UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`AQUESTIVE THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`NEURELIS, INC.,
`Patent Owner.
`____________________
`
`Case IPR2019-00451
`Patent 9,763,876
`____________________
`
`PATENT OWNER RESPONSE
`37 C.F.R. §42.120
`
`
`
`
`
`
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`AQUESTIVE THERAPEUTICS, INC.,
`Petitioner,
`
`v.
`
`NEURELIS, INC.,
`Patent Owner.
`____________________
`
`Case IPR2019-00451
`Patent 9,763,876
`____________________
`
`PATENT OWNER RESPONSE
`37 C.F.R. §42.120
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`TABLE OF AUTHORITIES ......................................................................... iv
`
`Cases ................................................................................................ iv
`
`Statutes...............................................................................................v
`
`Regulations .........................................................................................v
`
`Other Authorities .................................................................................v
`
`I.
`
`Precise Requested Relief .......................................................................1
`
`II.
`
`Statement of Reasons to Deny The Petition ..............................................2
`
`A.
`
`Background ...............................................................................2
`
`1.
`
`2.
`
`3.
`
`4.
`
`Epilepsy and epilepsy treatment ........................................... 2
`
`Benzodiazepine for intranasal administration ......................... 5
`
`The challenged patents and claims ....................................... 8
`
`The ’876 patent’s chain of priority ..................................... 10
`
`B.
`
`Claim Construction ................................................................... 12
`
`1.
`
`2.
`
`“consisting of” ................................................................ 12
`
`“in a combined amount” ................................................... 13
`
`C.
`
`The Level of Ordinary Skill in the Art ......................................... 15
`
`D. Aquestive’s Unpatentability Analysis and the Institution
`Decision Hinge on Incorrect Theories of Patent Priority ................. 17
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`1.
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`Aquestive Never Met its Burden to Establish a Facially
`Reasonable Likelihood of Unpatentability ........................... 18
`
`2. Misplaced Reliance on Rule 57 Cannot Save the Petition ...... 21
`
`E.
`
`The Combination Does Not Teach the Claimed Subject
`Matter ..................................................................................... 23
`
`1.
`
`2.
`
`3.
`
`The Alleged Prior Art ....................................................... 24
`
`Aquestive Fails to Demonstrate a Motivation to Combine
`the Disclosure of Gwozdz with that of Meezan’962
`(Ground 1 Fails) .............................................................. 27
`
`Aquestive Fails to Demonstrate a Motivation to Combine
`the Formulation of Cartt’784 to the Gwozdz and/or
`Meezan’962 Formulations (Ground 2 Fails) ........................ 38
`
`III. Secondary Considerations of Nonobviousness ........................................ 40
`
`IV. Conclusion ........................................................................................ 44
`
`EXHIBIT LIST .......................................................................................... 45
`
`TYPE VOLUME CERTIFICATE ................................................................. 48
`
`CERTIFICATE OF SERVICE ..................................................................... 49
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`TABLE OF AUTHORITIES
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`CASES
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`Page
`
`Alco Standard Corp. v. Tenn. Valley Auth., 808 F.2d 1490 (Fed. Cir.
`1986) ....................................................................................................... 46
`
`Aristocrat Techs. v. Int’l Game Tech., 543 F.3d 657 (Fed. Cir. 2008) ................ 24
`
`Carbino v. West, 168 F.3d 32 (Fed. Cir. 1999) ............................................... 23
`
`DowIn re Dow Chemical Co., 837 F.2d 469 (Fed. Cir. 1988).................................. 32
`
`EdwardsIn re Edwards, 568 F.2d 1349 (CCPA 1978) ................................................. 22
`
`Exela Pharma Sciences, LLC v. Lee, 781 F.3d 1349 (Fed. Cir. 2015) ................ 24
`
`Exxon Corp. v. Phillips Petroleum Co., 265 F.3d 1249 (Fed. Cir. 2001) ............ 24
`
`Gemstar-TV Guide Int’l, Inc. v. Int’l Trade Comm’n, 383 F.3d 1352 (Fed.
