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 PRELIMINARY RESPONSE
`35 U.S.C. § 313
`
`

`

`TABLE OF CONTENTS
`
`Page
`Precise Requested Relief .................................................................................. 1
`
`Statement of Reasons to Deny .......................................................................... 1
`
`I.
`
`II.
`
`A.
`
`B.
`C.
`
`Background .......................................................................................... 1
`1.
`Epilepsy and epilepsy treatment ................................................. 1
`2.
`The challenged patent and claims ............................................... 2
`3.
`Prosecution history ...................................................................... 3
`Claim Construction............................................................................... 4
`Denial Warranted Under Section 325(d) .............................................. 5
`1.
`Factors a-c: The Similarities and Material Differences
`Between the Asserted Art and the Prior Art Involved
`During Examination; the Cumulative Nature of the
`Asserted Art and the Prior Art Evaluated During
`Examination; and the Extent to which the Asserted Art
`was Evaluated During Examination ........................................... 9
`Factor d: The Extent of Overlap Between the Arguments
`Made During Examination and the Manner in which
`Petitioner Relies on the Prior Art or Patent Owner
`Distinguishes the Prior Art ........................................................ 13
`Factor e: Whether Petitioner has Pointed Out Sufficiently
`How the Examiner Erred in Evaluating the Asserted Prior
`Art ............................................................................................. 22
`Factor f: The Extent to which Additional Evidence and
`Facts Presented in the Petition Warrant Reconsideration
`of the Prior Art or Arguments ................................................... 23
`Denial Warranted Under Section 314(a) ............................................ 24
`D.
`III. Conclusion ......................................................................................................28
`
`2.
`
`3.
`
`4.
`
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`TABLE OF AUTHORITIES
`
`Page(s)
`
`CASES
`Acceleration Bay, LLC v. Activision Blizzard Inc., 908 F.3d 765 (Fed.
`Cir. 2018) ....................................................................................................... 26
`Allsteel Inc. v. DIRTT Envtl. Sols. Ltd., IPR2015-01690, Paper 13, 4-5
`(PTAB Apr. 4, 2016) ..................................................................................... 27
`Amneal Pharms, LLC v. Almirall, LLC, IPR2019-00207, Paper 13, 11-
`12 (PTAB May 10, 2019) .................................................................... 8, 10, 11
`Argentum Pharm., LLC v. Merck Patentgesellschaft, IPR2018-00423,
`Paper 7, 19 (PTAB July 23, 2018)................................................................. 23
`Becton Dickinson and Co. v. B. Braun Melsungen AG, IPR2017-
`01586, Paper 8 (PTAB Dec. 15, 2017) .................................................... 7, 8, 9
`Cisco Sys., Inc. v. C-Cation Techs., LLC, IPR2014-00454, Paper 12,
`9-10 (PTAB Aug. 29, 2014) ............................................................................ 5
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375
`(Fed. Cir. 2015) .............................................................................................. 25
`Edge Endo, LLC v. Maillefer Instruments Holding S.A.R.L., IPR2018-
`01349, Paper 15, 13-14 (PTAB Jan. 14, 2019) ............................................. 22
`General Plastic Industrial Co. v. Canon Kabushiki Kaisha, IPR2016-
`01357, Paper 19 (PTAB Sept. 6, 2017) ....................................................... 7, 8
`Hospira, Inc. v. Genentech, Inc., IPR2017-00739, Paper 16, 18
`(PTAB July 27, 2017) ...................................................................................... 8
`Juniper Networks, Inc. v. Mobile Telecomms. Techs., LLC, IPR2017-
`00642, Paper 31, 10-11 ............................................................................ 22, 23
`Microsoft Corp. v. Koninklijke Philips N.V., IPR2018-00279, Paper
`11, 12-15 (PTAB June 8, 2018) ..................................................................... 10
`Neil Ziegman, N.P.Z., Inc. v. Stephens, IPR2015-01860, Paper 11, 2
`(PTAB Feb. 24, 2016) ................................................................................... 11
`Sensata Techs. Inc. v. Danfoss Power Sols. Inc., IPR2017-02069,
`Paper 8, 16-17 (PTAB Feb. 26, 2018) ........................................................... 23
`Tech. Licensing Corp. v. Videotek, Inc., 545 F.3d 1316 (Fed. Cir.
