review process
`
`and the Board’s resources.”). The sixth factor strongly favors denial.
`
`vi.
`
`Factor 7 and its considerations under 35 U.S.C. §316(a)(11)
`also support denial
`
`Finally, the seventh General Plastic factor is concerned with “the
`
`requirement under 35 U.S.C. §316(a)(11) to issue a final determination not later
`
`than 1 year after the date on which the Director notices institution of review.”
`
`An institution decision in the instant proceeding should issue no later than
`
`July 29, 2019—less than two months before the final written decision in the ʼ739
`
`IPR. Given the similarity in issues in the petitions, the final written decision in this
`
`case will significantly overlap with the final written decision in the ʼ739 IPR. E.g.,
`
`SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348, 1356 (2018) (making clear that the Board
`
`may not conduct an inter partes review that departs from what was advanced in the
`
`-8-
`
`

`

`
`
`petition). The Board would also be issuing a final written decision in the instant
`
`proceeding well after it was originally presented with the same prior art and
`
`grounds in the ʼ739 IPR. Thus, this factor also weighs in favor of denial.
`
`B.
`
`Petitioner’s Conduct is an Abuse of the Inter Partes Review
`Process and Patent Owner Harassment
`
`Intended to address “undue inequities and prejudices to Patent Owner,” the
`
`General Plastic factors were expressly stated as non-exhaustive because
`
`“additional factors may arise in other cases for consideration.” General Plastic,
`
`Paper 19, 17-18. Here, Petitioner’s conduct raises several other issues that further
`
`justify denying institution.
`
`i.
`
`Petitioner largely ignores the issues raised and evidence
`presented in the ’739 IPR
`
`As discussed above, Petitioner waited for at least 10 months before
`
`proceeding with the instant petition. Despite the delay, the instant petition relies
`
`on the exact same art, the exact same grounds, and essentially the same reasoning
`
`presented in the ʼ739 IPR. E.g., Pet. 1. Indeed, the instant petition is largely a cut-
`
`and-paste of the petition from the ʼ739 IPR.
`
`Petitioner largely ignores the evidence that Patent Owner presented in the
`
`’739 IPR. Petitioner makes no attempt to reconcile its positions taken in the
`
`petition with arguments developed in the ’739 IPR regarding claim construction,
`
`toxicity of cationic lipids, evidence of surprising results, and objective indicia.
`
`-9-
`
`

`

`
`
`With respect to claim construction, Petitioner entirely foregoes the necessary
`
`analysis. Pet. 23; 37 C.F.R. §42.104(b)(3). Instead, Petitioner simply submits that
`
`the term “nucleic acid-lipid particle” should be interpreted in the same way that the
`
`Board did for purposes of institution in the ’739 IPR. Pet. 23; ʼ739 IPR, Paper 15,
`
`10-11. Petitioner provides no explanation as to why the Board’s preliminary
`
`construction under a different claim construction standard would be appropriate for
`
`the instant petition. Petitioner also fails to reconcile the three different
`
`constructions it offered in the ’739 IPR. ʼ739 IPR, Paper 2, 24 (arguing “nucleic
`
`acid-lipid particle” means “a composition of lipids and a nucleic acid to a target
`
`site of interest”; EX2001, 120:5-6, 121:14-25 (Dr. Janoff testifying “we’re talking
`
`about lipid particles of the invention, and it’s pretty clear we’re talking about
`
`SNALPs”); ʼ739 IPR, Paper 28, 3 (adopting the Board’s preliminary claim
`
`construction in the institution decision). Missing from the petition is any attempt
`
`to address the arguments Patent Owner advanced in the ’739 IPR against the
`
`construction it now adopts, or the testimony of its own expert that supported Patent
`
`Owner’s construction. ’739 IPR, Paper 34 (EX2007), 3-7; see infra Section IV.
`
`Additionally, Patent Owner presented evidence of secondary indicia
`
`throughout its briefing in the ʼ739 IPR. The evidence is extensive—covering long
`
`felt need, industry praise, commercial success, and failure of others. E.g., ʼ739
`
`IPR, Paper 24, 21-28, 53-61. Petitioner has done nothing to address any of this
`
`-10-
`
`

