Paper No. ___
`Filed: December 21, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`MODERNA THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`PROTIVA BIOTHERAPEUTICS, INC.,
`Patent Owner.
`_____________________________
`
`Case IPR2018-00680
`Patent No. 9,404,127
`_____________________________
`PATENT OWNER’S RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
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`TABLE OF CONTENTS
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`I.INTRODUCTION ................................................................................................... 1
`II.DR. JANOFF’S DECLARATION IS ENTITLED NO WEIGHT ........................ 2
`III.BACKGROUND .................................................................................................. 7
`A.
`The ʼ069 Patent ..................................................................................... 8
`B.
`The ʼ031 Publication ............................................................................. 9
`IV.THE ʼ127 PATENT ............................................................................................ 10
`V.PERSON OF ORDINARY SKILL IN THE ART ............................................... 11
`VI.CLAIM CONSTRUCTION ................................................................................ 13
`VII.THE PETITION FAILS TO ESTABLISH THAT CLAIMS 1-22 ARE
`ANTICIPATED, OR RENDERED OBVIOUS, BY THE ʼ069
`PATENT ........................................................................................................ 14
`A.
`There is No Presumption of Inherency ............................................... 14
`B.
`A Specific “Formulation” and “Formation Process” Lacks
`Identification ....................................................................................... 16
`None of the Identified Formulations in the ’069 Patent Were
`Produced by “the same Direct Dilution Method” ............................... 20
`There is No Reason to Presume That the Particles Disclosed by
`the ʼ069 Patent Inherently Meet the Required Morphology
`Limitation ............................................................................................ 24
`The 2:30 Formulation Produced Lamellar Particles ........................... 31
`Petitioner’s alternate obviousness theory is improper under
`section 103(c) ...................................................................................... 33
`Petitioner’s Alternate Obviousness Theory Fails ................................ 36
`G.
`Dependent Claims 2-20 ....................................................................... 38
`H.
`VIII.GROUND 2 FAILS ......................................................................................... 44
`IX.GROUND 3 FAILS ............................................................................................ 45
`X.GROUND 4 FAILS ............................................................................................. 46
`XI.CONCLUSION ................................................................................................... 47
`XII.APPENDIX ....................................................................................................... 49
`
`E.
`F.
`
`C.
`
`D.
`
`i
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`I.
`
`INTRODUCTION
`Moderna Therapeutics, Inc. (“Petitioner” or “Moderna”) filed a petition for
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`inter partes review of claims 1-22 of U.S. Patent No. 9,404,127 (‘the ’127 patent,”
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`EX1001). The Board issued its decision instituting trial (“Decision,” Paper 13).
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`Protiva Biotherapeutics, Inc. (“Patent Owner”) hereby requests that the Board now
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`issue a final written decision rejecting Petitioner’s challenges and confirming the
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`patentability of claims 1-22.
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`The Board should reject Petitioner’s challenges of claims 1-22 of the ’127
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`patent because the Petition fails to demonstrate the unpatentability of the challenged
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`claims by a preponderance of the evidence. Specifically, each of the stated grounds
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`of challenge fails to meet the non-lamellar morphology limitation of the claim 1,
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`which requires at least about 95% of the particles in the plurality of particles have
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`a non-lamellar morphology.
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`Ground 1 critically relies on the assertion that certain lipid particles in the
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`cited art (U.S. Patent No. 8,058,069, “the ’069 patent”) were allegedly generated
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`using “the same Direct Dilution Method” as in the ’127 patent. A review of the ’069
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`patent reveals that none of the lipid formulations cited are described in the reference
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`as being generated by the “Direct Dilution Method.” The petition materials cite
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`generally to U.S. Publication No. 2007/0042031 (“the ʼ031 publication”) referenced
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`in the ʼ069 patent, but neither the petition nor Dr. Janoff’s declaration provides any
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`meaningful discussion of the ’031 publication, the content of that reference, process
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`parameters, or how it would be understood to a person of ordinary skill in the art
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`(“POSITA”).
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`As experts from both parties agree, specific details of the formation process
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`and corresponding parameters (or sets of parameters) are important in affecting the
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`physical properties of resulting particles (such as particle morphology). As
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`Dr. Janoff conceded during cross-examination, modifying the parameters of a given
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`direct dilution method (e.g., flow rate, mixing parameters, temperature) would be
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`expected to alter the physical properties of any resulting particles—defeating the
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`alleged case of inherency. EX2028, 163:8-165:23; 191:14-17.
