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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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`AQUESTIVE THERAPEUTICS, INC.,
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`Petitioner,
`
`v.
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`NEURELIS, INC.,
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`Patent Owner.
`
`____________________
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`Case IPR2019-00451
`Patent 9,763,876
`____________________
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`PATENT OWNER’S SURREPLY
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`TABLE OF CONTENTS
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`I.
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`II.
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`Pages
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`Introduction ...................................................................................................... 1
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`Statement of Reasons to Deny .......................................................................... 2
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`A. Aquestive’s Untimely and New Arguments ........................................ 2
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`B.
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`C.
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`The ’558 Provisional Discloses Alkyl Glycosides ............................... 6
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`Aquestive Fails to Show Even Prima Facie Obviousness ................. 12
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`1.
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`2.
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`3.
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`4.
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`Claimed Solution Lacks Water—Even From Ethanol .............. 12
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`No Motivation to Combine Gwozdz with Meezan ................... 15
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`No Motivation to Combine Ethanol and Benzyl Alcohol
`with Tocopherol to Solubilize Benzodiazepines ....................... 16
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`Aquestive Fails to Rebut the Absence of Any Motivation
`to Combine or Reasonable Expectation of Success for the
`References ................................................................................. 17
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`5.
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`Cartt’874’s Particulate Formulations Not Relevant ................. 18
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`D.
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`Secondary Considerations Confirm Non-Obviousness...................... 19
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`1.
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`2.
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`Significant Unmet Need for Intranasal Benzodiazepine
`Formulation to Treat Epileptic Seizures ................................... 19
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`Dr. Wermeling’s Economic, Marketing and FDA
`Regulatory Opinions Lack Basis .............................................. 22
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`E.
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`Aquestive’s Expert Confirms Unexpected Results ............................ 24
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`III. Preservation of Termination Request .............................................................26
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`IV. Conclusion ......................................................................................................28
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`TABLE OF AUTHORITIES
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`Pages
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`CASES
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`Ariad Pharm., Inc. v. Eli Lilly, 598 F.3d 1336 (Fed. Cir. 2010) (en banc) .............11
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`Atlas IP v. Medtronic, Inc., 809 F.3d 599 (Fed. Cir. 2012) (en banc) .....................19
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`Dynamic Drinkware v. National Graphics, 800 F.3d 1375 (Fed. Cir.
`2015) ..................................................................................................................... 7
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`Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002) ..................12
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`Ex parte Maziere, 27 USPQ 1705 (BPAI 1993) ........................................................ 8
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`Falkner v. Inglis, 448 F.3d 1357, 1366 (Fed. Cir. 2006) .........................................11
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`Fujikawa v. Wattanasin, 93 F.3d 1559 (Fed. Cir. 1996) .................................. 11, 12
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`In re Voss, 557 F.2d 812 (CCPA 1977) ..................................................................... 7
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`In re Wertheim, 541 F.2d 257 (CCPA 1976) ...........................................................11
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`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359
`(Fed. Cir. 2016) .................................................................................................5, 6
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`Koninklijke Philips N.V. v. Google LLC, 948 F.3d 1330 (Fed. Cir. 2020) ................ 7
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`Motor Vehicle Mfrs. Ass’n v. State Farm, 463 U.S. 29 (1983) ................................. 8
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`Newell Co. v. Kenney Mfg., 864 F.2d 757 (Fed. Cir. 1988) ...................................... 7
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`Purdue Pharma v. Faulding Inc., 230 F.3d 1320 (Fed. Cir. 2000) .........................11
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`SAS Inst. Inc. v. Iancu, 138 S.Ct. 1348 (2018) .......................................................... 8
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`Sirona Dental v. Institut Straumann, 892 F.3d 1349 (Fed. Cir. 2018) ....................26
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`Sony Corp. v. Collabo Innovations, Inc., IPR2017-00938, Paper 23
`(PTAB 2017) .......................................................................................................23
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`South Corp. v. United States, 690 F.2d 1368 (Fed. Cir. 1982) (en banc) .................. 7
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`Velander v. Garner, 348 F.3d 1359 (Fed. Cir. 2003) ..............................................20
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`Wasica Finance GmbH v. Continental Automotive Sys., 853 F.3d 1272
`(Fed. Cir. 2017) ...................................................................................................10
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`STATUTES
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`5 U.S.C. §554(b) ........................................................................................................ 6
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`35 U.S.C. §103(a) ....................................................................................................24
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`35 U.S.C. §119 .......................................................................................................7, 8
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`35 U.S.C. §312(a)(3) .................................................................................................. 6
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`REGULATIONS
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`37 CFR §1.57 ............................................................................................................. 8
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`37 CFR §42.23(b) ...................................................................................................... 5
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`OTHER AUTHORITIES
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`Manual Patent Examining Procedure §608.01(p) ...................................................... 8
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`Office Patent Trial Practice Guide, 77 Fed. Reg. 48756 (2012) ............................... 5
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`I.
