Paper No. ___
`Filed: December 21, 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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`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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`PATENT OWNER’S RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
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`TABLE OF CONTENTS
`I.STATEMENT OF PRECISE RELIEF REQUESTED ........................................... 1 
`II.INTRODUCTION .................................................................................................. 1 
`III.DR. JANOFF’S DECLARATION IS ENTITLED NO WEIGHT ....................... 4 
`IV.STATE OF THE ART .......................................................................................... 8 
`V.PERSON OF ORDINARY SKILL IN THE ART ................................................. 9 
`VI.CLAIM CONSTRUCTION ................................................................................ 11 
`VII.RESPONSE TO GROUND 1............................................................................ 14 
`A. 
`The petition fails to address the claims as a whole ............................. 14 
`B. 
`The prior art does not teach each and every claim element ................ 15 
`1. The petition fails to identify a range for conjugated lipid ............... 15 
`2. The petition’s reliance on broad ranges and non-grounds
`references is misplaced .................................................................... 17 
`The petition fails to articulate a reason to combine the prior art
`disclosures ........................................................................................... 18 
`The petition fails to show any reasonable expectation of success ...... 20 
`The petition mischaracterizes and fails to address the full scope
`of unexpected results ........................................................................... 21 
`The petition fails to address prior art teachings contrary to the
`proffered obviousness theory .............................................................. 28 
`G.  Dependent Claims 2-20 ....................................................................... 29 
`1. Claim 5 ............................................................................................. 30 
`2. Claim 6 ............................................................................................. 31 
`3. Claim 7 ............................................................................................. 31 
`4. Claim 8 ............................................................................................. 31 
`5. Claim 13 ........................................................................................... 32 
`6. Claim 14 ........................................................................................... 32 
`7. Claims 16-20 .................................................................................... 32 
`VIII.RESPONSE TO GROUND 2 .......................................................................... 33 
`A. 
`The petition fails to assess the full scope and content of Lin and
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`C. 
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`D. 
`E. 
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`F. 
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`i
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`C. 
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`B. 
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`Ahmad ................................................................................................. 33 
`The petition fails to demonstrate motivation to combine ................... 36 
`B. 
`The petition fails to show any reasonable expectation of success ...... 37 
`C. 
`IX.RESPONSE TO GROUND 3 ............................................................................. 39 
`A. 
`The prior art does not disclose each and every element of the
`challenged claims ................................................................................ 39 
`1. L054 is not a nucleic acid-lipid particle .......................................... 39 
`2. The prior art ranges are not sufficiently specific ............................. 44 
`The challenged claims are not obvious over the ’554 publication
` ............................................................................................................. 46 
`Dependent Claims 2-20 ....................................................................... 48 
`1. Claim 5 ............................................................................................. 48 
`2. Claim 6 ............................................................................................. 49 
`3. Claim 7 ............................................................................................. 49 
`4. Claim 8 ............................................................................................. 49 
`5. Claim 11 ........................................................................................... 50 
`6. Claim 13 ........................................................................................... 51 
`7. Claims 14, 16-20 .............................................................................. 52 
`X.OBJECTIVE INDICIA OF NONOBVIOUSNESS ............................................ 53 
`A. 
`Long-felt need ..................................................................................... 55 
`B. 
`Failure of Others .................................................................................. 57 
`C. 
`Skepticism ........................................................................................... 58 
`D.  Unexpected Results ............................................................................. 59 
`E. 
`Commercial Success............................................................................ 61 
`XI.THE PETITION DOES NOT COMPORT WITH STATUTORY
`REQUIREMENTS ........................................................................................ 62 
`XII.CONCLUSION ................................................................................................. 63 
`XIII.APPENDIX ...................................................................................................... 65 
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`ii
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`I. STATEMENT OF PRECISE RELIEF REQUESTED
`Moderna Therapeutics, Inc. (“Petitioner”) filed a petition for inter partes
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`review of claims 1-20 of U.S. Patent No. 9,364,435 (the “’435 patent,” EX1001).
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`The Board issued its decision instituting trial (Paper 15) on all grounds set forth in
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`the petition. Protiva Biotherapeutics, Inc. (“Patent Owner”) hereby requests that the
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`Board now issue a final written decision confirming that claims 1-20 are not
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`unpatentable.