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`Grounds 2-4 were addressed in detail previously, and the Board’s Institution
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`Decision identifies numerous reasons why these grounds are critically defective.
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`E.g. Decision, 22-26. The record has not changed in any way since the time of
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`institution to alter or otherwise cure the defects previously identified by Patent
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`Owner and the Board.
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`Accordingly, the challenges presented in the petition should be rejected, and
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`the challenged claims 1-22 of the ’127 patent be found not unpatentable.
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`II.
`
`DR. JANOFF’S DECLARATION IS ENTITLED NO WEIGHT
`As an initial matter, the Declaration of Dr. Janoff submitted with the petition
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`(EX1007) should be 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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`declaration are based on the Petition ....”); see also id., ¶5 (“Based on studying the
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`petition...”), ¶6(“Based on studying the petition...”), ¶7(“Based on studying the
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`petition...”). During cross-examination, Dr. Janoff confirmed that his direct
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`testimony was based on the petition. EX2028, 93:10-11 (“There is a petition. I
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`based my opinions on the petition”); see also id., 91:18-92:20 (confirming the
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`petition was completed prior to declaration testimony), 92:21-93:11 (confirming the
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`lawyers drafted the petition), 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 at 6 (“We do not find the testimony of Petitioner’s expert
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`to be persuasive or helpful as it repeats the Petitioner’s arguments and offers little or
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`no elaboration.”)(citing 37 C.F.R. § 42.65(a) (“Expert testimony that does not
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`disclose the underlying facts or data on which the opinion is based is entitled to little
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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).
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`or no weight.”)). It is well-established that attorney argument is not evidence. Elbit
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`Sys. of Am., LLC v. Thales Visionix, Inc., 881 F.3d 1354, 1359 (Fed. Cir.
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`2018)(“‘Attorney argument is not evidence’”)(quoting Icon Health & Fitness, Inc. v.
`
`Strava, Inc., 849F.3d 1034, 1043 (Fed. Cir. 2017)); Estee Lauder Inc. v. L’Oreal,
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`S.A., 129 F.3d 588, 595 (Fed. Cir. 1997) (noting that attorney argument cannot take
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`the place of evidence lacking in the record).
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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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`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 (testifying that the term “lipid particle” is too vague to understand without
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`context); cf. EX1007¶¶32, 75; EX2028, 34:7-35:25 (testifying that the term
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`“therapeutic payload” is too vague), 36:1-37:5 (testifying that mailing a Tylenol pill
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`in a greasy envelope qualifies as “lipid particle [] use in the context of delivering
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`therapeutic payloads”); cf. EX1007, ¶32; EX2028, 86:6-87:1 (when asked “what a
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`PEG is, the abbreviation P-E-G,” testifying that “a peg is something that I could
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`hammer into a piece of wood.”).
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`Dr. Janoff refused to answer simple questions regarding statements in his own
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`patent (EX2007, U.S. Patent No. 7,491,409 – “the ’409 patent”). See e.g., EX2028,
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`138:12-139-23 (refusing to answer whether he is familiar with the concept of nucleic
`
`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 (refusing to answer questions about statements in the ’409 patent);
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`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 (“I don’t mean to be
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`rebarbative”), 123:19-20 (“I don’t meant to be vituperative or rebarbative”),
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`144:19-20 (“I don’t mean to be pejorative”), 143:23-145:5 (testifying that questions
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`demonstrate “ignorance” on the part of 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. See e.g., POPR at 5, 9-10, 24, 26; EX2008, 7:9-9:8. Accordingly, giving
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`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 directly 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, 77 Fed. Reg. 78755, 48772 (Aug. 14, 2012);
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`California Institute of Technology v. Enzo Life Sciences, Inc., Patent Interference
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`No. 105,496, Paper 117, 5-6(March 30, 2010) (giving no weight to the expert’s
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`direct testimony and resolving issues of fact in favor of the non-offending party an
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`appropriate remedy for violating cross-examination guidelines).
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`III.
`BACKGROUND
`RNA interference (“RNAi”) provides a way to downregulate or silence the
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`transcription and translation of a gene of interest. EX1002, 1:41-43; EX2009, ¶22.