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`INTRODUCTION
`Aquestive’s new theories in its Reply underscore its Petition’s deficiencies.
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`As an initial matter, Aquestive’s new theories fail to undo the damaging testimony
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`from its Petition expert, Dr. Peppas, despite a 125-page declaration from a brand-
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`new expert, Dr. Wermeling (which, remarkably, expressly ignores the original
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`Petition). The Reply materials consistently disregard and misstate the evidence—
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`including Dr. Wermeling’s clear recognition of a “significant unmet medical need
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`to serve the pharmacotherapeutic requirements of epilepsy patients through
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`commercial development and marketing of intranasal antiepileptic products” in
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`2009. EX1151, 352; EX2031, 127:4-130:3. Aquestive’s wholesale replacement of
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`its initial theories cannot rescue the failed Petition, and fundamentally prejudices
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`Neurelis because Neurelis cannot at this stage file its own rebuttal evidence.1
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`Because Aquestive cannot prevail without new theories and new evidence,
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`
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`1 Aquestive’s Reply shenanigans are part of an ongoing harassment
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`campaign against Neurelis—here, at the FDA, and in the press—to distract
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`investors from Aquestive’s failure to produce its buccal epilepsy therapy and has
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`forced Neurelis to pursue a tort action against Aquestive in California superior
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`court. Neurelis, Inc. v. Aquestive Therapeutics, Inc., No. 37-2019-00064665
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`(Super. Ct. Cal., San Diego).
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`this IPR should be terminated. Even taking the new evidence and theories into
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`account, the challenge to the claims should be denied.
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`II.
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`STATEMENT OF REASONS TO DENY
`A. Aquestive’s Untimely and New Arguments
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`The Reply offers a thin excuse for substituting a new expert without notice.
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`Reply, 1. In fact, the testimony from Aquestive’s original expert—Dr. Peppas—
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`shows how baseless the Petition was. Although Aquestive purports to use a new
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`expert—Dr. Wermeling—solely to provide evidence from someone with actual
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`experience in the relevant field (something the Petition should have provided), Dr.
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`Wermeling’s declaration (EX1150) completely replaces Dr. Peppas’ testimony—
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`only adopting Dr. Peppas’ ultimate conclusions (a question of law). Indeed, Dr.
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`Wermeling admits that his declaration was crafted without regard to Dr. Peppas’
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`opinions. See EX2031, 54:23-55:4.
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`
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`A joint statement identifies new Reply arguments and Aquestive’s response.
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`Paper 26. Aquestive’s response demonstrates the untimeliness of these arguments,
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`including issues that should have been addressed with supplemental information
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`before Neurelis’ Response and arguments contradicting Dr. Peppas’ testimony.
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`
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`For example, Aquestive’s newly-proffered construction for “consisting of”
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`contradicts Dr. Peppas’ testimony that the claimed formulation lacks water:
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`Q: So the way I’m approaching this is I believe that we agreed that the
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`phrase “consisting of” means that it excludes any ingredient that is not
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`specified following the “consisting of,” and that following the “consisting
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`of” in Claim 1, there’s no water, so water would be excluded from Claim 1.
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`That’s my question, if you agree with that.