`2008) .............................................................................................................. 25
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`Unified Patents Inc. v. Berman, IPR2016-01571, Paper 10, 11-12
`(PTAB Dec. 14, 2016) ................................................................................... 11
`Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991) .................................. 26
`Vestas-Am. Wind Tech., Inc. v. Gen. Elec. Co., IPR2018-01029, Paper
`9, 15-16 (PTAB Oct. 19, 2018) ..................................................................... 24
`STATUTES
`35 U.S.C. § 102(a) ................................................................................................... 25
`35 U.S.C. § 312(a)(3) ............................................................................................... 27
`35 U.S.C. § 314(a) ..................................................................................................... 8
`35 U.S.C. § 325(d) ..................................................................................................... 5
`35 U.S.C. § 120 ........................................................................................................ 26
`RULES
`37 C.F.R. § 42.1(b) .................................................................................................... 8
`37 C.F.R. § 42.6(a)(3) ................................................................................................ 5
`37 C.F.R. § 42.104(b)(4) .......................................................................................... 27
`83 Fed. Reg. 51340, 51342-43 ................................................................................... 5
`
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`PRECISE REQUESTED RELIEF
`I.
`The patent owner (“Neurelis”) requests that institution be denied because the
`
`petitioner (“Aquestive”) has failed to demonstrate a reasonable likelihood that any
`
`challenged claim is unpatentable.
`
`STATEMENT OF REASONS TO DENY
`II.
`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
`
`movement or function, sensation, awareness, and/or behavior. A seizure may last
`
`from a few seconds to a few minutes. Causes of epilepsy include head or brain
`
`injury, brain tumor, central nervous system infection, stroke, and genetics, but in
`
`most cases the etiology is unknown. EX2004, 3; EX2001.
`
`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. Uncontrolled seizures may result in injury, anxiety,
`
`depression, brain damage and death, while also interfering with normal day-to-day
`
`activities, such as working, going to school, and socializing with friends and
`
`family. Id. There are no quick, simple and effective treatments available to control
`
`epileptic seizures; however, nasal sprays could be the best solution. EX2003.
`
`Because of this, the United States Food and Drug Administration granted patent
`
`owner Neurelis a Fast Track designation to develop a diazepam intranasal solution
`
`for this very purpose. EX2002.
`
`2. The challenged patent and claims
`Diazepam belongs to a family of drugs (benzodiazepines) that are useful for
`
`treating seizures. EX1001, 1:29-39. While other benzodiazepine formulations are
`
`available for treating seizures, they suffer from solubility problems. EX1001,
`
`1:53-57. The existing formulations can also be very difficult to administer to a
`
`subject during a seizure, particularly if the person administering therapy is not a
`
`health professional. EX1001, 1:53-2:20. The present inventors realized that while
`
`nasal delivery would address the drug-administration problem, solubility problems
`
`can be especially difficult using a nasal administration route. The present
`
`inventors developed the use of vitamin E-analogs and alcohols as substantial
`
`fractions of the formulation to address the solubility problem, while still providing
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`an acceptable nasal-delivery formulation. The alkyl glycoside functions as a
`
`penetration enhancer to improve bioavailability. EX1001, 16:55-56, 34:45-48.
`
`Challenged claim 1, from which all the other challenged claims depend, defines the
`
`invention as (EX1001, 63:26-34):
`
`A method of treating a patient with a disorder which is treatable
`with a benzodiazepine drug, comprising:
`administering to one or more nasal mucosal membranes of a
`patient a pharmaceutical solution for nasal administration consisting
`of
`
`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 amount from about
`10% to about 70% (w/w); and
`an alkyl glycoside.
`
`The challenged patent (“Cartt’876”) issued in 2017, but claims benefit back
`
`to 2008. EX1001, cover.