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`However, in order for RNAi to be therapeutically effective, there needed to be a safe
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`and effective delivery system for the nucleic acid. Id. 1:52-53; EX2009, ¶22.
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`Physical characteristics of delivery particles include properties such as
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`particle size, polydispersity, nucleic acid encapsulation, and lipid-to-drug ratio.
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`EX2009, ¶23. Particle morphology, such as lamellar or non-lamellar form, is also a
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`physical characteristic of a particle. Id.
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`As explained by Dr. Thompson and confirmed by Dr. Janoff during
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`cross-examination, a POSITA would expect that altering either the lipid
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`composition of a formulation, or the process used to form the particles in a delivery
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`system, would affect the physical characteristics of resulting particles. EX2009, ¶24;
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`EX2028, 191:2-192:6. There are a myriad of parameters that may be varied as to the
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`formulation composition, as well as a myriad of parameters that can be varied in the
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`process used to formulate the particles (e.g., fluid flow rate, mixing parameters,
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`temperature, etc.). EX2009, ¶24. EX2028, 191:6-192:2 (Dr. Janoff conceding
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`multiple times that one might not expect to make the claimed particles if process
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`parameters such as speed of mixing and temperature are modified). But precisely
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`how such parameters, or a set of such parameters, determined the physical properties
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`of resulting particles was, at the time of invention, generally not well-understood.
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`EX2009, ¶24.
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`Prior art compositions at the time of invention avoided non-lamellar particle
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`morphology due to stability concerns. Id., ¶25 Particle compositions instead relied
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`upon lamellar form particles due to their ability to better maintain structural integrity
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`and retention of nucleic acid payload. Id.; see also EX1004, 6:2-6, 33:38-46.
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`A. The ʼ069 Patent
`The ’069 patent is directed to nucleic acid-lipid particles (“SNALP”).
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`EX1002, 5:44-61. The ’069 patent describes multiple methods for production of the
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`lipid particles of the invention without specifying a preference for any particular
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`method. Id. 57:50-55. According to the ʼ069 patent:
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`The lipid particles of the present invention, e.g., SNALP, in which an
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`active agent or therapeutic agent such as an interfering RNA is
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`encapsulated in a lipid bilayer and is protected from degradation, can be
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`formed by any method known in the art including, but not limited to, a
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`continuous mixing method or a direct dilution process.
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`Id.; see also EX2009, ¶¶26-28.
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`During cross-examination, Dr. Janoff explained that there is no single direct
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`dilution method or continuous mixing method, but many different ways (involving
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`many different parameters) to perform either of those methods. EX2028, 164:9-15
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`(confirming there are many ways to perform a direct dilution method). Dr. Janoff
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`further explained that modifying parameters of a direct dilution method (e.g., flow
`
`rate, mixing parameters, temperature) would be expected to alter the physical
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`properties of any resulting particles. Id. 191:14-17 (“But certain if you modify
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`maybe the speed of the direct dilution or mixing or temperature, certainly when you
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`do that, you might expect to not make the [claimed] particles”).
`
`B.
`The ʼ031 Publication
`The ʼ069 patent references, inter alia, the ʼ031 publication.2 EX1002,
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`59:12-16. The ʼ031 publication describes methods and apparatus for making lipid
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`vesicles. EX1019, ¶38. FIG. 3A and FIG. 3B of the ʼ031 publication, for example,
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`diagram two different approaches for directly diluting lipid solution and nucleic acid
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`2 Although the petition notes that the ’069 patent references the ’031 publication,
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`the petition materials fail to provide a single citation to, or otherwise rely on, any
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`specific provision of the ’031 publication. During cross-examination, Dr. Janoff
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`appeared to have little, if any, familiarity with this reference. See e.g., EX2028,
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`181:4-24 (incorrectly speculating that one of the references illustrates a figure of a
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`“syringe press.”).
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`solution into a reservoir. Id. ¶17, FIGS. 3A-3B. Each of those processes can involve
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`multiple different process parameters and sets of parameters. See also EX2009,
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`¶¶29-30.
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`IV.
`THE ʼ127 PATENT
`The ʼ127 patent discloses that the invention “is based, in part, upon the
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`surprising discovery that by controlling the lipid composition of a SNALP
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`formulation as well as the formulation process used to prepare the SNALP
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`formulation, a novel non-lamellar lipid nanoparticle (i.e., SNALP) can be
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`produced.” EX1001, 2:64-3:1.