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`A: Yes, it’s not—water is not there.
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`EX2011, 139:11-23. Despite this admission—undercutting any motivation to
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`combine aqueous Meezan formulations (EX1011) with the non-aqueous Gwozdz
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`formulations (EX1014)—Aquestive still argues the formulation has water, at least
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`for claims reciting “ethanol”. Notwithstanding Aquestive’s dubious distinction
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`between “ethanol” and “dehydrated ethanol” (detailed infra §II.C.1), this
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`indisputably new argument is procedurally improper. Aquestive proffered Gwozdz
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`for its use of ethanol and the Handbook of Pharmaceutical Excipients (“HPE”)
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`(EX1031) to show ethanol was “already well-known well in advance of the ‘876
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`Patent’s earliest filing date.” EX1041, ¶123. Aquestive now argues that “ethanol”
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`could contain up to 6% water so the claimed formulation may contain water, yet
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`the HPE defines ethanol as “≥ 99.5% v/v of C2H6O.” EX1031, 0003. Hence,
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`Aquestive pursues a new claim-construction theory contradicting Dr. Peppas’ clear
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`testimony, and seeks a mulligan for its “ethanol” definition.
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`This new evidence is not responsive to Neurelis’ Response. Instead of
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`rebutting Neurelis’ argument that a POSA would not have combined non-aqueous
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`Gwozdz formulations with aqueous Meezan formulations, Aquestive now argues
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`the formulation includes water (despite Dr. Peppas’ contrary testimony). Neurelis
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`is significantly prejudiced because it cannot introduce expert testimony to rebut
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`Aquestive’s new contentions on a claim term not previously construed. Paper 9, 6.
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`
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`Additionally, Aquestive newly construes “solution” to include particulates,
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`Reply, 1-2, claiming its untimely construction “[r]ebuts PO’s argument that
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`Gwozdz’s solution does not disclose particulate formulations.” Paper 26, 1. Yet,
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`Aquestive ignores Dr. Peppas’ testimony that “solution” does not include
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`particulates. See EX2011, 145:13-17 (Dr. Peppas: “No. Solution and particulates
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`don’t go together. Solution means total molecular dissolution of the active in the
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`solvent.”) (emphasis added). Aquestive’s failure to present this contrary claim-
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`construction before its Reply underscores the Petition’s failure to explain why a
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`POSA would have combined the references.
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`
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`Aquestive’s new “ternary co-solvent system,” “motivation and miscibility,”
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`“IV solutions,” and “commercialization” arguments rely on the new Florida EMS
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`Protocols Field Guide (“Florida EMS Guide”) (EX1069), citing it numerous times
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`in the Joint Submission. Paper 26, 2-5. Aquestive needs EX1069 to address the
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`gaping hole in its evidence for combining benzyl alcohol and ethanol in an
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`intranasal formulation, further demonstrating this is new evidence that Aquestive’s
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`Petition should have been provided.
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`Moreover, the Petition and Dr. Peppas broadly cite Gwozdz’s disclosure of
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`tocopherols/tocotrienols and alcohols, Petition, 23-24—yet, Aquestive now asserts
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`Gwozdz contains “express direction to use tocopherol+ethanol+benzyl alcohol”,2
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`citing EX1069 as evidence that POSAs would have “included ethanol and benzyl
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`alcohol” as solvents for diazepam, Reply, 18-19. Aquestive’s reliance on this new
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`reference is sufficient to disregard the Reply materials. Intelligent Bio-Systems,
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`Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1369-70 (Fed. Cir. 2016) (citing
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`Office Patent Trial Practice Guide, 77 Fed. Reg. 48756, 48767 (2012) (“Examples
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`of indications that a new issue has been raised in a reply include new evidence
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`necessary to make out a prima facie case for the…unpatentability of an
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`original…claim, and new evidence that could have been presented in a prior
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`filing.”)).
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`Aquestive also urges its Reply responds to the Institution Decision,
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`including its arguments on unexpected results and criticality, and bioavailability.
