Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`Paper: 8
`Entered: August 13, 2019
`
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`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`AQUESTIVE THERAPEUTICS, INC.,
`Petitioner,
`v.
`NEURELIS, INC.,
`Patent Owner.
`
`
`Case IPR2019-00451
`Patent 9,763,876 B2
`
`
`Before ZHENYU YANG, JON B. TORNQUIST, and JAMIE T. WISZ,
`Administrative Patent Judges.
`
`WISZ, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`Tel: 571-272-7822
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`Paper: 8
`Entered: August 13, 2019
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`AQUESTIVE THERAPEUTICS, INC.,
`Petitioner,
`v.
`NEURELIS, INC.,
`Patent Owner.
`
`
`Case IPR2019-00451
`Patent 9,763,876 B2
`
`
`Before ZHENYU YANG, JON B. TORNQUIST, and JAMIE T. WISZ,
`Administrative Patent Judges.
`
`WISZ, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`IPR2019-00451
`Patent 9,763,876 B2
`
`INTRODUCTION
`I.
`Aquestive Therapeutics, Inc. (“Petitioner”) filed a Petition (Paper 3,
`“Pet.”) requesting an inter partes review of claims 1–36 of U.S. Patent
`No. 9,763,876 B2 (Ex. 1001, “the ’876 patent”). Neurelis, Inc.1 (“Patent
`Owner”) filed a Preliminary Response (Paper 7, “Prelim. Resp.”).
`We have authority to determine whether to institute an inter partes
`review under 35 U.S.C. § 314, which provides that an inter partes review
`may be instituted only upon a showing that “there is a reasonable likelihood
`that the petitioner would prevail with respect to at least 1 of the claims
`challenged in the petition.” 35 U.S.C. § 314(a). After considering the
`Petition, the Preliminary Response, and the evidence of record, we
`determine that Petitioner has demonstrated a reasonable likelihood of
`prevailing with respect to at least one claim challenged in the Petition.
`Accordingly, we institute an inter partes review of all challenged claims of
`the ’876 patent, based on all of the grounds identified in the Petition. See
`SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348, 1359–60 (2018); PGS Geophysical
`AS v. Iancu, 891 F.3d 1354, 1360 (Fed. Cir. 2018) (interpreting the statute to
`require “a simple yes-or-no institution choice respecting a petition,
`embracing all challenges included in the petition”).
`The following findings of fact and conclusions of law are not final,
`but are made for the sole purpose of determining whether Petitioner meets
`the threshold for initiating review. Any final decision shall be based on the
`
`
`1 Patent Owner informs us that, subsequent to the filing of the Petition, Hale
`Biopharma Ventures, LLC, the originally named Patent Owner in this case,
`assigned its rights in the ’876 patent to Neurelis, Inc. Paper 6, 2 (citing Reel
`048271; Frame 0304).
`
`2
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`IPR2019-00451
`Patent 9,763,876 B2
`full trial record, including any response timely filed by Patent Owner. Any
`arguments not raised by Patent Owner in a timely-filed response may be
`deemed waived, even if they were presented in the Preliminary Response.
`
`A. Related Proceedings
`The parties indicate that the ’876 patent is being challenged by
`Petitioner in IPR2019-00449 and IPR2019-00450. Pet. 2; Paper 4, 2.
`
`B. The ’876 Patent
`The ’876 patent is directed to nasally administered pharmaceutical
`solutions containing one or more benzodiazepine drugs. Ex. 1001, 9:14–17.
`The ’876 patent explains that solubility challenges associated with
`benzodiazepine drugs previously hindered the development of formulations
`intended for oral, rectal, or parenteral administration. Id. at 1:53–57, 19:12–
`15. It was discovered, however, that vitamin E (which includes tocopherols
`and tocotrienols) is an effective carrier for benzodiazepine drugs, as these
`compounds are soluble, or at least partially soluble, in vitamin E. Id. at
`33:8–13, 33:42–45. The ’876 patent also reports that vitamin E “can have
`the added benefit of either avoiding irritation of sensitive mucosal
`membranes and/or soothing irritated mucosal membranes.” Id. at 33:47–49.
`The ’876 patent discloses that one or more lower alcohols, such as
`ethanol and benzyl alcohol, may be used in the formulation. Id. at 2:57–64,
`33:55–67 (noting that to “avoid the drawbacks of emulsions,” the disclosed
`solutions contain vitamin E and “one or more lower alkyl alcohols”).