`Cir. 2004) ................................................................................................. 15
`
`Harari v. Hollmer, 602 F.3d 1348 (Fed. Cir. 2010)......................................... 24
`
`Heinle In re Heinle, 342 F.2d 1001 (CCPA 1965) .................................................... 13
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
`Litig., 676 F.3d 1063, 1075-77 (Fed. Cir. 2012). ............................................ 43
`
`Intelligent Bio-Systems, Inc. v. Illumina, Inc., 821 F.3d 1359 (Fed. Cir.
`2016) ....................................................................................................... 23
`
`Magnivision, Inc. v. Bonneau Co., 115 F.3d 956 (Fed. Cir. 1997) ..................... 24
`
`MazEx parte Maziere, 27 USPQ2d 1705 (BPAI 1993) .......................................... 24
`
`McDonnell v. United States, 136 S. Ct. 2355 (2016) ....................................... 24
`
`Medgraph, Inc. v. Medtronic, Inc., 843 F.3d 942 (Fed. Cir. 2016) .................... 14
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`Millennium Pharm., Inc. v. Sandoz, Inc., 862 F.3d 1356 (Fed. Cir. 2017) .......... 43
`
`Multilayer Stretch Cling Film Holdings, Inc. v. Berry Plastics Corp.,
`831 F.3d 1350 (Fed. Cir. 2016) .................................................................... 13
`
`PiaIn re Piasecki, 745 F.2d 1468 (Fed. Cir. 1984)............................................... 46
`
`SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348 (2018) .............................................. 23
`
`Telebrands Corp. v. Tinnus Enterprises, LLC, PGR2017-00015, Paper 53
`(2019) ...................................................................................................... 23
`
`Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991) ............................ 13
`
`STATUTES
`
`5 U.S.C. §557(c) ........................................................................................ 24
`
`35 U.S.C. §120 .......................................................................................... 13
`
`35 U.S.C. §314(a) ...................................................................................... 19
`
`35 U.S.C. §316 ..................................................................................... 22, 25
`
`REGULATIONS
`
`37 CFR §1.57 ....................................................................................... 23, 24
`
`OTHER AUTHORITIES
`
`Manual of Patent Examining Procedure § 608.01(p)(1)(B) (9th ed.
`rev. R-08.2017, Jan. 2018) ..................................................................... 12, 24
`
`Manual of Patent Examining Procedure §2163.07(b) (9th ed.,
`rev. R-08.2017, Jan. 2018) .......................................................................... 12
`
`U.S. Constitution, Amendment V ................................................................. 24
`
`Webster's Third New Int’l Dictionary (1993) ................................................. 16
`
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`I.
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`
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`PRECISE REQUESTED RELIEF
`
`Treatment of epilepsy and epileptic seizures through the intranasal route of
`
`administration has been a long-sought alternative to intravenous and rectal
`
`medications in the market. Conventional medications are not only harder to
`
`administer during a seizure but are also not appropriate in most environments
`
`(requiring professional administration or a private setting). Despite this long-felt,
`
`unmet need for an effective intranasal treatment – particularly intranasal
`
`benzodiazepine treatment – no one prior to the patent owner (Neurelis) was able to
`
`develop an effective intranasal diazepam formulation – the invention claimed in
`
`the involved 9,763,876 patent (’876 patent).1 The petitioner (Aquestive) attempts
`
`to prove obviousness of this claimed formulation, but fails for various reasons,
`
`most importantly because the references are not actually prior art to the ’876
`
`patent. Indeed, Aquestive relies on the wrong priority date as the entire basis for its
`
`obviousness analysis – depending solely on a lack of written description theory
`
`that even Aquestive’s expert, Dr. Peppas, could not substantiate during his
`
`
`
`1 Indeed, the U.S. Food & Drug Administration granted Patent Owner Orphan
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`Drug status and Fast Track Review for its formulation for this very reason, as
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`further detailed infra.
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`deposition. Neurelis preserves its arguments that the petition never made out a
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`prima facie case and that the various theories of institution rest on misapprehension
`
`of controlling law and improper burden shifts.