`
`3. Prosecution history
`Aquestive proposes two obviousness grounds, both relying on a combination
`
`of references, PCT Publication WO2009/120933 (“Gwozdz”, EX1014) and U.S.
`
`Patent Application Publication No. 2006/0046962 (“Meezan’962”, EX1011). The
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`examiner (Adam Milligan) was very familiar with both references, which are both
`
`cited on the face of the challenged patent. EX1001, 2, 3. Indeed, Aquestive
`
`concedes that “Meezan’962 was relied on by the Examiner during prosecution of
`
`both the parent ‘546 Patent and grandparent ‘439 application.” Petition, 9. The
`
`same examiner held the challenged claims to be patentably indistinct from claims
`
`in the ’546 patent, requiring a terminal disclaimer to overcome the rejection.
`
`EX1002, 0169. Hence, the same examiner had already applied and allowed
`
`patentably indistinct claims in the parent application over U.S. Patent 6,193,985
`
`(“Sonne”, EX1013), in combination with Meezan’962.
`
`B. CLAIM CONSTRUCTION
`Aquestive offers constructions for Vitamin E, Bioavailability, % (w/w) and
`
`% (w/v) that are consistent with the use of those terms in the specification and
`
`claims. Petition, 9-13. Aquestive also offers a construction for about 56.47% (w/v)
`
`vitamin E, which Aquestive construes to mean “53.65% to 59.29% (w/v) vitamin
`
`E” based on an assumption that “about” means ±5%. Petition, 14. Aquestive does
`
`not explain why 5% is the proper amount of variation other than to refer to its
`
`expert’s declaration. Id. The expert simply says that ±5% is a middle range value
`
`for the values provided in the specification and seems right to him. EX1041, ¶98.
`
`To the extent that Aquestive intends to incorporate the expert’s reasoning
`
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`into the petition without explanation, this would be an improper incorporation and
`
`a self-help effort to avoid the word-limit in a petition that Aquestive has certified
`
`as being right at the limit. 37 C.F.R. § 42.6(a)(3); Cisco Sys., Inc. v. C-Cation
`
`Techs., LLC, IPR2014-00454, Paper 12, 9-10 (PTAB Aug. 29, 2014) (informative)
`
`(impermissible incorporation of arguments into petition from declaration);
`
`Petition, 94 (certifying a word count of 13,725). Even if incorporation were proper,
`
`however, the expert’s reasoning is arbitrary. Neurelis notes that the challenged
`
`patent contains a definition of “about”. EX1001, 17:60-65. Aquestive accepts that
`
`an applicant may act as its own lexicographer. Petition, 9.
`
`Aquestive also contends that it is not bound by its own constructions in other
`
`proceedings. Petition, 10. Such reservations are improper and, if accepted, would
`
`undermine the Board’s recent adoption of its present claim-construction standard.
`
`Changes to the Claim Construction Standard for Interpreting Claims in Trial
`
`Proceedings Before the Patent Trial and Appeal Board, 83 Fed. Reg. 51340,
`
`51342-43 (PTAB Oct. 11, 2018) (explaining the goals of promoting uniformity and
`
`predictability, while discouraging gamesmanship).
`
`C. DENIAL WARRANTED UNDER SECTION 325(d)
`The Board has authority to reject a petition if the Office has previously
`
`considered the same or substantially the same issues. 35 U.S.C. § 325(d).