`In addition, an alkyl glycoside may be added to the formulation to act as a
`penetration enhancer. Id. at 34:2–9.
`
`3
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`IPR2019-00451
`Patent 9,763,876 B2
`C. Illustrative Claim
`Petitioner challenges claims 1–36 of the ’876 patent. Claim 1, which
`is the only independent claim of the ’876 patent, is illustrative of the
`challenged claims, and is reproduced below:
`
`1. 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.
`Ex. 1001, 63:26–34 (formatting added). Challenged claims 2–36
`depend from claim 1, either directly or indirectly.
`
`D. The Asserted Grounds of Unpatentability
`Petitioner contends claims 1–36 of the ’876 patent are unpatentable in
`view of the following grounds. Pet. 5.
`
`4
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`IPR2019-00451
`Patent 9,763,876 B2
`Basis Claims Challenged
`Ground References
`1
`Gwozdz2 and Meezan ’9623 § 103
`1–16, 24–36
`
`2
`
`Gwozdz, Meezan ’962, and
`Cartt ’7844
`
`§ 103
`
`17–23
`
`Petitioner also relies on the Declaration of Nicholas A. Peppas, Sc.D.
`
`Ex. 1041.
`
`II. ANALYSIS
`
`A. Claim Construction
`In this inter partes review, claim terms are construed using the same
`claim construction standard that would be used to construe the claim in a
`civil action under 35 U.S.C. § 282(b). 37 C.F.R. § 42.100(b). Under this
`claim construction standard, claim terms are given their ordinary and
`customary meaning as would have been understood by one of ordinary skill
`in the art at the time of the invention. See id; Phillips v. AWH Corp., 415
`F.3d 1303, 1313 (Fed. Cir. 2005) (en banc). A patentee may define a claim
`term in a manner that differs from its ordinary and customary meaning;
`however, any special definitions must be set forth in the specification with
`reasonable clarity, deliberateness, and precision. See In re Paulsen, 30 F.3d
`1475, 1480 (Fed. Cir. 1994).
`Petitioner provides proposed constructions for the terms “vitamin E,”
`“bioavailability,” “% (w/w),” “% (w/v),” and “about 56.47% (w/v) vitamin
`
`
`2 PCT Pub. No. WO 2009/120933 A2, published October 1, 2009 (Ex. 1014,
`“Gwozdz”).
`3 U.S. Pub. No. 2006/0046962 A1, published March 2, 2006 (Ex. 1011,
`“Meezan ’962”).
`4 U.S. Pub. No. 2008/0279784 A1, published November 13, 2008 (Ex. 1015,
`“Cartt ’784”).
`
`5
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`IPR2019-00451
`Patent 9,763,876 B2
`E.” Pet. 11–14. Patent Owner contends that Petitioner’s constructions of
`“vitamin E,” “bioavailability,” “% (w/w),” and “% (w/v)” “are consistent
`with the use of those terms in the specification and claims,” but finds fault
`with the reasoning and support provided by Petitioner for its construction of
`the term “about 56.47% (w/v) vitamin E.” Prelim. Resp. 4–5. Patent Owner
`nevertheless does not propose its own construction for this term. Id.
`Upon review of the parties’ arguments and the evidence of record, we
`determine that no terms of the ’876 patent require express construction for
`purposes of this Decision. See Nidec Motor Corp. v. Zhongshan Broad
`Ocean Motor Co., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (citing Vivid Techs.,
`Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (“[O]nly
`those terms need be construed that are in controversy, and only to the extent
`necessary to resolve the controversy.”)).
`
`B. Priority Claim of the ’876 patent
`The ’876 patent was filed as U.S. Application No. 14/527,613
`(“the ’613 application”), and is a continuation of U.S. Application No.
`13/495,942 (“the ’942 application”) (issued as U.S. Patent No. 8,895,546)
`(“the ’546 patent”), which is in turn a continuation-in-part (“CIP”) of U.S.
`Application No. 12/413,439 (“the ’439 application”). Ex. 1001, (63). The
`’876 patent also claims priority to provisional applications 61/040,558 (“the
`’558 provisional”), 61/497,017 (“the ’017 provisional”), and 61/570,110
`(“the ’110 provisional”), filed on March 28, 2008; June 14, 2011; and
`December 13, 2011, respectively. Id. at (60).