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`The ’127 patent claims a composition of nucleic acid-lipid particles having
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`non-lamellar morphology. Claim 1, the only independent claim, is reproduced
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`below:
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`1. A composition comprising:
`a plurality of nucleic acid-lipid particles, wherein each particle in the plurality
`of particles comprises:
`(a) a nucleic acid;
`(b) a cationic lipid;
`(c) a non-cationic lipid; and
`(d) a conjugated lipid that inhibits aggregation of particles,
`wherein at least about 95% of the particles in the plurality of particles have a
`non-lamellar morphology.
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`In the Institution Decision, the Board suggested that the claimed nucleic
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`acid-lipid particles can be formed using any method known in the art. Decision, 12
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`(citing EX1001, 92:15-21). As explained by Dr. Thompson, that is a misreading of
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`the ’127 patent specification. The data presented by the ʼ127 patent makes clear that
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`not every process results in a composition in which at least about 95% of the
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`particles have a non-lamellar morphology. EX2009, ¶35; see also EX1001, FIG. 7;
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`EX2009, ¶¶31-34.
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`V.
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`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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`(citing Stewart-Warner Corp. v. City of Pontiac, Michigan, 767 F.2d 1563, 1570
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`(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 improper for a number of reasons. EX2009, ¶¶17-21. First, the petition
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`equating the level of skill of the artisan with the level of skill of the artisans of the
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`ʼ127 patent is indicative of impermissible hindsight. Pet. 5; EX1007, ¶32; EX2028,
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`44:8-12 (putting level of ordinary skill in the art in the context “knowledge of the
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`ʼ127 patent”). The inventors of the ʼ127 patent, however, are artisans of exceptional
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`skill. EX2009, ¶¶19-20. Thus, the petition has improperly assumed a much higher
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`level of skill than that of a person having ordinary skill in the art.
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`Second, other than being equated with the inventors of the ’127 patent,
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`Petitioner’s definition of a person of ordinary skill is ultimately indeterminable. The
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`petition materials define a POSITA as someone that “would have specific
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`experience with lipid particle formation and use in the context of delivering
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`therapeutic payloads.” Pet. 5; EX1007, ¶32. During cross-examination, Dr. Janoff
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`was unable (or unwilling) to clarify what this means, repeatedly indicating that
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`Petitioner’s own definition is “too vague” to understand. E.g. EX2028, 33:6-14,
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`34:7-35:25, 36:1-37:5.
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`Petitioner’s definition of a person of ordinary skill, at a minimum, taints any
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`obviousness arguments in the petition as being based on an incorrect and erroneous
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`perspective. Obviousness must be assessed from the perspective of “a person having
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`ordinary skill in the art” at the time the invention was made. 35 U.S.C. §103(a)
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`(2012); see generally Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966).
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`Petitioner has failed to conduct such an analysis. And it is axiomatic that Petitioner
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`has not met its burden of demonstrating obviousness where the threshold question of
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`how a person of skill is defined—a fundamental factual basis for any corresponding
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`analysis—is indeterminable.
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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); Cuozzo Speed Techs., LLC v. Lee, 136
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`S. Ct. 2131, 2142-45 (2016). However, the Board may not construe a term “so
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`broadly that its constructions are unreasonable under general claim construction
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`principles.” Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir.
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`2015).
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`No claim terms need express construction in order to find that Petitioner has
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`failed to demonstrate the challenged claims as unpatentable. The constructions
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`proposed in the petition, however, should be rejected as being unreasonably broad in
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`view of the specification.
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`In the Institution Decision, the Board already agreed that Petitioner’s
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`construction of the term “nucleic acid-lipid particle” is inappropriate. Institution
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`Decision, 8; see also EX2009, ¶¶37-38. As explained by Dr. Thompson, and
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`confirmed by Dr. Janoff during cross-examination, the Board’s alternate
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`construction adopted in the Institution Decision is also unreasonably broad in view
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`of the specification. EX2009, ¶¶38-41; see EX2028, 119:5-22. As discussed herein,
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`the challenges in the petition can be rejected no matter what construction is applied
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`in this regard. EX2009, ¶42.