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`Specifically, § 325(d) provides a mechanism for limiting harassment of patent
`
`owners by taking previous USPTO reviews of the claims into consideration. With
`
`respect to Ground I1—the only ground challenging the sole independent claim—
`
`Aquestive raises substantially the same issues that the Office already considered
`
`and rejected during examination of the ’876 patent. Specifically, the Office has
`
`already considered and discussed Sonne in combination with Meezan’962 in over
`
`five years and two applications’ worth of prosecution history. While admitting that
`
`the examiner cited Meezan’962 during examination of the ’876 Patent (Petition, 9),
`
`Aquestive now merely substitutes Gwozdz for Sonne. Gwozdz, which was before
`
`the Office during examination, however, is cumulative of Sonne with respect to the
`
`relevant limitations of the independent claim of the ’876 Patent. The examiner was
`
`1 Ground II challenges dependent claims 17-23 in light of Gwozdz in further view
`
`of Meezan’962 and Cartt’784 (EX1015). Cartt’784 is specifically cited for the
`
`limitations of dependent claims 17-23, including benzodiazepine amounts and
`
`formulation volumes, and does not remedy the deficiencies of Gwozdz and
`
`Meezan’962 noted by the Office during examination. Accordingly, because claims
`
`17-23 depend from independent claim 1, and Aquestive’s challenge to claim 1
`
`fails, Aquestive’s challenge against these dependent claims fails as well.
`
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`fully aware of Gwozdz, which (although not noted in the petition) is cited as a
`
`reference on the face of the patent. EX1001, 3, top of left column.
`
`The Board has listed the following factors as a framework for exercising its
`
`discretion under § 325(d) in: “(a) the similarities and material differences between
`
`the asserted art and the prior art involved during examination; (b) the cumulative
`
`nature of the asserted art and the prior art evaluated during examination; (c) the
`
`extent to which the asserted art was evaluated during examination, including
`
`whether the prior art was the basis for rejection; (d) the extent of the overlap
`
`between the arguments made during examination and the manner in which the
`
`Petitioner relies on the prior art or Patent Owner distinguishes the prior art;
`
`(e) whether the Petitioner has pointed out sufficiently how the examiner erred in its
`
`evaluation of the asserted prior art; and (f) the extent to which additional evidence
`
`and facts presented in the petition warrant reconsideration of the prior art or
`
`arguments.” Becton Dickinson and Co. v. B. Braun Melsungen AG, IPR2017-
`
`01586, Paper 8 (PTAB Dec. 15, 2017) (citation omitted) (informative).2 This
`
`2 Neurelis is aware that, after it filed responses in IPR2019-00449 and -00450, the
`
`Board issued a nonprecedential opinion holding that the first factor of the test in
`
`General Plastic Industrial Co. v. Canon Kabushiki Kaisha, IPR2016-01357, Paper
`
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`discretion “involves a balance between “several competing interests,” including
`
`‘“the interests in conserving the resources of the Office and granting patent owners
`
`repose on issues and prior art that have been considered previously.”’ Hospira, Inc.
`
`v. Genentech, Inc., IPR2017-00739, Paper 16, 18 (PTAB July 27, 2017) (citation
`
`omitted) (informative); see also 37 C.F.R. § 42.1(b) (setting policy “to secure the
`
`19 (PTAB Sept. 6, 2017) (precedential) had not been shown to apply when the
`
`earlier challenge was to a different patent. Amneal Pharms, LLC v. Almirall, LLC,
`
`IPR2019-00207, Paper 13, 11-12 (PTAB May 10, 2019). Respectfully, General
`
`Plastic is directed to a different statute (35 U.S.C. § 314(a)), while the Becton
`
`factors apply to the relief sought here. Moreover, the cases are factually
`
`distinguishable because Amneal does not purport to involve a challenged patent
`
`that is a continuation of, and was held to be patentably indistinct over, the patent
`
`with the claims that were the subject of the barring rejection. On the present facts,
`
`the relevance of the earlier rejection to the challenged claims is direct and
`
`undisputed, and is consistent with § 325(d)’s requirement that “the same or
`
`substantially the same prior art or arguments previously were presented to the
`
`Office.” Aquestive’s failure to address an issue raised on the face of its own
`
`exhibits does not warrant a do-over.
`
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`just, speedy, and inexpensive resolution of every proceeding”).