`Petitioner contends that the claims of the ’876 patent are not entitled
`to the benefit of priority to the ’558 provisional (Ex. 1008). Pet. 18–20. On
`
`6
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`IPR2019-00451
`Patent 9,763,876 B2
`that basis, Petitioner contends that Gwozdz and Cartt ’784 qualify as prior
`art to the ’876 patent at least under 35 U.S.C. § 102(e)(1). Pet. 6–8.
`With respect to Gwozdz, Petitioner also contends that Gwozdz
`qualifies as prior art to the ’876 patent based on the March 28, 2008 filing
`date of its U.S. Provisional Application No. 61/040,281 (“Gwozdz
`provisional”) (Ex. 1046). Pet. 6. Petitioner has shown that the claims of
`Gwozdz are supported by the Gwozdz provisional, “at least because
`Gwozdz’s claims are literally identical to the claims filed in [the] Gwozdz
`provisional.” Id. (citing Ex. 1014, 14–15; Ex. 1046, 19–20); see Ex. 1014,
`4–10; Ex. 1046, 9–15. Therefore, on this record, we are persuaded that
`Petitioner has satisfied its burden that Gwozdz is entitled to the effective
`filing date of the Gwozdz provisional. See Dynamic Drinkware, LLC v.
`Nat’l Graphics, Inc., 800 F.3d. 1375, 1381 (Fed. Cir. 2015) (holding that
`“[a] reference patent is only entitled to claim the benefit of the filing date of
`its provisional application if the disclosure of the provisional application
`provides support for the claims in the reference patent in compliance with
`§ 112, ¶ 1.”).
`Patent Owner argues that Gwozdz5 is not prior art to the challenged
`claims of the ’876 patent because the claims are properly supported by the
`’558 provisional, which was filed on March 28, 2008.6 Prelim. Resp. 24–27.
`We address the parties’ arguments below.
`
`
`5 Patent Owner does not appear to contest that Cartt ’784 is prior art to the
`’876 patent. See Prelim. Resp. 24–27.
`6 At this stage of the proceeding, Patent Owner has the burden of production
`to show entitlement of priority to the ’558 provisional by presenting
`evidence that every limitation of the ’876 patent claims are supported by
`every patent application along the chain of priority, rather than just showing
`
`7
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`IPR2019-00451
`Patent 9,763,876 B2
`Petitioner contends that the ’558 provisional does not provide
`adequate support for the “alkyl glycoside” limitation recited in the
`challenged claims7 because the presence of any alkyl glycoside is not
`disclosed, described, or enabled by the ’558 provisional. Pet. 19–20.
`Petitioner further contends that the ’558 provisional’s “generic disclosure of
`‘surface active agents (especially non-ionic materials)’ . . . does not disclose,
`describe, and/or enable alkyl glycosides in general (or dodecyl maltoside in
`particular).” Id. at 20 (citing Ex. 1008 ¶ 152; Ex. 1041 ¶ 68). Petitioner,
`therefore, asserts that the claims of the ’876 patent are not entitled to the
`priority date of the ’558 provisional and have an effective filing date of no
`earlier than the March 27, 2009 filing date of the ’439 application. Id.
`Patent Owner argues that the ’558 provisional does disclose alkyl
`glycosides as part of the formulation claimed. Prelim. Resp. 25–26.
`Specifically, Patent Owner points to the following disclosure from the
`’558 provisional:
`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).
`
`support for the limitations or applications specifically challenged by
`Petitioner. See Dynamic Drinkware, 800 F.3d. at 1379–80. We need not
`address the other claim limitations or applications in the priority chain at this
`time because we agree with Petitioner that the ’558 provisional lacks support
`for the “alkyl glycoside” limitation.
`7 Claim 1 requires “an alkyl glycoside.” Ex. 1001, 63:34. Since all of the
`remaining claims of the ’876 patent depend, directly or indirectly, from
`Claim 1, they also require the presence of “an alkyl glycoside.”
`
`8
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`IPR2019-00451
`Patent 9,763,876 B2
`Id. (quoting Ex. 1008 ¶¶ 150–152 (emphasis added)). Patent Owner
`contends that the excerpt from the 1988 SIGMA catalog referenced in the
`’558 provisional includes alkyl glycosides such as n-Dodecyl β-D-
`Maltoside, n-Dodecyl β-D-Glucopyranoside, n-Heptyl β-D-
`Glucopyranoside, n-Hexyl β-D-Glucopyranoside, n-Nonyl β-D-
`Glucopyranoside, n-Octyl β-D-Glucopyranoside, and Octyl β-D-
`Thioglucopyranoside, amongst others. Id. at 26 (citing Ex. 2006, 319–320).