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`II. INTRODUCTION
`The nucleic acid-lipid particles claimed by the ’435 patent have achieved
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`tremendous recognition in the field of genetic therapy. The ’435 patent is now listed
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`in FDA’s Orange Book as protecting the patisiran—tradename “Onpattro”—
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`commercial product. EX2027. Patisiran received regulatory approval in the U.S. and
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`Europe and has been designated by the FDA as a “first-in-class” drug. EX2024.
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`The therapeutic potential of genetic therapy has been appreciated for over 25
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`years, but effectively delivering nucleic acids to target cells without eliciting
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`vehicle-related toxicity has prevented realization of this potential. See e.g., EX2011
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`at 38, 42; EX2014 at 11. By 2008, the industry-wide failure to identify a solution to
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`the delivery problem resulted in waning confidence. EX2015 at 2, 10. Dr. Phillip
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`Sharp, Nobel Laureate and co-founder of Alnylam Pharmaceuticals, was asked
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`about the challenges that lie ahead for RNAi drugs he answered “Delivery, delivery,
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`1
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`delivery.” EX2014 at 11; see also EX2016, Title of Article (“Merck’s Alan Sachs,
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`on RNAi’s Big Challenge: Delivery, Delivery, Delivery”); EX2011 at 42
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`(“Delivery, delivery, delivery.”).
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`The nucleic acid-lipid particle formulations of the ’435 patent solved a
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`long-felt need for compositions that could safely and effectively deliver nucleic
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`acids to target cells of patients. Skilled artisans were skeptical that compositions
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`having high levels of cationic lipid (i.e., 50 mol % to 85 mol %) and low levels of
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`conjugated lipid (i.e., 0.5 mol % to 2 mol %) would be effective, let alone
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`well-tolerated when administered in vivo. The combination of effectiveness and low
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`toxicity that characterizes the claimed compositions surprised many in the field, and
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`finally solved the delivery problem that hindered the field for decades.
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`Given the innovation protected by the ’435 patent, the petition is a poorly
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`conceived challenge. It seeks troubling shortcuts rather than providing any bona fide
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`obviousness analysis addressing motivation to combine and reasonable expectation
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`of success in view of the state of the art at the time. In numerous instances, the
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`petition fails to coherently identify the specific invalidity theories on which its
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`challenge is based.
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`The obviousness challenges of Grounds 1 and 3 argue for a prima facie case
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`of obviousness on a per-limitation basis for what it contends are overlapping ranges
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`of individual claim elements. Petitioner then rests on its putative “prima facie” case
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`2
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`as though that alone meets its ultimate burden of proof. But Petitioner fails to
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`address the claimed subject matter as a whole (i.e., the claimed particle formulation),
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`as mandated by statute, instead repeatedly arguing only that each “limitation is
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`prima facie obvious.” Analysis of whether there would have been a motivation to
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`combine or any reasonable expectation of success is wholly absent from the petition.
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`Moreover, the petition provides no meaningful analysis of the full scope of
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`experimental data presented in the ’435 patent itself. Instead, Petitioner
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`incompletely addresses a subset, never explains what would be
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`expected/unexpected, and operates on the erroneous assumption that comprehensive
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`superiority relative to the prior art is necessary. Patent Owner’s expert, Dr. David
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`Thompson, explains that the experimental results reported in the ’435 patent (as well
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`as numerous post-filing publications) demonstrate that the claimed formulations are
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`surprisingly well-tolerated and efficacious at far lower dosages than prior art
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`compositions.
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`Ground 3 does not work any better as an anticipation argument. While the
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`challenged claims are directed to a nucleic acid-lipid particle, the petition relies on
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`disclosure in the reference of a lipid mixture used to make particles. As confirmed
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`by Petitioner’s own expert, the petition has wrongly assumed that the lipid mixture
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`in a starting solution would have the same molar ratio of components as the resulting
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`3
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`particle. See e.g., 2028, 155:2-25; 156:1-158:16; see also EX2012 at 7242; EX2013
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`at 3.
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`Ground 2 is an undeveloped attempt to backfill Ground 1. The petition
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`incompletely addresses the challenged claims (addressing only claim element “1(b)”
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`and claim 4), ignores the claimed subject matter as a whole, and lacks explanation as
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`to whether there would be any reasonable expectation of success. The later point is
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`particularly pertinent in this instance, as Petitioner cites to the references of “Lin
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`and/or Ahmad”—both of which are addressing “lipoplex” formulations, a
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`fundamentally different type of lipid delivery system. Petitioner’s own expert has
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`characterized lipoplexes as fundamentally distinct, both during cross-examination
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`and in his previous publications. EX2028, 122:18-24; EX2007, 2:27-40.