`
`As detailed below, all of the Becton factors weigh in favor of denying
`
`institution:
`
`1. Factors a-c: The Similarities and Material Differences
`Between the Asserted Art and the Prior Art Involved
`During Examination; the Cumulative Nature of the
`Asserted Art and the Prior Art Evaluated During
`Examination; and the Extent to which the Asserted Art
`was Evaluated During Examination
`The first three factors heavily favor the Board exercising its discretion to
`
`deny institution. Aquestive’s Ground I references—Gwozdz and Meezan’962—
`
`were before the examiner during examination. Moreover, the same examiner
`
`applied a reference substantially the same as Gwozdz—Sonne—in combination
`
`with Meezan’962 to reject, then allow, claims that he considered patentably
`
`indistinct from the challenged claims.3 Indeed, the examiner detailed the
`
`3 Notably, the same examiner was responsible for examining both the
`
`challenged claims and the earlier applications in which Sonne and Meezan’962
`
`were applied. The same examiner allowed the earlier claims over the combined
`
`teachings of Sonne and Meezan’962, but rejected the challenged claims as being
`
`patentably indistinct from those earlier claims, resulting in a terminal disclaimer
`
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`disclosures of the Sonne and Meezan’962 references in numerous rejections;
`
`rejections that were extensively discussed in a lengthy back-and-forth between the
`
`examiner and applicant.
`
`As discussed, Gwozdz was before the examiner, was repeatedly cited in
`
`Information Disclosure Statements (“IDS”) submitted during examination, and is
`
`cited as a reference on the challenged patent itself. See, e.g., EX1002, 0126, 0179,
`
`0515 (IDS submitted with the ’876 Patent); EX1004, 2057, 2137 (IDS submitted
`
`with the ’546 Patent); EX1007, 2366, 2814 (IDS submitted with the ’439
`
`Application); EX1001, 3; see also EX1041, ¶ 31 (“Sonne, Gwozdz, Meezan ’962,
`
`and Cartt’865 were of record during prosecution of the ’876 Patent.”). While the
`
`examiner did not apply Gwozdz during examination, Aquestive uses Gwozdz to
`
`for the challenged claims. The Board has declined to institute review under similar
`
`circumstances. See, e.g., Microsoft Corp. v. Koninklijke Philips N.V., IPR2018-
`
`00279, Paper 11, 12-15 (PTAB June 8, 2018) (prosecution history shows the
`
`examiner was familiar with the asserted references and applied them, including in
`
`related applications); Edge Endo, LLC v. Scianamblo, IPR2018-01320, Paper 15,
`
`11-12 (PTAB Jan. 14, 2019) (similar).
`
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`replicate the examiner’s use of Sonne and his related arguments. E.g., Unified
`
`Patents Inc. v. Berman, IPR2016-01571, Paper 10, 11-12 (PTAB Dec. 14, 2016)
`
`(informative) (denying institution where petitioner asserted prior art “in
`
`substantially the same manner as the Examiner used” different prior art during
`
`examination); Neil Ziegman, N.P.Z., Inc. v. Stephens, IPR2015-01860, Paper 11, 2
`
`(PTAB Feb. 24, 2016).
`
`In particular, Aquestive cites Gwozdz as teaching the claimed invention by
`
`disclosing a “pharmaceutical solution comprising a therapeutic agent dissolved in
`
`one or more natural or synthetic tocopherols or tocotrienols, or any combination
`
`thereof and one or more alcohols or glycols, or any combination thereof” and
`
`“methods of treatment of a patient with these pharmaceutical solutions.” Petition,
`
`23. Aquestive further contends that Gwozdz relates to “solving generally-
`
`recognized problems associated with, inter alia, intranasal administration of low-
`
`solubility drugs.” Petition, 33. However, during examination, the examiner
`
`considered Sonne for these same features. Specifically, the examiner argued that
`
`Sonne teaches tocopherol compositions for the delivery of biologically active
`
`agents which are sparingly soluble in water, such as diazepam, where “[o]ne
`
`particular nasal formulation contains 5g of diazepam, 44g Tenox GT2 (70%
`
`tocopherol),” “the composition may be in the form of a spray formulation,” and
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`where the “[n]asal . . . administrations are particularly preferred.” EX1007, 2806-
`
`08, 3316; EX1004, 2125-27. The examiner additionally argued Sonne further
`
`discloses that “co-solvents such as ethanol, benzyl alcohol, sesame oil or propylene
`
`glycol can be used in order to optimize the formulations bioadhesion, sprayability
`
`and viscosity.” EX1007, 2807, 3070-72, 3098, 3473, 3475; EX1004, 2125.