`Patent Owner asserts that this incorporation by reference of the SIGMA
`catalog’s disclosure of non-ionic detergents, including numerous alkyl
`glycosides, “would have reasonably conveyed to the artisan that the inventor
`had possession at that time of the claimed alkyl glycosides.” Id.
`
`Although Patent Owner contends that the disclosure of alkyl
`glycosides from the SIGMA catalog was incorporated by reference into the
`’558 provisional, our Rules do not permit the incorporation by reference of
`essential material from non-patent publications. See 37 C.F.R. § 1.57(d)
`(“‘Essential material’ may be incorporated by reference, but only by way of
`an incorporation by reference to a U.S. patent or U.S. patent application
`publication, which patent or patent application publication does not itself
`incorporate such essential material by reference.”); see also 37 C.F.R.
`§ 1.57(h) (“An incorporation of material by reference that does not comply
`with paragraphs (c), (d), or (e) of this section is not effective to incorporate
`such material unless corrected within any time period set by the Office, but
`in no case later than the close of prosecution”). Essential material includes
`material that is necessary to:
`Provide a written description of the claimed invention,
`and of the manner and process of making and using it, in such
`full, clear, concise, and exact terms as to enable any person
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`IPR2019-00451
`Patent 9,763,876 B2
`skilled in the art to which it pertains, or with which it is most
`nearly connected, to make and use the same . . . .
`
`Id.
`
`The “alkyl glycoside” limitation appears to be essential material.
`Therefore, reliance on the disclosure of the SIGMA catalog for adequate
`support for the “alkyl glycoside” limitation recited in the challenged claims
`is improper.
`In view of the above, at this stage of the proceeding, we conclude that
`the claims of the ’876 patent are not entitled to the benefit of priority to the
`’558 provisional. Therefore, we determine that Gwozdz and Cartt ’784 are
`§ 102(e)(1) prior art to the claims of the ’876 patent.
`
`C. Asserted Obviousness of Claims 1–16 and 24–36 over Gwozdz and
`Meezan ’962
`Petitioner contends that the subject matter of claims 1–16 and 24–36
`of the ’876 patent would have been obvious over the combined disclosures
`of Gwozdz and Meezan ’962. Pet. 23–86. At this stage of the proceeding,
`aside from arguing that Gwozdz is not prior art, Patent Owner does not
`dispute that the combination of Gwozdz and Meezan ’962 teaches the
`limitations of claims 1–16 and 24–36. See Prelim. Resp. 24–27.
`
`1. Gwozdz
`Gwozdz is directed to the use of tocopherols and/or tocotrienols and
`one or more alcohols and/or glycols as pharmaceutically acceptable solvents
`for solubilizing hydrophobic or lipophilic therapeutic agents, in order to
`provide increased bioavailability. Ex. 1014, 4:29–33, 7:3–8. Such
`therapeutic agents include benzodiazepines, including Diazepam. Id. at 8:6–
`10. Specifically, Gwozdz discloses a “pharmaceutical solution comprising a
`therapeutic agent dissolved in one or more natural or synthetic tocopherols
`
`10
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`IPR2019-00451
`Patent 9,763,876 B2
`or tocotrienols, or any combination thereof and one or more alcohols or
`glycols, or any combinations thereof.” Id. at 4:14–17.
`Gwozdz teaches that the combination of a tocopherol and an alcohol
`“is much less irritating to the skin and/or mucous membranes than pure
`alcohol solutions and generally provides higher loading of a therapeutic
`agent than emulsions, liposomes, encapsulations, or cyclodextrins.” Id. at
`5:2–7. Gwozdz also recognizes that “diluting a tocopherol or tocotrienol
`with an alcohol or glycol dramatically reduces the inherent viscosity of the
`tocopherol or tocotrienol thereby allowing for generation of sprayable
`formulations.” Id. at 6:29–7:2. Gwozdz further discloses methods of
`treatment with these pharmaceutical solutions, including via intranasal
`administration, and states that such solutions are “particularly useful in
`formulations to be administered to mucosal membranes, i.e. the nasal
`mucosa.” Id. at 4:24–27, 9:2–8, 9:19–21.