`
`
`
`Yet, even if the Board considers the merits of Aquestive’s prior-art
`
`references – which the Board should not – Aquestive fails to establish a motivation
`
`to combine the references and a reasonable expectation of success in doing so.
`
`Instead, Aquestive shows a misunderstanding of its cited references and,
`
`importantly, an oversimplification of the art at issue (which Dr. Peppas ultimately
`
`demonstrates). Additionally, a review of the long-felt yet unmet need for a
`
`diazepam intranasal formulation (considering also the failure of others in
`
`developing such a formulation) further supports a finding of non-obviousness.
`
`
`
`Accordingly, Neurelis requests termination of this review or at least a final
`
`written decision denying the IPR2019-00451 petition and holding that Aquestive
`
`has failed to prove that any challenged claim is unpatentable.
`
`II.
`
`STATEMENT OF REASONS TO DENY THE PETITION
`
`A. BACKGROUND
`
`1. Epilepsy and epilepsy treatment
`
`
`
`Epilepsy is a general term for conditions with recurring seizures, involving
`
`abnormal electrical activity in the brain that causes an involuntary change in body
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`movement or function, sensation, awareness, and/or behavior. A seizure may last
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`from a few seconds to a few minutes. While epilepsy is known as a brain disorder,
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`its cause is still unknown and may have many etiologies, including developmental
`
`disorders, brain injury, illness and infection. EX2012, ¶44; EX2019, 166.
`
`
`
`Epilepsy actively affects over 3.4 million people in the United States (about
`
`1.2% of the total population) and ranks as the second most burdensome
`
`neurological disorder worldwide in terms of disability-adjusted life years, with
`
`associated stigma, psychiatric co-morbidity and high economic costs. EX2004, 3;
`
`EX2001; EX2005, 296. Nearly half a million children in the United States alone
`
`have active epilepsy. EX2001. Medications exist to help prevent seizures, but
`
`success varies and about one-third of epileptics receiving care still experience
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`seizures. EX2004, 3.
`
`
`
`Moreover, there are no quick, simple and effective treatments available to
`
`control and treat epileptic seizures once they occur. Immediate cessation is
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`essential to treating epileptic seizures as they significantly increase morbidity and
`
`mortality rates – with an increased likelihood for progression into an epileptic state
`
`when a seizure lasts longer than 5 minutes. EX2012, ¶45. Benzodiazepines proved
`
`to be a promising treatment – with past studies highlighting the benefits of
`
`administering benzodiazepines (e.g., diazepam) for treatment of epileptic seizures,
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`especially in the young and elderly. Id., ¶45. By 2008, benzodiazepine
`
`formulations were developed for intravenous administration (Valium®) and rectal
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`administration (Diastat®).2 See EX1042; EX2012, ¶46. However, their use was
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`still limited to specific situations, and not conducive to administration in a public
`
`setting. EX2012, ¶¶51-52.
`
`
`
`2 Throughout his declaration, Dr. Peppas refers to formulations directed to other
`
`routes of administration – e.g., intravenous formulations and rectal formulations
`
`such as Valium® and Diastat® – as being informative of what a POSA would
`
`know regarding intranasal formulation. See EX1041, ¶133; see also ¶136
`
`(comparing topical preparations to transmucosal preparations). This fails to
`
`appreciate the unique characteristics of each given therapeutic agent and intricacies
`
`of each administration route. See EX2012, ¶¶28-32, Section VII.D. Dr. Peppas
`
`ultimately agrees. When asked whether Diastat® could be reformulated for nasal
`
`administration, Dr. Peppas acknowledged that he would need more information
`
`(e.g., other ingredients, form, delivery method, bioavailability, etc.) and would
`
`need to conduct additional studies, including human studies. EX2011, 118:18-
`
`120:19; see also EX2012, ¶52 (re-formulating Diastat® to intranasal
`
`administration would not have been clinically possible and would not have
`
`worked).