`

`
`
`evidence. See Praxair, Paper 10, 9 (denying institution where Petitioner failed to
`
`“address the compelling evidence of secondary considerations set forth during
`
`prosecution and in the Preliminary Response in the earlier proceedings”); infra
`
`Sections VII-VIII.
`
`ii.
`
`The instant petition was filed to harass Patent Owner
`
`Instituting review would essentially be requiring the Board to re-litigate the
`
`issues of the ʼ739 IPR, forcing Patent Owner to again incur the considerable time
`
`and costs that have already been invested. For example, Patent Owner will have
`
`to, at an absolute minimum, file another Patent Owner Response and depose
`
`Petitioner’s expert yet again. Given the overlap in subject matter and prior art, it
`
`would clearly have been more cost effective for Patent Owner, as well as the
`
`Board, to address any challenge of the ʼ069 patent at the same time as the ʼ435
`
`patent.
`
`Notably, there is no underlying district court dispute over the ’069 patent.
`
`Phigenix, Inc. v. ImmunoGen, Inc., 845 F.3d 1168, 1176 (Fed. Cir. 2017) (finding
`
`that the petitioner lacked standing to appeal the Board’s decision because there was
`
`no injury in fact). Thus, rather than addressing any genuine dispute, Petitioner
`
`appears to be using the petition process to develop and test potential future
`
`litigation strategies. E.g., ’739 IPR, Paper 29, 10-20 (discussing written
`
`description and enablement only in terms of mRNA).
`
`-11-
`
`

`

`
`
`Patent Owner understands the Board’s desire “to balance the equities
`
`between the parties, i.e., Petitioner’s desire to be heard against Patent Owner’s
`
`interest in avoiding harassment through repeated challenges.” Hamilton Beach
`
`Brands, Inc. v. F’Real Food, LLC, IPR2017-00765, Paper 9, 5. Here, Petitioner
`
`has already been heard. If Petitioner had a genuine dispute over the ’069 patent, it
`
`would have filed this petition over a year ago at the same time as the ’739 IPR.
`
`Petitioner is abusing the IPR process for harassment and dramatically increasing
`
`costs for Patent Owner to defend its intellectual property. This is the not the
`
`appropriate function of a petition for inter partes review. See H.R. Rep. No. 112-
`
`98, pt.1, at 48 (2011) (explaining that inter partes reviews “are not to be used as
`
`tools for harassment or a means to prevent market entry through repeated litigation
`
`and administrative attacks on the validity of a patent.”); see also 35 U.S.C.
`
`§316(a)(6) (permitting “sanctions for … abuse of process, or any other improper
`
`use of the proceeding, such as to harass or to cause unnecessary delay or an
`
`unnecessary increase in the cost of the proceedings.”).
`
`The General Plastic factors and Petitioner’s conduct all weigh in favor of
`
`denial. The Board should not let Petitioner, for which Article III standing has not
`
`been established, engage in abuse of process and improper gamesmanship by
`
`retrying challenges. The Board should exercise its discretion to deny institution.
`
`-12-
`
`

`

`
`
`III. OVERVIEW OF THE ʼ069 PATENT AND THE PRIOR ART
`
`The ’069 patent is directed to the surprising discovery that nucleic acid-lipid
`
`particle formulations with high levels of cationic lipids and low levels of
`
`conjugated lipids exhibit favorable in vivo transfection efficiencies as well as
`
`“improved tolerability of the formulations in vivo, resulting in a significant
`
`increase in the therapeutic index [a measure of dosage relative to toxic effect] as
`
`compared to nucleic acid-lipid particle compositions previously described.”
`
`EX1001, 5:55-6:2; see also id., 11:26-32 (defining the inventive formulations as
`
`“extremely useful for systemic applications”). Reflecting this discovery, the ’069
`
`patent claims nucleic acid-lipid particle formulations with high levels of cationic
`
`lipids (50–65 mol %) and low levels of conjugated lipids (0.5–2 mol %)—as well
`
`as specific levels of cholesterol/derivative (30-40 mol %) and phospholipid (4-10
`
`mol %).
`
`-13-
`
`