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`For these reasons, and those explained in further detail herein, the petition
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`challenges should be rejected.
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`III.
`DR. JANOFF’S DECLARATION IS ENTITLED NO WEIGHT
`The Declaration of Dr. Janoff submitted with the petition (EX1007) should be
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`accorded no weight for at least the reasons set forth below.
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`First, Dr. Janoff’s declaration merely adopts the attorney arguments set forth
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`in the petition and should be weighted accordingly. The direct testimony itself
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`characterizes the declaration as such, where Dr. Janoff repeatedly states his opinions
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`“are based on the petition.” EX1007, ¶27 (“My opinion[s] expressed in this
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`4
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`declaration are based on the Petition ....”), ¶¶5-7. During cross-examination, Dr.
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`Janoff confirmed that his direct testimony was based on the petition. EX2028,
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`93:10-11 (“There is a petition. I based my opinions on the petition”), 91:18-92:20,
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`92:21-93:11, 26:12-27:5.1
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`Attorney argument is not elevated to testimonial evidence simply by virtue of
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`being parroted by a witness. E.g. InfoBionic, Inc. v. Braemar Manufacturing, LLC,
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`IPR2015-01704, Paper 11; Elbit Sys. of Am., LLC v. Thales Visionix, Inc., 881 F.3d
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`1354, 1359 (Fed. Cir. 2018)(“‘Attorney argument is not evidence’”)(quoting Icon
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`Health & Fitness, Inc. v. Strava, Inc., 849F.3d 1034, 1043 (Fed. Cir. 2017)); Estee
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`Lauder Inc. v. L’Oreal, S.A., 129 F.3d 588, 595 (Fed. Cir. 1997).
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`Second, conduct by both the witness and counsel during cross-examination of
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`Dr. Janoff should give the Board considerable pause in crediting any direct
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`testimony of the witness. Petitioner’s counsel, for instance, interjected to accuse the
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`questioning lawyer of misstating the witness’ testimony over 20 times. E.g.,
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`EX2028, 32:11-2, 35:1-2, 43:13-14, 49:11-12, 119:5-17, 148:18-149:5, 170:11-12.
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`Petitioner’s counsel repeatedly interrupted questioning by instructing the witness to
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`review certain documents prior to answering the question pending. E.g., id., 42:7-17,
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`1 Dr. Janoff demonstrated a general unfamiliarity with the petition materials
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`throughout the deposition. E.g. EX2028, 31:9-32:25 (unable to recall using the term
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`“lipid particle”); 90:3-91:8 (seemingly unable to recognize the petition).
`5
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`50:23-51:1, 101:4-15, 151:8-9. Improper witness coaching was discussed multiple
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`times. E.g., id., 41:9-42:17, 48:13-25, 101:15, 138:20-139:25. Questions were
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`objected to as allegedly “vague” more than 40 times. E.g., id., 28:5, 32:11, 35:9,
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`36:22, 45:19, 57:1, 58:4, 76:15, 85:11, 104:17, 126:22-23, 138:12-18, 146:6-18,
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`157:18-19; Trial Practice Guide, 77 Fed. Reg. 78755, 48772 (Aug. 14, 2012)
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`(identifying “Objection, vague” as an improper objection).
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`Such conduct was disruptive and prejudicial as it often prompted recalcitrance
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`from the witness and, in some instances, refusal to answer straightforward questions
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`about terms or statements in Dr. Janoff’s own documents. For example, taking cue
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`from the defending lawyer, Dr. Janoff repeatedly protested about questions being
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`“vague” or lacking context. EX2028, 35:7-19, 45:5-22, 29:19-30:11 (“it’s a vague,
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`vague, vague question.”), 56:21-57:25, 62:17-65:17 (refusing to answer questions
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`about experience working with liposomes at “The Liposome Company, Inc.” as too
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`vague to understand).
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`Dr. Janoff refused to clarify terms and statements made in his declaration. Id.,
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`33:6-14 (“lipid particle” is too vague to understand without context); cf.