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`Paper 26, 3-4. This justification contravenes 37 CFR §42.23(b), which provides
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`2 Dr. Wermeling admitted Gwozdz contains no express direction to use a “ternary”
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`combination of “tocopherol+ethanol+benzyl alcohol” (or even contain the word
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`“ternary”), and teaches many combinations of tocopherols and tocotrienols with
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`one or more alcohols or glycols. EX2031, 140:24-144:8.
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`that a “reply may only respond to arguments raised in the corresponding opposition
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`or patent owner response,” which does not include the Institution Decision.3
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`Aquestive’s remaining explanations also lack merit, ranging from again changing
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`the POSA definition (“transmembrane” becomes “transmembrane/transmucosal”,
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`Paper 26, 2), to avoiding the Petition’s complete failure to address the SIGMA
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`Catalog (EX2006) incorporation in the ‘558 provisional (Petition, 5-6). See
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`35 U.S.C. §312(a)(3) (petitions must identify “with particularity…the grounds on
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`which the challenge to each claim is based”) (emphasis added); Intelligent Bio-
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`Systems, Inc., 821 F.3d at 1369 (“the expedited nature of IPRs bring with it an
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`obligation for petitioners to make their case in their petition to institute.”).
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`Aquestive’s new Reply arguments should be given no weight.
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`B.
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`The ’558 Provisional Discloses Alkyl Glycosides
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`Preliminarily, Aquestive incorrectly states the parties’ respective burdens on
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`priority. Reply, 1-2. As patentability-challenger, Aquestive bears both the ultimate
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`3 To preserve these new theories, Aquestive could have timely filed supplemental
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`information before the Response to give Neurelis the opportunity to respond with
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`arguments and evidence. Instead, Aquestive invites the Board to violate basic due-
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`process norms. 5 U.S.C. §554(b).
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`burden of persuasion (as it concedes) and the initial burden of production to
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`demonstrate that Neurelis is not entitled to its claimed priority.4 In re Voss,
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`557 F.2d 812, 817 (CCPA 1977) (Office failed to meet burden before applying
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`art).5 Aquestive relies on Dynamic Drinkware v. National Graphics, but the
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`decision actually supports keeping the burden on Aquestive. Reply, 3-4. In
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`Dynamic Drinkware, the petitioner failed to meet its facial burden to show that a
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`reference applied against the patent claims was entitled to an earlier date. 800 F.3d
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`1375, 1379 (Fed. Cir. 2015). The burden of production does not shift to Neurelis
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`until Aquestive meets its initial burden. Because Aquestive never even addressed
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`the express incorporation in its Petition, the burden never shifted to Neurelis, and
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`Aquestive’s dependence on a new theory in its Reply warrants termination of the
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`IPR as improvidently instituted. Koninklijke Philip N.V. v. Google LLC, 948 F.3d
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`4 Aquestive urges (without explanation) that foreign-priority precedent does not
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`apply to provisional applications. Reply, 9. The same statute, 35 U.S.C. §119,
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`governs priority for both, providing facial relevance. If Aquestive has a theory, it
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`has failed to present it.
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`5 Voss is controlling. South Corp. v. United States, 690 F.2d 1368, 1370 (Fed. Cir.
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`1982) (en banc) (adopting CCPA precedent); Newell Co. v. Kenney Mfg., 864 F.2d
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`757, 765 (Fed. Cir. 1988) (in the event of a conflict, the earliest case controls).
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`1330 (Fed. Cir. 2020) (institution decision may not fix defective ground) (citing
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`SAS Inst. Inc. v. Iancu, 138 S.Ct. 1348, 1355 (2018)).
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`Aquestive also asserts Rule 57 for the first time in its Reply, underscoring its
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`failure to do so in its Petition, and improperly shifting the burden to Neurelis on
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`whether this rule even applies to a provisional application rather than establishing
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`the applicability of the rule in the first instance. Reply, 9. Aquestive simply asserts
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`that the rule “expressly” applies without any further explanation. Aquestive also
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`asserts that the contrary Ex parte Maziere does not apply because it involved
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`foreign priority (rather than provisional priority as here) without explaining why
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`this difference matters. Reply, 9. Since both priority claims are made under §119,
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`facially there is no legal distinction and Official practice makes no distinction.