`Examples of alcohols for use in the compositions disclosed in Gwozdz
`include “ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol,
`and any isomers thereof, and any combination thereof.” Id. at 6:16–19.
`Gwozdz discloses that, “[i]n some embodiments, the tocopherol(s) and/or
`tocotrienol(s) is in an amount from about 30% to about 99% (w/w) and the
`alcohol(s) and/or glycol(s) is in an amount from about 1% to about 70%
`(w/w).” Id. at 4:17–21. Gwozdz also discloses that ethanol can constitute
`1% to 40% or 10% to 30% of the pharmaceutical solution and that the
`tocopherol and ethanol can be used in ratios of approximately 95:5, 90:10,
`85:15, 80:20, 75:25, 70:30, 65:35, or 60:40, respectively. Id. at 7:20–28.
`
`11
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`IPR2019-00451
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`2. Meezan ’962
`Meezan ’962 discloses using an alkyl glycoside and/or saccharide
`alkyl ester to improve the bioavailability of drug molecules. Ex. 1011 ¶ 4.
`According to Meezan ’962, the compositions of the invention can be used
`with “small molecule organic drug molecules” and can be delivered nasally.
`Id. The active drug used in its formulations can include many different
`types of active ingredients, including anti-seizure agents. Id. ¶¶ 52, 136.
`
`3. Analysis
`
`a. Claim 1
`Claim 1 recites “[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.” Ex. 1001, 63:26–
`30. Petitioner presents evidence that Gwozdz teaches methods of treating a
`patient with pharmaceutical solutions, which may be administered
`intranasally, and can include benzodiazepines. Pet. 37, 65–66 (citing
`Ex. 1014, 4:24–26, 8:6–13, 9:19–21).
`Claim 1 also recites “one or more natural or synthetic tocopherols or
`tocotrienols, or any combinations thereof, in an amount from about 30% to
`about 95% (w/w).” Ex. 1001, 63:30–32. Petitioner presents evidence that
`Gwozdz teaches the use of tocopherols or tocotrienols in amounts of about
`30–99%. Pet. 38–39, 67 (citing Ex. 1014, 4:18–19, 5:12–14, 7:8–10). The
`percentage range for tocopherols/tocotrienols disclosed by Gwozdz (about
`30–99%) significantly overlaps with the claimed range of about 30–95%.
`Furthermore, Petitioner, with supporting testimony from Dr. Peppas,
`contends that Patent Owner never demonstrated any criticality with respect
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`to the amount of tocopherols. Id. at 39–40 (citing Ex. 1041 ¶ 61). On this
`record, we are persuaded that Patent Owner has not established that a range
`of about 30% to about 95% (w/w) of tocopherols/tocotrienols achieves
`unexpected results. See E.I. du Pont de Nemours & Co. v. Synvina C.V., 904
`F.3d 996, 1006 (Fed. Cir. 2018) (explaining that prior art ranges that overlap
`with a claimed range create “a presumption of obviousness,” which may be
`rebutted if the patentee comes forward with evidence showing, inter alia,
`that the prior art teaches away from the claimed invention or that the claimed
`invention achieves unexpected results).
`Claim 1 also recites “ethanol and benzyl alcohol in a combined
`amount from about 10% to about 70% (w/w).” Ex. 1001, 63:33–34.
`Petitioner presents evidence that Gwozdz teaches the use of ethanol, benzyl
`alcohol, and combinations thereof wherein “[t]he alcohol (or combinations
`of alcohols) may be present in amounts of about 1-70%” and “[e]thanol may
`be present in amounts of 1-40% or 10-30%.” Pet. 40, 68 (citing Ex. 1014,
`4:19–21, 7:10–11, 7:20–24). Therefore, the range of combined alcohol in
`Gwozdz overlaps with the claimed range. Furthermore, Petitioner, with
`supporting testimony from Dr. Peppas, contends that Patent Owner never
`demonstrated any criticality with respect to the amount of alcohol(s). Id.
`(citing Ex. 1041 ¶¶ 52–57). On this record, we are persuaded that Patent
`Owner has not established that a range of ethanol and benzyl alcohol in a
`combined amount from about 10% to about 70% (w/w) achieves unexpected
`results.8 See E.I. du Pont, 904 F.3d. at 1006.