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`EX1007¶¶32, 75; EX2028, 34:7-35:25 (“therapeutic payload” is too vague),
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`36:1-37:5; cf. EX1007, ¶32; EX2028, 86:6-87:1 (when asked “what a PEG is, the
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`abbreviation P-E-G,” testifying that “a peg is something that I could hammer into a
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`piece of wood.”).
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`6
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`Dr. Janoff refused to answer simple questions regarding statements in his own
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`patent (U.S. Patent No. 7,491,409 – “the ’409 patent,” EX2007). E.g., EX2028,
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`138:12-139-23 (refusing to answer whether he is familiar with the concept of nucleic
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`acids being encapsulated in a liposome); cf. EX2007, 3:1-2 (“the concept of
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`encapsulating bioactive agents in liposomes is not new”); EX2028, 136:5-138:11;
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`145:15-147:17; see generally id., 133:9-151:20.
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`The impropriety of the conduct was not lost on the witness. EX2028, 36:24-25
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`(“I’m not trying to be rebarbative here.”), 57:11-13, 123:19-20, 144:19-20,
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`143:23-145:5 (testifying that questions demonstrate “ignorance” on the part of
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`Patent Owner’s lawyer).
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`Such conduct is particularly prejudicial in the context of the present
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`proceeding, as Patent Owner has repeatedly raised issues as to the lack of clarity in
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`the petition materials. E.g., POPR at 5, 9-10, 24, 26; EX2008, 7:9-9:8. Accordingly,
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`giving no weight to Dr. Janoff’s direct testimony is appropriate under the present
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`circumstances where the petitioner and the witness have frustrated the discovery
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`process and declined to provide clarity when asked. Furthermore, given the
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`extraordinary actions to frustrate the discovery process and preclude a fair
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`examination of the witness in the present case, any disputed issue of material fact
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`should be resolved in favor of Patent Owner. See e.g., 37 C.F.R. §42.12(a)(5) and
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`(b)(1); Office Trial Practice Guide at 48772; California Institute of Technology v.
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`7
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`Enzo Life Sciences, Inc., Patent Interference No. 105,496, Paper 117, 5-6 (March 30,
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`2010) (giving no weight to the expert’s direct testimony and resolving issues of fact
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`in favor of the non-offending party an appropriate remedy for violating
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`cross-examination guidelines).
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`IV.
`STATE OF THE ART
`An objective of genetic therapy was the development of drugs — that is,
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`nucleic acids — to treat systemic diseases such as cancer, inflammation, virus
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`infection, and cardiovascular disease. Delivery of nucleic acids has been particularly
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`challenging because they are large, negatively charged molecules that cannot simply
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`be given to a patient systemically (e.g., intravenously) and allowed to passively enter
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`cells, as would be the case with many small molecule drugs. Therapeutic nucleic
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`acids require an effective delivery vehicle, which has proved to present considerable
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`technical obstacles. See, e.g., EX2014 (“The major hurdle right now is delivery,
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`delivery, delivery,” said Sharp in 2003); EX2014 at 11 (stating in 2003, “Khvorova
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`believes that the medical benefits of RNAi will be huge if the delivery issues can be
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`resolved.”); see also EX2009 ¶25.
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`The first generation of nucleic acid delivery systems that were developed
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`included cationic liposome nucleic acid complexes (also known as liposomes). See
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`EX1002 ¶8; EX2007, 2:27-40, 2:57-67. Lipoplexes were found to be unsuitable for
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`many applications, particularly systemic uses, due in large part to the toxic nature of
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`the cationic lipids. See, e.g., EX1008 at 5; see also EX2009 ¶26.
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`The toxicity of cationic lipids occurs at the cellular and organ levels, as these
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`lipids are often not readily biodegradable and accumulate to cytotoxic
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`concentrations in the liver and spleen. Cationic lipids also have immunostimulatory
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`capacity and are associated with immunogenic and inflammatory responses. The
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`obstacles to using cationic lipids as a nucleic acid delivery vehicle posed by, e.g.,
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`toxicity, immunogenicity, and aggregation, were well known prior to 2008. As one
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`industry executive stated, “I wouldn’t want anyone injecting cationic lipids into my
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`bloodstream.” EX1004 ¶136; EX1006 at 7; EX1008 at 5-6, 9; EX2011 at 42; see
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`also EX2009 ¶¶28-35.