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`MPEP §608.01(p). Aquestive also argues that the Board is not bound by the
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`USPTO’s examination manual, which fails to address the merits and misses the
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`point. Aquestive is luring the Board into an arbitrary-and-capriciousness trap—
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`even assuming Maziere and the manual are not controlling, an agency cannot
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`ignore existing rule interpretations without supplying “a reasoned analysis for the
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`change.” Motor Vehicle Mfrs. Ass’n v. State Farm, 463 U.S. 29, 42 (1983).
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`Aquestive makes no effort to justify a contrary interpretation, but simply invites
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`reversible error. Instead, the Board should recognize that Aquestive’s baseless
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`reinterpretation of Rule 57 needed for its new Reply theory further warrants
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`termination.
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`Aquestive improperly supplements its Petition with new evidence regarding
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`the priority date, but to no avail. Dissatisfied with its original expert’s—Dr.
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`Peppas—testimony, Aquestive presents new expert testimony that “the SIGMA
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`catalogue [EX2006] does not convey to a POSA either a directed disclosure of
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`alkyl glycosides as absorption enhancer or even that the inventors knew that alkyl
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`glycosides would necessarily work as such.” EX1150, §IX. Yet, this new
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`testimony cannot make up for Aquestive’s failure to address the SIGMA-pages
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`incorporation in the Petition.6 Aquestive’s Reply ignores that Aquestive’s Dr.
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`Peppas testified that he did not consider EX2006 for his declaration (EX2011, 151)
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`despite his recognition that it was incorporated (id., 153) and disclosed alkyl
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`glycosides (id., 153-54). Dr. Peppas’ only explanation was that “there were so
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`many documents. And you have a number of documents and you have your own
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`opinion and you know what you’re doing” (id. at 154). Dr. Wermeling’s belated
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`6 Instead, Aquestive’s Reply bootstraps off the Institution Decision and Decision
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`Denying Rehearing. Reply, 1-9. Aquestive only cites its Petition for the statement
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`“Petitioner was only required to show lack of support in ’558 provisional for
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`essential and material claim element ‘alkyl glycosides’....” Id., 3 (citing Petition,
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`18-20). Pages 18-20 never mentions the incorporation of EX2006.
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`testimony is untimely and prejudicial. Wasica Finance GmbH v. Continental
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`Automotive Sys., 853 F.3d 1272, 1286 (Fed. Cir. 2017) (rejecting new theory after
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`petition). Thus, Aquestive’s and Dr. Wermeling’s evidence regarding EX2006 is
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`improper, untimely new theory that should be disregarded.
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`Nevertheless, Aquestive’s and Dr. Wermeling’s argument regarding
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`EX2006, even if timely presented, is wrong and cannot save Aquestive’s Petition.
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`Preliminarily, neither Aquestive expert denies that EX2006 is incorporated into
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`the ’558 provisional and discloses alkyl glycosides.7 Aquestive’s Dr. Peppas
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`further recognized alkyl glycosides were known biological detergents (EX2011,
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`107-09). Aquestive’s and Dr. Wermeling’s new argument that the ’558 provisional
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`does not “reasonably lead a POSA to any particular sub-class” of enhancers
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`misapprehends written-description law. The test—“whether the disclosure of the
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`application relied upon reasonably conveys to those skilled in the art that the
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`inventor had possession of the claimed subject matter as of the filing date”—
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`7 Indeed, Dr. Wermeling’s CV lists a patent with a much broader incorporation of
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`“[a]ll documents (patents, patent applications and other publications) cited in this
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`application.” EX2030, 30:65-67. Dr. Wermeling testified that he reviewed and
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`worked on the patent with counsel (id., 106-08), thus negating Aquestive’s
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`implication that such incorporations necessarily impair a POSA’s understanding.