`
`Furthermore, Aquestive combines Gwozdz with Meezan’962 recognizing
`
`that Gwozdz itself does not disclose alkyl glycosides. Petition, 30 (“A POSITA
`
`looking to optimize the bioavailability of solutions prepared according to Gwozdz
`
`would be motivated to add small amounts of dodecyl maltoside . . . as preferred by
`
`Meezan’962.”). The examiner combined Sonne with Meezan’962 for the same
`
`reason. EX1007, 3070-71; EX1004, 2125-27. Thus, Gwozdz contains no relevant
`
`additional content beyond what the examiner applied in rejecting and then allowing
`
`claims he considered patentably indistinct.
`
`Aquestive provides no explanation why the Board should analyze the
`
`Gwozdz-Meezan’962 combination differently than how the examiner analyzed the
`
`Sonne-Meezan’962 combination during examination. Cf. Unified Patents,
`
`Paper 10, 11-12 (“Petitioner fails to present any argument distinguishing the
`
`Examiner’s prior consideration of [other prior art] or to provide a compelling
`
`reason why we should readjudicate substantially the same prior art and arguments
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`…”). Accordingly, the first three factors weigh strongly in favor of denying the
`
`petition.
`
`2. Factor d: The Extent of Overlap Between the Arguments
`Made During Examination and the Manner in which
`Petitioner Relies on the Prior Art or Patent Owner
`Distinguishes the Prior Art
`Since the references are the same or substantially the same, Aquestive’s
`
`arguments substantially overlap those made during examination of the ’546 Patent
`
`and the ’439 Application, which weighs in favor of denying institution under
`
`§ 325(d). As detailed in the chart below, the arguments of Aquestive and Dr.
`
`Peppas mirror those made during examination.
`
`Aquestive argues:
`
`Examiner argued:
`
`Ground 1: unpatentable (§ 103) over
`
`’439 Application: unpatentable (§ 103)
`
`Gwozdz and Meezan’962. Petition, 5.
`
`over Sonne, EX1007, 0476-79, 0514-15;
`
`over Sonne and Meezan’962, EX1007,
`
`0480-81, 0515-0516; and over Lehat in
`
`view of Sonne and Meezan’962,
`
`EX1007, 2806-10, 2938-39, 3069-72,
`
`3095-99, 3313-18, 3472-77.
`
`’546 Patent: unpatentable (§ 103) over
`
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`Aquestive argues:
`
`Examiner argued:
`
`Sonne and Meezan’962. EX1004, 2125-
`
`27.
`
`Gwozdz teaches a “pharmaceutical
`
`’439 Application:
`
`solution comprising a therapeutic agent
`
`Sonne teaches tocopherol compositions
`
`dissolved in one or more natural or
`
`for the delivery of biologically active
`
`synthetic tocopherols or tocotrienols, or
`
`agents which are sparingly soluble in
`
`any combination thereof and one or
`
`water, such as diazepam . . . One
`
`more alcohols or glycols, or any
`
`particular nasal formulation contains 5g
`
`combination thereof” and “methods of
`
`of diazepam, 44g Tenox GT2 (70%
`
`treatment of a patient with these
`
`tocopherol) . . . the composition may be
`
`pharmaceutical solutions.” Petition, 23.
`
`in the form of a spray formulation . . .
`
`Sonne teaches that “transmucosal
`
`Gwozdz relates to “solving generally-
`
`delivery is preferred” and “[n]asal . . .
`
`recognized problems associated with,
`
`administrations are particularly
`
`inter alia, intranasal administration of
`
`preferred.”
`
`low-solubility drugs.” Petition, 33.
`
`EX1007, 2806-08, 3316.
`
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`Aquestive argues:
`
`Examiner argued:
`
`Gwozdz’s invention can be used with
`
`Meezan’962 teaches that alkyl glycoside
`
`various benzodiazepines, including
`
`is an absorption enhancer for drug
`
`diazepam. Petition, 23.