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`VII. THE PETITION FAILS TO ESTABLISH THAT CLAIMS 1-22 ARE
`ANTICIPATED, OR RENDERED OBVIOUS, BY THE ʼ069 PATENT
`The petition asserts that claims 1-22 of the ’127 patent were inherently
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`anticipated by or obvious in view of the ’069 patent, which is commonly owned by
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`Patent Owner. This ground, or grounds, of challenge fail for multiple reasons—as
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`explained in detail below. Petitioner, at a minimum, fails to show that “at least about
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`95% of the particles in the plurality of particles have non-lamellar morphology” as
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`claimed is inherently disclosed, or obvious, in view of the cited art.
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`A. There is No Presumption of Inherency
`As a threshold matter, the remaining challenge in the petition must be rejected
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`for being based on an unsubstantiated presumption of inherency. There is no
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`presumption of inherency in an inter partes review.
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`It is well-established that the petitioner, as moving party, bears the evidentiary
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`burden to establish inherency. 35 U.S.C. §316(e); Crown Operations Intern., Ltd. v.
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`Solutia Inc., 289 F.3d 1367, 1377-1378 (Fed. Cir. 2002) (explaining that the moving
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`party “bears an evidentiary burden to establish that the limitation was necessarily
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`present…. Instead, Crown offers only an assumption and its own contentions.”). As
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`the Board has previously explained, “[a]llowing Petitioner to rely solely on a
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`presumption of inherency would improperly shift the burden to Patent Owner to
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`establish that the claimed properties are not necessarily present in the prior art.”
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`Titex International, Ltd., v. Precision Fabrics Group, Inc. IPR2014-01248, Paper 39
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`at 10-12. In an inter partes review, the burden of proof is on the petitioner to prove
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`unpatentability by a preponderance of the evidence, and that burden never shifts to
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`the patent owner. Dynamic Drinkware, LLC v. National Graphics, Inc., 800 F.3d
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`1375, 1378 (Fed. Cir. 2015). Here, Petitioner’s attempt to shift the burden to Patent
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`Owner to prove no inherency based on mere assertions of similarity with the prior art
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`is improper.
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`Similar arguments were presented previously. Patent Owner’s Preliminary
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`Response (Paper 10, “POPR”), at 7, 9-11. The Board, however, instituted review on
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`the basis that “the analysis at the institution stage is ‘very different’ and ‘made under
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`a qualitatively different standard’ than the standard applicable in reaching the Final
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`Written Decision.” Decision, 13 (quoting Trivascular, Inc. v. Samuels, 812 F.3d
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`1056, 1068 (Fed. Cir. 2016)).
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`This proceeding, however, is no longer at institution stage, and the petition
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`fails to establish the inherent anticipation of the claims by a preponderance of the
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`evidence. Petitioner has not provided any evidence in this case demonstrating that
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`the particles of the ʼ069 patent inherently have the morphology required by the
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`challenged claims, that is, at least about 95% non-lamellar as claimed. In fact, Dr.
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`Janoff testified during cross-examination that he did not conduct any experimental
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`testing, nor was he aware of any experimental testing that had been performed.
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`EX2028, 94:15-95:20.
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`Petitioner cannot remedy the failings of the Petition at this late stage of the
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`proceeding. See Office Trial Practice Guide, 77 Fed. Reg. 78755, 48767 (Aug. 14,
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`2012) (noting that improper issues for a reply include new evidence to make out
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`prima facie case of unpatentability, or evidence that could have presented in a prior
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`filing). See also EX2008, 6:4-7:8.
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`Ground 1 in the petition should be rejected on this basis alone.
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`B. A Specific “Formulation” and “Formation Process” Lacks
`Identification
`Petitioner’s contends that the 95% non-lamellar morphology is a physical
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`property that is inherently possessed by certain compositions of the ’069 patent. E.g.
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`Pet. 25, 29, 31. As an initial matter, any aspect of the petition materials that fail to
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`identify which specific formulation made by a specific formation process are
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`believed to inherently possess the claimed morphology lack sufficient explanation
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`and should be given no weight. EX2009, ¶¶44-45, 70.Various provisions of the
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`petition materials speak in vague generalities and lack identification of a specific
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`formulation generated by a specific formation process. E.g., Pet. 25-28; see also
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`Decision, 14 (referencing “several formulations” but failing to identify any specific
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`formulation).