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`focuses on a POSA’s understanding. Ariad Pharm., Inc. v. Eli Lilly, 598 F.3d
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`1336, 1351 (Fed. Cir. 2010) (en banc). While Aquestive and Dr. Wermeling argue
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`that alkyl glycosides are not specifically called-out in the provisional, precedent
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`recognizes that such explicit disclosure is not required. Falkner v. Inglis, 448 F.3d
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`1357, 1366 (Fed. Cir. 2006) (“examples are not necessary to support the adequacy
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`of written description” and “the written description standard may be met [] even
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`where actual reduction to practice of an invention is absent”) (affirming priority for
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`claimed subgenus from generic description and previous focus on a different
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`subgenus, partially based on expert testimony regarding what the art knew); see
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`also Union Oil v. Atlantic Richfield, 208 F.3d 989, 1000 (Fed. Cir. 2000)
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`(cautioning not to “‘let form triumph over substance’ if it allowed the written
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`description requirement to eviscerate claims that are narrowed during prosecution,
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`simply because the patent applicant broadly disclosed in the original patent
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`application but then narrowed his claims during prosecution.”); In re Wertheim,
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`541 F.2d 257, 265 (CCPA 1976) (reversing rejection of claimed subrange where
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`specification provided full range and other guidance).
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`Purdue Pharma v. Faulding Inc., 230 F.3d 1320 (Fed. Cir. 2000) and
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`Fujikawa v. Wattanasin, 93 F.3d 1559 (Fed. Cir. 1996) are distinguishable. In
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`Purdue, the patentee “pick[ed] a characteristic…that is not discussed even in
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`passing in the disclosure, and then ma[de] it the basis of the claims that cover…any
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`formulation that has that characteristic”. 230 F.3d at 1327. In Fujikawa, the
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`patentee claimed a “sub-genus [that] diverges from [the] preferred elements”.
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`93 F.3d at 1571. Here, the ’558 provisional provides adequate disclosure of the
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`relevant characteristics of the claimed alkyl glycosides—by disclosing enhancing
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`agents, which are described as “any material which acts to increase absorption
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`across the mucosas and/or increases bioavailability” EX1008, 0031; Enzo
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`Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002) (adequate
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`disclosure can take various forms and must be considered as a whole). Here, when
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`the disclosure is considered as a whole, including the functional requirements and
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`the contextual incorporation of alkyl glycosides in EX2006, from a POSA’s
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`perspective (something only Dr. Gizurarson did), the ’558 provisional amply
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`satisfies the written-description requirement.
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`C. Aquestive Fails to Show Even Prima Facie Obviousness
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`1. Claimed Solution Lacks Water—Even From Ethanol
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`Once again, Aquestive would erase a clear, of-record admission with new
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`argument; here, that ethanol in the claims contains water. This belated contention
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`both confirms Aquestive’s admission that Meezan relates to aqueous formulations
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`(undercutting any motivation to combine Gwozdz with Meezan) and contradicts
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`Dr. Peppas’ crystal-clear testimony that the claimed formulation lacks water.
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`EX2011, 138:16-139:23 (Dr. Peppas: “Yes, it’s not—water is not there.”).
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`Moreover, even if this improper argument is not struck, it is entirely based
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`on a flawed, false claim-differentiation argument. Specifically, Aquestive asserts
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`the “USP standards that ethanol ‘contains not less than 92.3% and not more than
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`93.8% by weight, corresponding to not less than 94.9% and not more than 96.0%,
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`by volume, at 15.56o, of C2H5OH.’” Reply, 10-11 (citing EX1078, 0004-0005)
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`(original emphasis). Aquestive’s assertion is wrong for several reasons. First,
`
`Aquestive incorrectly assumes the 4-5% balance “to be mostly—if not all—
`
`water.”8 Second, Aquestive cites a generic standard for “Alcohol”, while the claims
`
`recite “ethanol” (mixed with benzyl alcohol), as Dr. Wermeling recognized
`
`(EX2031, 72:7-10). Aquestive’s USP’s definition for “alcohol” is inconsistent with
`
`the claims. As Dr. Gizurarson testified, a POSA knew that water decreases
`
`benzodiazepine solubility exponentially, and would have known to use ethanol
`
`with little-to-no water. EX1149, 70:7-23 (Dr. Gizurarson: “And my experience
`
`working with benzodiazepine is that, if you add water…the solubility decreases
`
`exponentially.”).