`
`
`8 Further discussion of whether Patent Owner demonstrated unexpected
`results for narrower ranges of individual amounts of ethanol and benzyl
`alcohol can be found infra, for example, with respect to claims 8 and 15.
`
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`Claim 1 also recites “an alkyl glycoside.” Ex. 1001, 63:34. Petitioner
`presents evidence that Meezan ’962 discloses the use of alkyl glycosides in
`pharmaceutical solutions, including nasal sprays. Pet. 41, 69 (citing
`Ex. 1011 ¶¶ 4, 8, 12–13, 63, 70, 73).
`Petitioner, with supporting testimony from Dr. Peppas, asserts that a
`person of ordinary skill in the art would have had reason to combine the
`teachings of Gwozdz and Meezan ’962. Pet. 33–34 (citing Ex. 1041 ¶¶ 193–
`194, 225–226, 257–260, 364, 424). Specifically, Petitioner contends that
`“Gwozdz relates to solving generally-recognized problems associated with,
`inter alia, intranasal administration of low-solubility drugs” and was
`“directed to using solvents to increase the dissolved drug percentage.” Id. at
`33 (citing Ex. 1014, 4:29–33, 9:22–28; Ex. 1041 ¶¶ 193–194). Therefore,
`Petitioner concludes, one of ordinary skill in the art “seeking to optimize and
`improve upon Gwozdz would be motivated to modify Gwozdz with the
`teachings of another reference that solved the same general problems.” Id.
`Petitioner contends that one of ordinary skill in the art “would be
`motivated to look to Meezan ’962” because it is “similarly directed to
`solving generally-recognized problems associated with, e.g., intranasal
`administration of drugs” and that Meezan ’962 recognized the utility of
`including solvents. Id. (citing Ex. 1011 ¶¶ 2–3, 74, 146; Ex. 1041 ¶¶ 225–
`226). According to Petitioner, Meezan ’962 solves the problems differently
`than Gwozdz in that “Meezan ’962 recognized that alkyl glycosides
`‘stabilize[] the biological activity and increase[] the bioavailability of the
`drug’” and, therefore, “solved the known problems by increasing the drug
`amount available to the body, instead of increasing the % of drug that was
`
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`dissolved and administered.” Id. at 33–34 (citing Ex. 1011 ¶ 5; Ex. 1041
`¶ 226).
`On this record, and upon review of Petitioner’s arguments and
`supporting evidence, we determine that Petitioner sufficiently explains why
`one of ordinary skill in the art would have looked to Meezan ’962’s
`disclosure when seeking to enhance the bioavailability of the therapeutic
`agents in the compositions disclosed in Gwozdz. Petitioner also sufficiently
`explains how the combined disclosures of Gwozdz and Meezan ’962 would
`have taught or suggested the subject matter of claim 1. Accordingly,
`Petitioner has demonstrated a reasonable likelihood that the subject matter of
`claim 1 would have been obvious over the combined disclosures of Gwozdz
`and Meezan ’962.
`
`b. Claim 2
`Claim 2 depends from claim 1 and further requires that “the natural or
`synthetic tocopherols or tocotrienols is Vitamin E.” Ex. 1001, 63:35–36.
`Petitioner, with supporting testimony from Dr. Peppas, presents evidence
`that Gwozdz discloses vitamin E. Pet. 41, 69 (citing Ex. 1014, 6:1–2;
`Ex. 1041 ¶ 373).
`Accordingly, Petitioner has demonstrated a reasonable likelihood that
`the subject matter of claim 2 would have been obvious over the combined
`disclosures of Gwozdz and Meezan ’962.
`
`c. Claims 3–4
`Claim 3 depends from claim 1 and further requires that “the
`benzodiazepine drug is selected from the group consisting of” twenty-two
`different benzodiazepines, including diazepam “or any pharmaceutically-
`acceptable salts thereof, and any combinations thereof.” Ex. 1001, 63:37–
`
`15
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`IPR2019-00451
`Patent 9,763,876 B2
`44. Claim 4 depends from claim 3 and specifies that the benzodiazepine
`drug is diazepam (or salt thereof). Id. at 63:45–47. Petitioner, with
`supporting testimony from Dr. Peppas, presents evidence that Gwozdz
`discloses the use of benzodiazepines such as diazepam as well as ten other
`benzodiazepines that are recited in claim 3. Pet. 42, 69–70 (citing Ex. 1014,
`8:9–13; Ex. 1041 ¶ 376).