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`Specificity in this regard is critically important. As both experts agree, a
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`POSITA would expect that differences in lipid composition of a formulation to
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`affect the physical properties of resulting lipid particles. EX2009, ¶¶46-48; EX2028,
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`182:12-20 (Dr. Janoff testifying that the physical properties of particles is dependent
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`on the lipid composition and its ratios). Both Dr. Thompson and Dr. Janoff also
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`agree that different formulation process and parameters would affect the particle’s
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`physical properties. EX2009, ¶¶46, 51, 53; EX2028, 191:6-192:2 (Dr. Janoff
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`admitting that one would expect that modifying process parameters such as speed,
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`mixing, and temperature in a direct dilution process might not produce the claimed
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`composition). A POSITA would also understand that there are many parameters that
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`may be varied as to the formulation composition, as well as a myriad of parameters
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`that can be varied in the process used to formulate the particles. EX2009, ¶¶46, 51,
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`53; see also EX2028, 191:14-21 (explaining that speed of direct dilution, mixing,
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`and temperature are process parameters that may be varied).
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`In this regard, the petition’s broad reference to “2:30, 2:40, 1:57, and 1:62
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`formulations” is misleading and provides little information. EX2009, ¶¶46, 50, 54.
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`Such terminology only identifies classes of formulations, and not any specific
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`formulation. That is, the first number refers to the approximate molar percentage of
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`the conjugated lipid, and the second number refers to the approximate molar
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`percentage of the cationic lipid. Id., ¶47; EX2028, 152:10-14 (noting that “2:30”
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`references the mole percentages of conjugated lipid and cationic lipid”); EX1002,
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`3:36-56 (discussing 1:62 and 1:57 formulations).
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`Similarly, broadly referencing formation processes such as “continuous
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`mixing method” and “direct dilution process” does not identify any specific process,
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`but refers to classes of processes that may encompass innumerable process
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`parameters. EX2009, ¶51. During cross-examination, Dr. Janoff testified that
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`“continuous mixing may mean different things in different contexts to different
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`practitioners.” EX2028, 162:4-22. Dr. Janoff further conceded there is no such thing
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`as “the Direct Dilution Method.” Id. 164:11-12 (“[t]here are varieties of methods
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`that practitioners call direct dilution method”), 165:10-22 (explaining that if
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`someone claimed to have used “the Direct Dilution Method,” his response would be
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`“what direct dilution method?”).
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`The petition at times vaguely refers to a “direct dilution method,” but never
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`identify any specific direct dilution method with any specific parameters. E.g. Pet.
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`31. The petition materials also cite generally to the ʼ031 publication as being
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`referenced in the ʼ069 patent, but neither the petition nor Dr. Janoff’s declaration
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`provides a single citation to any specific content of the ’031 publication. The petition
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`fails to provide any meaningful discussion of the ’031 publication, the content of
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`that reference, process parameters, or how it would be understood by a POSITA.
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`As Dr. Thompson explains, the ʼ031 publication does not provide only a
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`single direct dilution process. EX2009, ¶52; see also EX2028, 181:4-14; EX1002,
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`58:57-59:1; EX1007, ¶86. Instead, the ʼ031 publication shows different examples of
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`apparatuses that may be used, separate processes and variety of different parameters.
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`E.g. EX1019, ¶38, FIGS. 3A-3B. As Dr. Janoff conceded, there is no “the Direct
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`Dilution Method, and modifying parameters of a direct dilution method (e.g., flow
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`rate, mixing parameters, temperature) would be expected to alter the physical
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`properties of any resulting particles. See e.g., EX2028, 165:18-22 (“what direct
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`dilution method?”); 191:14-17 (“But certain if you modify maybe the speed of the
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`direct dilution or mixing or temperature, certainly when you do that, you might
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`expect to not make the [claimed] particles”).
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`As such, broadly referring to “2:30, 2:40, 1:57, and 1:62 formulations” and “a
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`direct dilution method,” at best, only differentially identifies classes of formulations
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`and classes of formation processes. Such vague and general descriptions of
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`formulations and formation processes lacks sufficient specificity for a meaningful
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`assessment of what physical properties may or may not be observed in
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`corresponding particles. EX2009, ¶54.
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`As explained in further detail below, where the petition does identify specific
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`formulations, those formulations are not identified in the ’069 patent as having been
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`used together with “the Direct Di