`
`
`
`Third, Aquestive’s own exhibit, the HPE (EX1026) explains that in the
`
`British Pharmacopeia “[t]he term alcohol, without other qualification, refers to
`
`
`
`8 The balance could be chemical impurities or additives, such as methanol or
`
`methyl isobutyl ketone. EX1026, 0004 (denatured alcohol).
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`IPR2019-00451
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`ethanol 96.0-96.6% v/v” while “the term ‘ethanol’ used without other qualification
`
`refers to ethanol containing > 99.5% v/v of C2H6O.”9 EX1026, 0004. Thus, in
`
`context, a POSA knew “ethanol” meant “>99.5% ethanol”, not Aquestive’s watery
`
`substitute.
`
`
`
`Fourth, Aquestive wrongly assumes that only two types of ethanol exist:
`
`1) ethanol with water and 2) dehydrated ethanol. Reply, 9-11. Yet Dr. Wermeling
`
`knew more than one type of >99.5% ethanol exists. EX2031, 99:13-16. Anhydrous
`
`ethanol, which also contains >99.5% ethanol, was known to pharmaceutical
`
`formulators, as the 2006 HPE shows. See EX2029, 18. This comports with Dr.
`
`Gizurarson’s understanding that other pharmacopeias (European, British, and
`
`American, for example) could have different >99.5% ethanol requirements,
`
`including anhydrous ethanol and dehydrated ethanol. EX1149, 64:24-65:4. Thus, a
`
`POSA would have understood “ethanol” in claim 1 without a modifier as meaning
`
`ethanol—not some watery alternative. The POSA would also understand that
`
`claim 28 and other references to dehydrated alcohol in the specification excludes
`
`other ethanols containing >99.5% v/v of C2H6O—e.g., anhydrous ethanol.
`
`
`
`9 Dr. Wermeling provides no basis for using the generic USP definition over, for
`
`example, a specific British or European Pharmacopeia one. EX2031, 66:24-67:1.
`
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`2. No Motivation to Combine Gwozdz with Meezan
`
`
`
`The Reply materials fail to address the lack of motivation to combine
`
`Gwozdz’s non-aqueous, lipophilic/hydrophobic active ingredient formulation
`
`(EX1014, 0000, abstract) with Meezan’s aqueous, peptide/protein formulation
`
`(EX1011, 0001, abstract). Aquestive simply asserts a POSA “would have looked to
`
`increasing drug solubility and using penetration enhancers,” and points to Dr.
`
`Gizurarson’s patent applications with surfactant and alcohols. Reply, 13 (citing
`
`EX1070). Aquestive’s naked assertions ignore Dr. Gizurarson’s testimony that the
`
`components in EX1070, including solubility agents, alcohols, surfactants and
`
`penetration enhancers, were chosen based on the targeted mucosal route. EX1149,
`
`115:13-117:2. Aquestive’s disregard of EX1070’s different mucosal routes—
`
`despite direct knowledge from Dr. Gizurarson—is disingenuous.
`
`
`
`Importantly, Aquestive fails to discuss how alkyl glycosides function in a
`
`non-aqueous environment. Meezan discloses alkyl glycosides as a stabilizer only in
`
`aqueous formulations. EX2011, 140:20-23 (discussing EX1011). Aquestive’s
`
`reliance on an absence of evidence as proof that it must work is telling, and an
`
`improper burden-shift at the crux of the motivation analysis. Even Dr. Peppas
`
`testified that he has no understanding of how Meezan’s formulations would
`
`function in the absence of water. Id., 141:23-142:2. Nothing in Aquestive’s Reply
`
`shows a POSA would have been motivated to combine Gwozdz’s non-aqueous
`
`
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`-15-
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`IPR2019-00451
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`formulation with Meezan’s aqueous formulation.