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`V. PERSON OF ORDINARY SKILL IN THE ART
` It is well-settled that an “invention must be evaluated not through the eyes of
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`the inventor, who may have been of exceptional skill, but as by one of ‘ordinary
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`skill.’” Interconnect Planning Corp. v. Feil, 774 F.2d 1132, 1138 (Fed. Cir. 1985).
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`The level of skill of the ordinary artisan upon which the petition materials are
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`based is incorrect for a number of reasons. First, the petition equates the level of skill
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`of the ordinary artisan with the level of skill of the inventors of the ʼ435 patent. This
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`is indicative of impermissible hindsight. EX1007, ¶31; EX2028, 44:9-12 (putting
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`level of ordinary skill as that of the inventors of the patent). Thus, the petition has
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`9
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`improperly assumed a much higher level of skill than that of a person of ordinary
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`skill in the art (“POSITA”). See also EX2009, ¶¶22-24.
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`Second, Petitioner’s definition of a POSITA is ultimately indeterminable. The
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`petition defines a POSITA as someone that “would have specific experience with
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`lipid particle formation and use in the context of delivering therapeutic payloads.”
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`Pet. 5-6; EX1007, ¶31. During cross-examination, Dr. Janoff was unable (or
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`unwilling) to clarify what this means, repeatedly indicating that Petitioner’s own
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`definition is “too vague” to understand. EX2028, 33:6-11, 34:7-35:25, 38:20-39:9;
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`see also id., 36:1-37:5; see generally EX2028, 27:6-43:8.
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`Petitioner’s definition of a POSITA, at a minimum, taints the obviousness
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`arguments in the petition as using an incorrect and erroneous perspective.
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`Obviousness must be assessed from the perspective of “a person having ordinary
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`skill in the art” at the time the invention was made. 35 U.S.C. §103(a) (2012); see
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`generally Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966). Because the petition
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`sets the level much higher, to that of the inventors, Petitioner has failed to conduct an
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`appropriate analysis. It is axiomatic that Petitioner has not met its burden of
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`demonstrating obviousness where the threshold question of how a person of skill is
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`defined—a fundamental factual basis for any corresponding analysis—is, by its
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`expert’s own admission, indeterminable. Id. at 17; see also EX2009 ¶¶23-24.
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`VI. CLAIM CONSTRUCTION
`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 (“BRI”). See 37 C.F.R. § 42.100(b). However, the Board may not construe a
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`term “so broadly that its constructions are unreasonable under general claim
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`construction principles.” Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298
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`(Fed. Cir. 2015).
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`The petition was based on an overbroad construction of “nucleic acid-lipid
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`particle.” Pet. 24. The Board rejected Petitioner’s construction and offered one of its
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`own — that is, “nucleic acid-lipid particle” is “a particle that comprises a nucleic
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`acid and lipids, in which the nucleic acid may be encapsulated in the lipid portion of
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`the particle.” Paper 15 at 10-11 (citing EX1001, 11:14–22). According to Dr.
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`Thompson, both of these constructions are unreasonably broad, at least to the extent
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`they encompass lipid particles lacking any encapsulated nucleic acid. See also
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`EX2009 ¶¶39-40.
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`A “nucleic acid-lipid particle” expressly includes a nucleic acid. According to
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`the ʼ435 patent, “nucleic acids, when present in the lipid particles of the present
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`invention, are resistant in aqueous solution to degradation with a nuclease.”
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`EX1001, 11:51-54. The ’435 patent describes nucleic acid encapsulation in the lipid
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`particle as conferring resistance to such enzymatic degradation. EX1001, 11:20-22;
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`11
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`see also EX2007, 4:15-19; 22:40-47; 23:1-3; 23:27-29; 26:35-37. A “lipid particle”
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`“may [include a nucleic acid] encapsulated in the lipid portion of the particle,
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`thereby protecting it from enzymatic degradation.” EX1001, 11:14–22. A “nucleic
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`acid-lipid particle,” however, does include 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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`11:23-31, 11:51-54; see also EX2009 ¶39.
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`Petitioner’s expert testified multiple times that the lipid particles as claimed
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`are defined as SNALPs. See, e.g., EX2028, 118:18-119:4, 119:9-17, 120:5-6,
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`121:14-25. He cited to a provision of U.S. Patent No. 9,404,127 (“the ’127 patent,”
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`EX2029) at 5:15-22 that is identically recited in the ’435 patent. Compare EX2029,
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`5:15-22 with EX1001, 19:19-26. Indeed, the ’435 patent specification repeatedly
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`identifies SNALPs as the invention for delivering a nucleic acid payload. See e.g.,
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`EX1001, 3:9-13 (“The present invention provides novel, serum-stable lipid
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`particles ….”), 47:23-24 (“[T]he lipid particles of the invention are serum-stable
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`nucleic acid-lipid particles (SNALP)…”), 3:32-37, 14:20-25; see also EX2009
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`¶¶41-42.