`
`administration and demonstrates that
`
`alkyl glycosides can increase drug
`
`Meezan’962 teaches alkyl glycosides
`
`absorption when administered via nasal
`
`compositions for delivery of therapeutic
`
`spray, where the active ingredient may
`
`agents that are combined with
`
`be in the form of nanoparticles.
`
`therapeutic agents resulting in increased
`
`EX1007, 2806-08.
`
`absorption and bioavailability when
`
`It would have been obvious to a POSA
`
`administered. A POSA would also apply
`
`administering the nasal spray
`
`Meezan’962 to benzodiazepines.
`
`formulation of Sonne to use the
`
`Petition, 28-30, 33-34, 37-41.
`
`surfactant taught by Meezan’962 to
`
`improve the bioavailability of drug
`
`Peppas Declaration:
`
`administration via a nasal spray.
`
`Gwozdz discloses all elements of the
`
`EX1007, 3070-71.
`
`claims of the ’876 patent, with the
`
`exception of alkyl glycosides and some
`
`“Sonne explicitly teaches ‘[t]o optimize
`
`-15-
`
`IPR2019-0045
`
`

`

`Aquestive argues:
`
`Examiner argued:
`
`dosing regiments. Specifically, Gwozdz
`
`the stability of the emulsions, it may be
`
`discloses a pharmaceutical solution
`
`appropriate to add surfactants such as
`
`comprising a therapeutic agent dissolved
`
`Vitamin E TPGS poloxamers (e.g.,
`
`in one or more natural or synthetic
`
`Pluronic RTM), cetearyl glucoside,
`
`tocopherols or tocotrienols, or any
`
`polysorbates or sorbitan esters of fatty
`
`combination thereof and one or more
`
`acids, or any of the other surfactants
`
`alcohols or glycols, or any combination
`
`well known in the art.’ Given an explicit
`
`thereof. EX1041, ¶ 192.
`
`teaching to include a surfactant, there is
`
`no reason for one of skill in the art to be
`
`Meezan’962 discloses intranasal
`
`taught away from including a
`
`solutions with the addition of alkyl
`
`surfactant.” EX1007, 3316.
`
`glycosides to greatly increase
`
`’546 Patent:
`
`bioavailability. EX1041, ¶¶ 222-223.
`
`Sonne teaches tocopherol compositions
`
`for the delivery of biologically active
`
`A POSA seeking to optimize the
`
`agents which are sparingly soluble in
`
`bioavailability of the solutions in
`
`water, such as diazepam . . . One
`
`Gwozdz would look to Meezan’962 to
`
`particular nasal formulation contains 5g
`
`-16-
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`IPR2019-0045
`
`

`

`Aquestive argues:
`
`Examiner argued:
`
`add alkyl glycoside. EX1041, ¶¶ 363-
`
`of diazepam, 44g Tenox GT2 (70%
`
`370.
`
`tocopherol) . . . the composition may be
`
`in the form of a spray formulation . . .
`
`EX1004, 2125-27.
`
`Meezan’962 teaches that alkyl
`
`glycosidase is an absorption enhancer
`
`for drug administration and discloses
`
`use of alkyl glycoside in nasal
`
`administration. Specifically, Meezan
`
`demonstrates that the addition of 0.25%
`
`of alkyl glycoside can increase drug
`
`absorption from about 3%
`
`bioavailability to about 90%
`
`bioavailability when the drug is
`
`administered via a nasal spray. Meezan
`
`further teaches that active ingredients
`
`for the nasal spray may be in the form of
`
`-17-
`
`IPR2019-0045
`
`

`

`Aquestive argues:
`
`Examiner argued:
`
`nanoparticles.
`
`It would have been obvious to one of
`
`ordinary skill in the art formulating the
`
`composition of Sonne to incorporate the
`
`alkyl glycosidase of Meezan in order to
`
`increase nasal absorption.