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`2. Benzodiazepine for intranasal administration
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`
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`With these concerns in mind, nasal sprays became a promising method of
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`administering benzodiazepines. EX2012, ¶¶53-54; EX2008. However, the known
`
`solubility challenges of benzodiazepines thwarted efforts to treat epilepsy with
`
`intranasal benzodiazepines. EX2012, ¶54; see also, ¶¶47-50. Specifically, before
`
`2008, benzodiazepines were known to pose challenges in administering a high
`
`enough clinical dose to act as a rescue agent during a seizure because of their low
`
`solubility. Id., ¶47; EX2013. For example, benzodiazepine’s low solubility created
`
`a challenge for administering a high enough dose (clinical dose) to act as a rescue
`
`agent during a seizure. EX2012, ¶47. An additional challenge was dealing with
`
`variances in clinical dose threshold for a given benzodiazepine used – with
`
`diazepam, specifically, requiring a high clinical dose for treatment. Id., ¶48. Thus,
`
`a POSA would need to consider the ratio between the threshold clinical dose
`
`needed for treatment and the solubility of the benzodiazepine drug. But the
`
`solubility issue was not only critical because of the threshold clinical dose needed
`
`to obtain effectiveness in treating cluster seizures in a rapid manner, it was also
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`critical because of the risk of precipitates forming. Id. Precipitates could not only
`
`further irritate the nasal cavity, but also reduce uptake of a therapeutic agent
`
`through the nasal mucosa and cellular wall. Id. The known tendency to precipitate
`
`with lower solubility benzodiazepines meant that the clinical dose could not
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`overlap or be close to the saturation dose of the agent. Id., ¶¶64-65; EX2007, 293.
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`Dr. Peppas does not address any of these concerns in his declaration and instead
`
`oversimplifies a POSAs ability, as of 2008-2009, to develop benzodiazepine
`
`formulations. While Dr. Peppas makes blanket assertions that “there simply is no
`
`criticality to (or unexpected results stemming from) the specific types or amounts
`
`of . . . benzodiazepines” (EX1041, ¶51) and that “benzodiazepines . . . have been
`
`known for decades, and their effects on the human body are generally predictable”
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`(id., ¶63), he admitted in deposition testimony that he has zero experience working
`
`with benzodiazepines (directly or indirectly). See EX2011, 13:3-18, 22:16-21,
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`24:10-15, 25:2-21, 26:19-22, 34:21-35:8; 44:5-8, 47:19-24.
`
`
`
`As Neurelis’ expert Dr. Gizurarson explains, developing benzodiazepine
`
`formulations has proven not to be a straightforward task. EX2012, ¶48. Despite its
`
`therapeutic promise in stopping and preventing seizures in patients,
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`benzodiazepine use was not widespread in 2008 because of its known challenges.
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`Id., ¶51. Even today, the only FDA approved intranasal benzodiazepine
`
`formulation is NAYZILAM® (an aqueous midazolam formulation3), which was
`
`
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`3 Midazolam has a higher solubility index than diazepam. EX2012, ¶¶66-67. As
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`Dr. Gizurarson, who developed NAYZILAM®, opines, a POSA would have been
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`approved this year. EX2012, ¶67; see also EX2011, 49:9-13 (admitting he could
`
`not identify any FDA-approved intranasal benzodiazepine formulations).
`
`
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`Additional technical challenges and obstacles to developing intranasal
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`formulations existed and were known to POSAs prior to 2008. EX2012, ¶55. These
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`included at least: (1) limited delivery volume because of the small volume of the
`
`nasal cavity – requiring an effective dose 5-10 times more concentrated than with
`
`intravenous administration (EX2012, ¶56); (2) mucosal and ciliary clearance
`
`mechanisms – limiting residence time of a solution placed in the nasal cavity (id.,
`
`¶¶57-59); and (3) nasal cell anatomy – known to physically block foreign agents
`
`from entering through the cell wall (id., ¶60).
`
`
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`Thus, by 2008, POSAs knew obtaining true intranasal absorption to be
`
`difficult, and in the case of some therapeutic agents insurmountable.