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`According to Dr. Thompson, a fair and reasonable reading of the ’435 patent
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`specification supports Dr. Janoff’s position in that there is no meaningful distinction
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`between the ’435 patent specification’s descriptions of a “lipid particle” containing a
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`nucleic acid (i.e., a nucleic acid-lipid particle) and particle characteristics that confer
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`serum stability. Compare EX1001, 11:14-22, 11:51-54 with 13:32-37.
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`(“‘Serum-stable’ in relation to nucleic acid-lipid particles such as SNALP means
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`that the particle is not significantly degraded after exposure to a serum or nuclease
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`assay that would significantly degrade free DNA or RNA”); see also EX2009 ¶43.
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`It is Dr. Thompson’s opinion that a narrow focus on a linguistic difference
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`between a nucleic acid-lipid particle and the term “SNALP” is misguided and risks
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`overlooking pertinent disclosure and context provided in the ’435 patent. For
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`example, the ’435 patent specification states that “nucleic acids, when present in the
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`lipid particles of the invention, are resistant in aqueous solution to degradation with
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`a nuclease.” Id., 11:51-54 (emphasis added). Such physical properties of the
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`particles providing nuclease degradation resistance, or encapsulation of the nucleic
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`acid, are also as described in the ’435 patent specification as conferring the
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`identified serum stability. Id., 13:32-37. This is certainly true if the claimed particles
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`are SNALP, as supported not only by the specification of the ’435 but as affirmed by
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`petitioner’s expert. EX2009 ¶44.
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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 (thereby protecting it from enzymatic degradation); or under the broad
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`construction presented in the Institution Decision, the petition fails to establish the
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`unpatentability of claims 1-20. EX2009 ¶¶45-46.
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`VII.
`RESPONSE TO GROUND 1
`The claimed invention is a nucleic acid-lipid particle comprised of relatively
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`high levels of cationic lipids and low levels of conjugated lipids. This combination
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`was counter-intuitive to the then-existing state of the art, as cationic lipids were
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`known to be cytotoxic, systemically toxic, to elicit an adverse complement-mediated
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`immune response, and to cause particle aggregation that resulted in rapid clearance.
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`Conjugated lipids were used to shield the cationic lipids from interacting with
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`negatively charged serum proteins and thereby diminish the adverse effects. Thus,
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`when employing an increased amount of cationic lipid, a POSITA would have had
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`every reason to correspondingly increase the amount of conjugated lipid. EX2009,
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`¶¶25-35. The inventors of the ’435 patent did just the opposite.
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`A. The petition fails to address the claims as a whole
`The petition separately parses the claimed amounts of cationic lipids,
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`conjugated lipids, and non-cationic lipids from the references without regard to one
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`another. The petition even states that individual limitations are allegedly “prima
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`facie obvious.” See, e.g., Pet. 34 (“this limitation is prima facie obvious”), 39
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`(same), 40 (same). Missing from Ground 1 is a showing that the challenged claims
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`as a whole are obvious. In re Kahn, 441 F.3d 977, 986 (Fed. Cir. 2006) (“[M]ere
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`identification in the prior art of each element is insufficient to defeat the patentability
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`of the combined subject matter as a whole.”); In re NTP, Inc., 654 F.3d 1279, 1299
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`14
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`(Fed. Cir. 2011). Indeed, as the statute itself states: “if the differences between the
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`subject matter sought to be patented and the prior art are such that the subject matter
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`as a whole would have been obvious.” 35 U.S.C. § 103(a) (2012) (emphasis added);
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`see generally Graham, 383 U.S. at 17-18; TriVascular, Inc. v. Samuels, 812 F.3d
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`1056, 1066 (Fed. Cir. 2016).
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`The petition fails to address the fact that the concentrations of different lipid
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`components are highly interdependent. See EX2009, ¶¶57-59. At best, the petition
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`attempts to show that some prior art formulations had high concentrations of
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`cationic lipid. However, these also use a high concentration of conjugated lipid, or
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`are not nucleic acid-lipid particles. See also Section VII.C.,D..