`

`
`
`Prior art instructed precisely the opposite of what is disclosed and claimed in
`
`the ’069 patent. Largely ignored by the Petition,1 prior art at the time of invention
`
`(including all references cited by Petitioner) instructed that formulations with a
`
`high level of cationic lipid were toxic and poorly tolerated in vivo and had little to
`
`no in vivo transfection efficiency. E.g., EX1003, ¶6. Moreover, the prior art
`
`instructs that the level of cationic lipid should be minimized, as high levels were
`
`deemed unsuitable for in vivo transfection. EX1007, 745. Additionally, where
`
`conjugated lipids were utilized, the art instructed much higher levels as compared
`
`to those claimed. EX1009, E97.
`
`Yet, contrary to these expectations, the claimed formulations uniformly
`
`withstood rigorous in vivo tests that established stability following systemic (in
`
`vivo) administration, suitability for mammals with no considerable toxicity, and
`
`transfection efficiencies that were superior to conventional formulations.
`
`
`1 In view of the overwhelming evidence of the toxicity of cationic lipids, Petitioner
`
`argued in reply in the ʼ739 IPR that certain cationic lipids were known to be
`
`nontoxic. As pointed out by Patent Owner, that false narrative is expressly
`
`contradicted by, inter alia, Petitioner’s own publications. EX2007, 27-29.
`
`Petitioner declined to address this issue in the instant challenges.
`
`-14-
`
`