`
`Benzodiazepines were such known therapeutic agents due to their poor water
`
`solubility characteristics, as shown in at least one study (Lau, EX2009) conducted
`
`on diazepam (0.05mg/ml) and lorazepam (0.08mg/ml) in 1989. EX2012, ¶61.
`
`Lau’s studies on intranasal administration of diazepam and lorazepam showed
`
`
`
`discouraged from pursuing a lower solubility index benzodiazepine for
`
`development since this would have been a potential set-up for failure. Id., ¶66.
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`(1) time to peak concentration was significantly delayed as compared to
`
`intravenous administration (EX2012, ¶62); and (2) bioavailability was also
`
`significantly less than with intravenous administration (id., ¶63). Lau ultimately
`
`concluded that “[i]t would appear that this [intranasal] route of administration may
`
`be of limited utility for benzodiazepines in the treatment of status epilepticus
`
`where rapid onset of effect is essential.” EX2009, 173; EX2012, ¶63. Other
`
`researchers had similar difficulties in administering benzodiazepines. See EX2012,
`
`¶¶63-67.
`
`3. The challenged patents and claims4
`
`
`
`The application for the ’876 patent, titled “Administration of
`
`Benzodiazepine Compositions”, was filed on October 29, 2014. EX1001. The
`
`
`
`4 While Dr. Peppas provides his rendition of the prosecution history of the ’876
`
`patent (EX1041, ¶¶29-37), his alleged “expert opinions” regarding statements and
`
`decisions made by the applicant during prosecution should not be considered as
`
`they are improper legal opinions. See 37 C.F.R. §42.65(a). Indeed, Dr. Peppas
`
`admitted that he was not an expert on this subject matter during deposition
`
`testimony. See EX2011, 70:13-89:6 (“I agree with you I did express on a matter
`
`that I was not an expert on.”).
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`abstract states that the patent “relates to pharmaceutical compositions comprising
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`one or more benzodiazepine drugs for nasal administration, methods for producing
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`and for using such compositions.” Id., Abstract. The inventors realized that while
`
`nasal delivery would address the drug-administration problem, known solubility
`
`problems could be especially difficult using a nasal administration route. The
`
`inventors thus developed the use of vitamin E-analogs and alcohols as substantial
`
`fractions of the formulation to address the solubility problem, while still providing
`
`an acceptable nasal-delivery formulation. The alkyl glycoside functions as a
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`penetration enhancer to improve bioavailability. EX1001, 16:55-56, 34:45-48.
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`
`
`Challenged claim 1, from which all the other challenged claims depend,
`
`defines the invention as (EX1001, 63:26-34):
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`A method of treating a patient with a disorder which is treatable with a
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`benzodiazepine drug, comprising:
`
`administering to one or more nasal mucosal membranes of a patient a
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`pharmaceutical solution for nasal administration consisting of
`
`a benzodiazepine drug,
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`one or more natural or synthetic tocopherols or tocotrienols, or
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`any combinations thereof, in an amount from about 30% to about 95%
`
`(w/w);
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`ethanol and benzyl alcohol in a combined amount from about 10% to
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`about 70% (w/w); and
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`an alkyl glycoside.
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`The challenged ’876 patent issued in 2017 but claims benefit back to 2008.
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`EX1001, cover.
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`4. The ’876 patent’s chain of priority
`
`The ’876 patent claims priority to U.S. Provisional Patent Application No.
`
`61/040,558 (’558 Provisional) (EX1008), filed on March 28, 2008. The ’558
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`Provisional discloses alkyl glycosides as part of the formulation claimed.
`
`Specifically, the ’558 Provisional provides:
`
`In some embodiments, the drug delivery system of the invention may
`
`advantageously comprise an absorption enhancer . . . . In some
`
`embodiments, enhancing agents that are appropriate include . . . acyl
`
`glycerols, fatty acids and salts, tyloxapol and biological detergents listed
`
`in the SIGMA Catalog, 1988, page 316-321 (which is incorporated
`
`herein by reference).