`
`It would have also been obvious to
`
`include the active ingredient in the form
`
`of nanoparticles, given that such a form
`
`is taught to be suitable by Meezan’962.
`
`EX1004, 2125-27.
`
`Examples of alcohols in Gwozdz
`
`’439 Application: Sonne also teaches
`
`include ethanol and benzyl alcohol.
`
`that a co-solvent such as ethanol, benzyl
`
`Petition, 23.
`
`alcohol, sesame oil or propylene glycol
`
`can be used in order to optimize the
`
`Gwozdz teaches that the dilution of a
`
`formulations bioadhesion, sprayability
`
`tocopherol/tocotrienol with alcohol
`
`and viscosity. When ethanol is used in
`
`-18-
`
`IPR2019-0045
`
`

`

`Aquestive argues:
`
`Examiner argued:
`
`reduces inherent viscosity of the
`
`the formulations, it may be used in an
`
`tocopherol and tocotrienol thereby
`
`amount of 11% by weight of the
`
`allowing for generation of sprayable
`
`formulation . . . viscosity can be reduced
`
`formulations. The combination
`
`by the addition of co-solvents such as
`
`additionally provides increased
`
`ethanol.
`
`bioavailability of the therapeutic agent.
`
`EX1007, 2807.
`
`Petition, 27-28.
`
`To increase viscosity, co-solvents such
`
`Peppas Declaration:
`
`as ethanol can be added. Since ethanol
`
`Gwozdz teaches a pharmaceutical
`
`can be irritating to certain mucosal
`
`solution by dissolving a difficult to
`
`tissue, Sonne alternatively teaches
`
`solubilize therapeutic agent in one or
`
`emulsification as a means to lower
`
`more tocopherols and/or tocotrienols
`
`viscosity. Thus, Sonne teaches three
`
`and one or more alcohols and/or glycols
`
`formulating alternatives, (1) high
`
`as therapeutically acceptable solvents.
`
`viscosity, (2) co-solvents (i.e., ethanol)
`
`Examples of alcohols include ethanol,
`
`addition and (3) emulsification.
`
`propyl alcohol, butyl alcohol, pentanol,
`
`EX1007, 3070-72.
`
`-19-
`
`IPR2019-0045
`
`

`

`Aquestive argues:
`
`Examiner argued:
`
`benzyl alcohol, and any isomers thereof,
`
`and any combinations thereof. A
`
`Sonne teaches the inclusion of ethanol,
`
`solution of a tocopherol and alcohols
`
`benzyl alcohol or propylene glycol in an
`
`will provide increased bioavailability of
`
`amount sufficient to provide the desired
`
`the therapeutic agent. EX1041, ¶¶ 195-
`
`formulation bioadhesion, sprayability
`
`197, 363-370.
`
`and viscosity.
`
`Further disagreeing with applicant that
`
`Sonne does not disclose 7.5% alcohol:
`
`Anticipation may require such a specific
`
`embodiment, but the standard for
`
`obviousness does not require that a
`
`reference provide an exemplary
`
`formulation.
`
`EX1007, 3473, 3475, 3477.
`
`’546 Patent
`
`Sonne teaches a composition that may
`
`contain co-solvents such as ethanol,
`
`-20-
`
`IPR2019-0045
`
`

`

`Aquestive argues:
`
`Examiner argued:
`
`benzyl alcohol, sesame oil and
`
`propylene glycol used in order to
`
`optimize the formulations bioadhesion,
`
`sprayability and viscosity.
`
`It would have been obvious to POSITA
`
`to optimize the type and amount of co-
`
`solvent to provide the desired
`
`bioadhesion, sprayability, and viscosity
`
`given that Sonne teaches that the
`
`purpose of the co-solvents is to modify
`
`the bioadhesion, sprayability and
`
`viscosity of the formulation.
`
`EX1004, 2125.
`
`Ultimately, the examiner allowed the’546 Patent claims and later allowed
`
`the’876 Patent claims despite his prior rejections that substantially the same prior
`
`art rendered earlier claims unpatentable. Aquestive