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`B.
`The prior art does not teach each and every claim element
`The disclosure and ranges relied upon in the petition do not actually overlap
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`with what is claimed. Based on this, the petition fails to show that the prior art taught
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`each and every claim element, and for this reason alone, Ground 1 fails. E.g., In re
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`Royka, 490 F.2d 981, 983-85 (CCPA 1974); see also EX2009, ¶¶50-55.
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`1.
`The petition fails to identify a range for conjugated lipid
`Claim 1 recites in part, “a conjugated lipid that inhibits aggregation of
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`particles comprising from 0.5 mol % to 2 mol % of the total lipid present in the
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`particle.” The petition represents that the ’196 PCT teaches conjugated lipids at
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`concentrations of 0.5% to 25%. Pet. 39. Rather than identifying disclosure in the
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`15
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`’196 PCT disclosing a conjugated lipid range, the petition cites to a range provided
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`for “a bilayer stabilizing component.” Pet. 392; EX1007 ¶117; see also EX2009,
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`¶¶51-54.
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`The ’196 PCT makes clear that a “bilayer stabilizing component” is not the
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`same as a “conjugated lipid that inhibits aggregation of particles.” See EX1002 ¶92.
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`Bilayer stabilizing components include a broad class of structurally and chemically
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`diverse molecules. As Dr. Thompson explains, numerous bilayer stabilizing
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`components (e.g., polyamide oligomers, peptides, proteins, detergents, and
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`lipid-derivatives) would not be considered a conjugated lipid. EX2009, ¶¶52-53.
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`While the ’196 PCT lists a general range for the bilayer stabilizing component
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`category, according to Dr. Thompson, a POSITA would not have interpreted the
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`stated range (e.g., 0.5% to 25%) as being applicable to each listed bilayer stabilizing
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`component example. For example, a POSITA would have appreciated that if the
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`bilayer stabilizing component were a detergent, 25% would have been an
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`unreasonably high level. At this concentration of detergent, the lipids would be
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`solubilized and would no longer be in particle form. EX2009, ¶¶52-53.
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`2 The petition seemingly acknowledges the lack of disclosure by arriving at the
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`“teaching” in the ’196 PCT through splicing together isolated phrases from two
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`paragraphs. Compare Pet. 39 with EX1002 ¶¶92-93.
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`16
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`Moreover, while the ’196 PCT discloses exemplary compositions with
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`conjugated lipid, all have much higher levels of conjugated lipid than is claimed.
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`EX1002 ¶¶216, 223, 228, 232 (disclosing nucleic acid-lipid particle compositions
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`with 10 mol % conjugated lipid); see also EX2009, ¶¶54-55.
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`Accordingly, the petition fails to identify in ’196 PCT “a conjugated lipid that
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`inhibits aggregation of particles” as required by claim 1. EX2009, ¶55.
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`2.
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`The petition’s reliance on broad ranges and non-grounds
`references is misplaced
`Petitioner fails to demonstrate that the recited concentration of cationic lipid
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`is taught by the asserted prior art. Specifically, claim 1 recites, “a cationic lipid
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`comprising from 50 mol % to 85 mol % of the total lipid present in the particle.”
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`Petitioner cited the ’196 PCT’s disclosure of “about 2% to about 60%” and
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`“about 40% to about 50%” for the cationic lipid component. Pet. 33 (citing EX1002
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`¶88). The ’196 PCT, however, emphasizes that “for systemic delivery, the cationic
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`lipid may comprise from about 5% to about 15% of the total lipid.” EX1002, ¶88.
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`This range does not overlap with the recited range in claim 1, and was not addressed.
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`The petition also cites to the ’618 patent, a non-Grounds document, solely for
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`the contention that prior art taught formulations “containing over 50% cationic
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`lipid.” Id. This contention highlights the petition’s legally-deficient approach of
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`identifying individual components without regard to the claimed invention as a
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`whole. The ’618 patent does not disclose any compositions that include a conjugated
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`17
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`lipid. Id. According to Dr. Thompson, a POSITA would not find the cited
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`formulation of the ʼ618 instructive for the development of the claimed invention.
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`EX2009, ¶89.
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`C. The petition fails to articulate a reason to combine the prior art
`disclosures
`As explained by Dr. Thompson, there would have been no reason for a
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`POSITA to combine th