`
`EX1008, [150]-[152] (emphasis added). The excerpt from the 1988 SIGMA
`
`Catalog lists biological detergents and includes alkyl glycosides such as
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`n-dodecyl β-D-maltoside,
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`n-dodecyl-β- D-glucopyranoside,
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`n-heptyl- β-D-glucopyranoside,
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`n-hexyl- β-D- glucopyranoside,
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`n-nonyl- β-D-glucopyranoside,
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`n-octyl- β-D-glucopyranoside,
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`n-octyl- β-D-thioglucopyranoside,
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`among others. EX2006, 319-320. Notably, of the 10 non-ionic biological
`
`detergents5 listed on page 316 of the catalog, 9 of them are alkyl glycosides.
`
`EX2012, ¶71. Additional alkyl glycosides are listed within pages 319-321 of the
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`excerpt – showing, overall, a prominent representation within the 1988 SIGMA
`
`catalog pages incorporated by reference into the ’558 Provisional. Id. As Dr.
`
`Gizurarson states – and as Aquestive’s expert (Dr. Peppas) confirms – alkyl
`
`glycosides were known to fall in the category of “biological detergents”, as listed
`
`in the 1988 SIGMA catalog. EX2012, ¶¶69-75; EX2011, 107:10-13. Thus, Dr.
`
`Peppas ultimately agreed that the 1988 SIGMA catalog teaches alkyl glycosides.
`
`
`
`Applicants to the Patent Office routinely employ the long-established and
`
`
`
`5 A POSA would have understood that in the context of pharmaceutical
`
`formulations, biological detergents would have been limited to detergents
`
`appropriate for administering to the nasal cavity of a human or other animal subject
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`– which, in such a case, would have been non-ionic detergents. EX2012, ¶70.
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`recognized method of incorporation by reference to avoid repeating information
`
`contained in a publicly available document, such as the SIGMA catalog. See
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`MPEP §§608.01(p)(1)(B), 2163.07(b) (9th ed., rev. R-08.2017, Jan. 2018). The
`
`inclusion of the SIGMA catalog disclosure of non-ionic detergents, preponderantly
`
`including numerous alkyl glycosides, thus would have reasonably conveyed to a
`
`POSA that the inventor possessed at the time of filing the claimed alkyl glycosides
`
`as part of the invention. Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1564-67 (Fed.
`
`Cir. 1991) (reversing judgment of no support under 35 U.S.C. §120) (citing In re
`
`Heinle, 342 F.2d 1001, 1007 (C.C.P.A. Apr. 8, 1965) (reversing rejection,
`
`explaining that incorporating drawing dimensions into specification would not
`
`constitute new matter and therefore properly support the claims). Indeed, Dr.
`
`Peppas testified an incorporation by reference is an admission of fact by the
`
`applicant. See EX1041, ¶¶148-150; see also EX2011, 117:9-19.
`
`
`
`Accordingly, the ’876 patent properly claims priority to the ’558
`
`Provisional, including its inherent disclosure of alkyl glycosides.
`
`B. CLAIM CONSTRUCTION
`
`1. “consisting of”
`
`
`
`The ’876 patent has one independent claim – claim 1 – which discloses “a
`
`pharmaceutical solution for nasal administration consisting of” a list of elements.
`
`EX1001, 63:25-34 (emphasis added). The transitional phrase “consisting of” is a
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`close-ended exclusive term that limits the claimed invention to contain “only what
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`is expressly set forth in the claim.” Multilayer Stretch Cling Film Holdings, Inc. v.
`
`Berry Plastics Corp., 831 F.3d 1350, 1358 (Fed. Cir. 2016) (citation omitted). The
`
`prosecution history of the parent application, U.S. Patent Application No.
`
`13/495,942 (’942 Application), suggests the same: in amending independent Claim
`
`1 in response to an Office action, Neurelis argued that the “transitional phrase
`
`‘consisting of’ excludes any element, step, or ingredient not specified in the claim.