`
`3. No Motivation to Combine Ethanol and Benzyl Alcohol
`with Tocopherol to Solubilize Benzodiazepines
`
`Given the hole in its Petition—no evidence on motivation to combine
`
`ethanol and benzyl alcohol in Gwozdz, Meezan, or Carrt’874—Aquestive brazenly
`
`contends that “all three co-solvents are specifically disclosed by Gwozdz—no
`
`modification is necessary.” Reply, 18 fn.1. Yet Dr. Wermeling could not identify
`
`such disclosure of tocopherol, ethanol and benzyl alcohol in Gwozdz:
`
`Q: …So I’m asking if you agree with me that this reference, 1014,
`does not explicitly teach, give an example of, recite specifically, a
`formulation that contains a tocopherol ethanol and benzyl alcohol?
`A: You have chosen a specific example. It does describe tocopherol
`with one or more alcohols and one or more glycols.
`
`EX2031, 141:7-15. Dr. Wermeling further admits that Gwozdz’s express language
`
`provides “many examples” of a combination of tocopherol or tocotrienol with one
`
`or more glycol or alcohol, including a binary co-solvent. Id., 142:16-143:12. Dr.
`
`Peppas similarly agreed that the many solvents of Cartt’784 would have made “too
`
`many combinations.” EX2011, 147:21-148:2.
`
`
`
`Moreover, Dr. Gizurarson analyzes Gwozdz’s data and testifies that a POSA
`
`would not have added benzyl alcohol as a solvent because Gwozdz’s solubility
`
`levels were highest when 95% tocopherol:5% ethanol was used. EX2012, ¶82. The
`
`
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`IPR2019-00451
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`formulation lacks room for a POSA to add benzyl alcohol, much less alkyl
`
`glycosides; rather, a POSA would have avoided adding benzyl alcohol to the
`
`binary tocopherol+ethanol co-solvent, expecting such additions would decrease
`
`benzodiazepine solubility. Id.
`
`
`
`The cited references lack suggestion for a POSA to adopt the claimed
`
`tocopherol+ethanol+benzyl alcohol combination to solubilize. The hindsight-
`
`driven statements of Aquestive’s experts lack support. Without such support,
`
`Aquestive cannot show motivation to combine the references, or a reasonable
`
`expectation of success.
`
`4. Aquestive Fails to Rebut the Absence of Any Motivation
`to Combine or Reasonable Expectation of Success for the
`References
`
`The Reply provides another new, baseless theory that a POSA would have
`
`circumvented benzodiazepine precipitation by cutting the dose in half and
`
`administering the drug in both nostrils. Reply, 14-15. In doing so, Aquestive
`
`overlooks the Nayzilam® label’s requirement to dose one nostril, wait at least 10
`
`minutes, and then dose the other nostril if the patient has not responded. EX1072,
`
`0001. As Dr. Wermeling explained, with benzodiazepines a high risk exists that
`
`patients would be overdosed and stop breathing. EX2031, 134:6-22. Dosing both
`
`nostrils simultaneously eliminates the caregiver’s option to dose the second nostril
`
`if seizures continue after 10 minutes until the initial dose clears from the nasal
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`cavity. Id., 135:17-136:2.
`
`Moreover, Aquestive ignores that spreading the clinical dose over twice the
`
`volume would unnecessarily expose patients to an increased volume of irritants,
`
`such as ethanol and benzyl alcohol. Aquestive asserts some irritation is acceptable
`
`for acute treatment, but a POSA would have considered the warning from Dr.
`
`Wermeling’s own patent that benzyl alcohol is irritating to the mucosa, and thus
`
`“not acceptable for intranasal spray administration.” EX2012, ¶90 (citing EX2014,
`
`6:31-39). A POSA instead would have maintained the standard of care of treating a
`
`seizing patient one nostril at a time.
`
`5. Cartt’874’s Particulate Formulations Not Relevant
`
`
`
`Aquestive would erase Dr. Peppas’ testimony that the claims exclude
`
`particulates (as in Cartt’784) using a baseless claim-differentiation argument.
`
`EX1041, 145:13-17 (Dr. Peppas: “No. Solution and particulates don’t go together.
`
`Solution means total molecular dissolution of the active in the solvent.”)
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