`

`
`
`IV. CLAIM CONSTRUCTION
`
`Petitioner does not conduct any claim construction analysis. Pet. 23.2
`
`Instead, Petitioner adopts the Board’s preliminary interpretation of the term
`
`“nucleic acid-lipid particle” from the institution decision in the ʼ739 IPR. There,
`
`the Board rejected Petitioner’s proffered construction and postulated that “nucleic
`
`acid-lipid particle” means “a particle that comprises a nucleic acid and lipids, in
`
`which the nucleic acid may be encapsulated in the lipid portion of the particle.”
`
`ʼ739 IPR, Paper 15, 10-11. However, as explained in the Patent Owner’s response
`
`of the ’739 IPR, the Board’s interpretation is overly broad. ʼ739 IPR, Paper 24,
`
`11-13; see also EX2007, 3-7.
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`First, Petitioner is flatly wrong that “this construction is based upon express
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`disclosures in the specification.” Pet. 23. The portion of the ’069 patent
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`describing that “the active agent or therapeutic agent may be encapsulated in the
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`lipid” is directed to the term “lipid particle” and not “nucleic acid-lipid particle” as
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`2 Each of the petition challenges are additionally flawed for being based on an
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`improper, if not indeterminable, proffered level of skill. Indicative of
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`impermissible hindsight, the petition equates the level of skill of the artisan with
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`the level of skill of the artisans of the ʼ069 patent. Pet. 6; EX1008, ¶31; EX2001,
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`44:8-12 (framing level of ordinary skill in the context of one with knowledge of
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`the challenged patent); see also ʼ739 IPR, Paper 28, 9-11.
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`-15-
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`recited in the claims. EX1001, 11:4-12 (emphasis added). In contrast, a “nucleic
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`acid-lipid particle” necessarily includes a nucleic acid encapsulated in the lipid
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`portion of the particle, thereby protecting it from enzymatic degradation. EX1001,
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`11:41-44; EX2007, 3-7.
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`Next, prosecution history confirms that the preliminary proffered
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`construction here is unduly broad. E.g. Phillips v. AWH Corp., 415 F.3d 1303,
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`1317 (Fed. Cir. 2015). During prosecution of Application No. 12/424,367, the
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`underlying application of the ’069 patent, applicants explained that the claimed
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`“SNALP formulations advantageously impart increased activity of the
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`encapsulated nucleic acid (e.g., an interfering RNA such as siRNA) and improved
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`tolerability of the formulations in vivo.” EX1016, 38 (emphasis in original). A
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`“nucleic acid-lipid particle” includes the encapsulated nucleic acid.
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`Lastly, Petitioner’s proposed construction should also be rejected because
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`testimony from Petitioner’s own expert, Dr. Janoff, confirms that the proposed
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`construction is too broad. Dr. Janoff testified multiple times that the lipid particles
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`as claimed are defined as SNALPs. E.g., EX2001, 118:19-119:4, 119:9-17, 120:5-
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`6, 121:14-25 (“we’re talking about lipid particles of the invention, and it’s pretty
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`clear we’re talking about SNALPs”). Dr. Janoff cited to a provision of U.S. Patent
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`No. 9,404,127 (“the ’127 patent”), EX2013, 5:15-22 that is identically recited in
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`the ’069 patent. Compare EX2013, 5:15-22 with EX1001, 19:9-17. Dr. Janoff’s
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`testimony during his deposition was consistent with the specification and the
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`prosecution history—the claimed nucleic acid-lipid particle necessarily includes a
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`nucleic acid encapsulated in the lipid portion of the particle
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`Regardless of whether the Board construes “nucleic acid-lipid particle” as a
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`SNALP as indicated by Petitioner’s expert; as a lipid particle with an encapsulated
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`nucleic acid; or under the broad construction advanced by the Petitioner, the
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`petition fails to show that there is a reasonable likelihood that the Petitioner would
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`prevail on any of the grounds of challenge.
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`V. GROUNDS 1-3: PRIOR ART DOES NOT DISCLOSE THE CLAIMED
`PHOSPHOLIPID RANGE.
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`The asserted grounds of invalidity cover both anticipation and obviousness
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`theories, without much distinction between the two. Pet. 5. Regardless of which
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`theory is applied, it is axiomatic that each and every limitation must be addressed.
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`E.g. Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628, 631 (Fed. Cir.
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`1987) (“A claim is anticipated only if each and every element as set forth in the
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`claim is found”); CFMT, Inc. v. Yieldup Intern. Corp., 349 F.3d 1333, 1342 (Fed.
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`Cir. 2003) (“[O]bviousness requires a suggestion of all limitations in a claim.”)
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`(quoting In re Royka, 490 F.2d 981, 985 (C.C.P.A. 1974)).
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`Independent claim 1 recites four components at different concentrations,
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`including phospholipid “from 4 mol % to 10 mol % of the total lipid.” While the
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`petition challenges are constructed on an assertion of “explicit disclosure” of
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`overlapping lipid ranges being disclosed in the cited art, the petition fails to
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`substantiate this charge. The petition fails to show that prior art disclosed
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`phospholipid ranges that overlap with those recited in independent claim 1.
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`Petitioner attempts to address this limitation at two points in the petition. Pet. 38-
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`39 (Ground 1), 57-58 (Ground 3).3 In both incidences, Petitioner fails.
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`A. Grounds 1 & 2 – The ’196 PCT and the ’189 Publication do not
`teach the recited phospholipid concentration range.
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`For Ground 1, the petition (39) alleges “explicit disclosure of encompassing
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`ranges” for the phospholipid concentration range recited in the challenged claims.
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`But neither the ’196 PCT nor the ’189 publication discusses concentration ranges
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`for phospholipids. See Pet. 38-39 (failing to identify any teaching in the asserted
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`prior art regarding phospholipid concentrations). Petitioner instead pivots to the
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`’618 patent—an entirely different document—and cites an embodiment with 14%
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`phospholipid. Id., 38. The relevance of this embodiment is not explained. The
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`14% phospholipid concentration is not within the “4 mol % to 10 mol %” range
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`recited in independent claim 1, and is therefore not anticipatory. See Ineos USA
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`LLC v. Berry Plastics Corp., 783 F.3d