`
`Thus, the pending claims exclude such additional ingredients as water, poloxamer
`
`and benzalkonium chloride, which Sonne teaches.” EX1004, 2148-2149 (citing
`
`MPEP § 2111.03.). Accordingly, the “consisting of” language should be construed
`
`to limit the pharmaceutical solution to “a benzodiazepine drug, one or more natural
`
`or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount
`
`from about 30% to about 95% (w/w); ethanol and benzyl alcohol in a combined
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`amount from about 10% to about 70% (w/w); and an alkyl glycoside” to the
`
`exclusion of any other excipients. See also EX2012, ¶41.
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`2. “in a combined amount”
`
`
`
`Independent claim 1 additionally discloses “ethanol and benzyl alcohol in a
`
`combined amount from about 10% to about 70% (w/w).” EX1001, 63:25-34
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`(emphasis added). The use of the conjunctive “and” with “in a combined amount”
`
`requires that each of ethanol and benzyl alcohol be present in an amount >0%
`
`
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`IPR2019-00451
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`
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`(w/w). Medgraph, Inc. v. Medtronic, Inc., 843 F.3d 942, 949 (Fed. Cir. 2016)
`
`(giving “and” its plain meaning requiring both conditions when not mutually
`
`exclusive). The prosecution history supports this construction. For example, during
`
`prosecution of the parent ’942 Application, Neurelis amended independent claim 1
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`from requiring “one or more alcohols or glycols, or any combination thereof, in an
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`amount from about 10% to about 70% (w/w)” to “ethanol and benzyl alcohol in a
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`combined amount from about 10% to about 70% (w/w)” (EX1004, 2139) and
`
`argued that “[n]owhere does Sonne or Meezan teach solutions consisting of
`
`benzodiazepine, 30-90% tocopherol or tocotrienol, an alkyl glycoside and both
`
`ethanol and benzyl alcohol in a combined concentration of 10-70% (w/w)”
`
`(EX1004, 2148-49 (emphasis in original)). Thus, construing “in a combined
`
`amount” to include 0% (w/w) of either ethanol or benzyl alcohol would render the
`
`“combined” term meaningless.6 See Gemstar-TV Guide Int’l, Inc. v. Int’l Trade
`
`
`
`6 Strangely, and without opining that “in a combined amount” means anything
`
`other than adding two or more ingredients, Dr. Peppas states that a disclosure in
`
`Gwozdz of 10% ethanol and 0% benzyl alcohol meets the claim limitation of a
`
`combined total of 10-30%. E.g., EX1041, ¶397. Dr. Peppas’ interpretation of this
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`claim term is unsupported by the claim language or the law.
`
`
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`-14-
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`IPR2019-00451
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`
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`Comm’n, 383 F.3d 1352, 1375 (Fed. Cir. 2004) (“The ordinary meaning of
`
`‘combining,’ which is a present participle of ‘combine,’ is ‘to cause (as two or
`
`more things or ideas) to mix together: MINGLE: BLEND.”) (emphasis added)
`
`(quoting Webster's Third New Int’l Dictionary 452 (1993)). Additionally, the
`
`specification only discloses examples of benzyl alcohol and ethanol in amounts
`
`>0%. EX1001, passim. Accordingly, “in a combined amount” should be construed
`
`to mean “in a combined amount from about 10% to about 70% (w/w), where each
`
`of ethanol and benzyl alcohol is present in an amount >0%”. See also EX2012,
`
`¶42.
`
`C. THE LEVEL OF ORDINARY SKILL IN THE ART
`
`
`
`Neurelis disputes certain aspects of Aquestive’s description of the level of
`
`ordinary skill in the art. First, Aquestive and its expert – Dr. Peppas – describe the
`
`POSA as one having at least a bachelor’s degree in chemical, biological, or
`
`pharmaceutical sciences or a medial degree and “several years of experience in the
`
`field of transmucosal . . . pharmaceutical formulation development.” EX1041, ¶74.
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`As Neurelis’ expert Dr. Gizurarson explains and as further detailed below, the
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`formulation of a benzodiazepine for intranasal administration is a difficult and
`
`complex science requiring a higher skill set and knowledge than a POSA with a
`
`bachelor’s degree “with several years of experience.” EX2012, ¶¶28-29.
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`Specifically, the POSA would be working against physiological constraints of
`
`
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`IPR2019-00451
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`
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`active ingredient uptake due to the nasal anatomy, as well as the very low
`
`solubility of benzodiazepines in formulating the pharmaceutical composition
`
`disclosed in the ’876 patent. Id.
`
`
`
`Accordingly, a POSA would at least have held a Master’s degree with many
`
`years of experience, or a Ph.D. or Pharm.D degree with several years of
`
`experience, or its equivalent research experience. Id., ¶29.
`
`
`
`Second, Aquestive and Dr. Peppas describe the POSA as a “medicinal
`
`chemist, pharmaceutical chemist, chemist, or biologist involved in the research and
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`development of pharmaceutical formulations for the treatment of epilepsy and
`
`related diseases/disorders.” EX1041, ¶74. Chemists are primarily concerned with
`
`chemical structures and synthesizing new chemical compounds and Dr. Peppas
`
`does not explain what role a medicinal chemist would play in the research and
`
`development of benzodiazepine pharmaceutical formulations for intranasal
`
`administration – especially where, as here, the chemical structures were all known.
`
`EX2012, ¶30.
`
`
`
`Accordingly, a POSA would have had knowledge of benzodiazepine
`
`structure and function, including solubility issues with benzodiazepines in general.
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`Id., ¶31. The POSA would further have knowledge and practical experience
`
`working with intranasal formulations, including knowledge of the physiology and
`
`anatomy of the nasal cavity, with relevant experience in developing intranasal
`
`
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`IPR2019-00451
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`
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`formulations. Id. Notably, Aquestive and Dr. Peppas’ description of a POSA
`
`having experience in “rectal, vaginal, ocular, lacrimal, nasolacrimal, buccal,
`
`sublingual, urethral, inhalation, and auricular” delivery as “related fields” does not
`
`take into consideration the differences in formulating an intranasal product and
`
`complexities of the intranasal pathway. Id., ¶32; see also EX2011, 118:18-120:19.
`
`D. AQUESTIVE’S UNPATENTABILITY ANALYSIS AND THE INSTITUTION
`DECISION HINGE ON INCORRECT THEORIES OF PATENT PRIORITY
`
`
`
`Aquestive’s entire theory of unpatentability rests on an alleged lack of
`
`written description in the ’558 Provisional. Compare Pet. 6 (arguing prior art
`
`Gwozdz (EX1011) entitled to 28 March 2008 priority) and 18-20 (arguing
`
`challenged patent not entitled to its 28 March 2008 priority). Specifically,
`
`Aquestive and Dr. Peppas represent that the ’876 patent cannot claim priority to
`
`the ’558 Provisional because the ’876 patent requires the presence of an alkyl
`
`glycoside and “the presence of any alkyl glycoside (either generally or particularly)
`
`– regardless of amount – was not disclosed, described, or enabled by ’558
`
`Provisional.” Pet. 20; see also EX1041, ¶¶64-70. Aquestive needs this theory to be
`
`true because its primary reference, Gwozdz (EX1011), has the same filing date as
`
`the ’876 patent and, thus, would not otherwise qualify as prior art. Yet, as detailed
`
`below, Aquestive facially failed to consider the entire disclosure of the provisional
`
`application, including the most relevant disclosure for what Aquestive alleged
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`IPR2019-00451
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`
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`was missing from the description. Pet., passim. For a separate reason not raised by
`
`Aquestive, the Board concluded that the ’876 patent was not entitled to the ’558
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`Provisional priority date based on a flawed understanding of prosecution formality.
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`Neither theory of priority is supported in law or in fact.
`
`1. Aquestive Never Met its Burden to Establish a Facially
`Reasonable Likelihood of Unpatentability
`
`
`
`Under 35 U.S.C. §314(a), the Director may not institute an IPR unless:
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`the information presented in the petition filed under section 311 and any
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`response filed under section 313 shows that there is a reasonable
`
`likelihood that the petitioner would prevail with respect to at least 1 of
`
`the
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