`Accordingly, Petitioner has demonstrated a reasonable likelihood that
`the subject matter of claims 3 and 4 would have been obvious over the
`combined disclosures of Gwozdz and Meezan ’962.
`
`d. Claims 5–6
`Claim 5 depends from claim 1 and further requires that “the solution
`contains about 1 to about 20% (w/v) of benzodiazepine.” Ex. 1001, 63:48–
`49. Claim 6 depends from claim 5 and requires that the benzodiazepine is
`diazepam. Id. at 63:50–51. Petitioner, with supporting testimony from
`Dr. Peppas, presents evidence that Gwozdz teaches “that it is possible to
`make diazepam solutions of 6.67% (in ethanol); in combinations of
`tocopherol and alcohol (ethanol), it is possible to make diazepam solutions
`of ‘greater than or equal to 8%’, ‘greater than or equal to 9%’, and
`‘approaching the 10% level.’” Pet. 43, 70–71 (citing Ex. 1014, 7:12–19;
`Ex. 1041 ¶ 379).
`Accordingly, Petitioner has demonstrated a reasonable likelihood that
`the subject matter of claims 5 and 6 would have been obvious over the
`combined disclosures of Gwozdz and Meezan ’962.
`
`e. Claim 7
`Claim 7 depends from claim 1 and requires that the one or more
`tocopherols or tocotrienols are selected from a group of nine different
`
`16
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`IPR2019-00451
`Patent 9,763,876 B2
`tocopherols or tocotrienols, including α-tocopherol, β-tocopherol, γ-
`tocopherol, and δ-tocopherol, or any isomers thereof, any esters thereof, any
`analogs or derivatives thereof, or any combinations thereof. Ex. 1001,
`63:52–58. Petitioner, with supporting testimony from Dr. Peppas, presents
`evidence that Gwozdz teaches use of α-tocopherol, β-, γ-, and δ-tocopherol,
`as well as isomers thereof and esters thereof. Pet. 43–44, 71 (citing Ex.
`1014, 6:2–13; Ex. 1041 ¶ 382).
`Accordingly, Petitioner has demonstrated a reasonable likelihood that
`the subject matter of claim 7 would have been obvious over the combined
`disclosures of Gwozdz and Meezan ’962.
`
`f. Claims 8 and 15
`Claim 8 depends from claim 1 and requires that “the solution contains
`ethanol from 1 to 25% (w/v) and benzyl alcohol from 1 to 25% (w/v).”
`Ex. 1001, 63:59–61. Claim 15 depends from claim 1 and requires that “the
`solution comprises ethanol from 10 to 22.5% (w/v) and benzyl alcohol from
`7.5 to 12.5% (w/v).” Ex. 1001, 64:15–17.
`Petitioner contends that Gwozdz teaches that the alcohols can be
`ethanol, benzyl alcohol, and combinations thereof, and that the total
`alcoholic content can be about 1–70%, of which ethanol can be 1–40%, or
`10–30%. Pet. 44 (citing Ex. 1014, 4:19–21, 6:16–19, 7:10–11, 7:20–24).
`Petitioner further asserts that Patent Owner “never demonstrated any
`criticality to the amount(s) or types of alcohol(s)” and, therefore, “lacking
`criticality, [one of ordinary skill in the art] would easily and routinely
`experiment with various amounts of ethanol between 10-30%, combined
`with benzyl alcohol making up the remainder of the total of 1-70% alcohol
`(i.e., 1-40%).” Id. at 44–45 (citing Ex. 1041 ¶¶ 52–57). Petitioner contends
`
`17
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`IPR2019-00451
`Patent 9,763,876 B2
`that these values overlap with or encompass the amounts recited in claims 8
`and 15, and, therefore, render the claims obvious. Id. at 45.
`In support of the assertion that Patent Owner never demonstrated any
`criticality to the amounts or types of alcohols, Petitioner directs our attention
`to an office action issued by the European Patent Office (“EPO”) in related
`proceedings, addressing nearly identical claims, wherein the EPO Examiner
`asserted that:
`in the absence of any unexpected effect associated therewith,
`the person skilled in the art would consider adjusting the
`amounts of ethanol and benzyl alcohol by mere routine
`experimentation and, by doing so, would inevitably arrive at the
`claimed amounts, without exercising inventive skill.
`Ex. 1040, 298.
`In the EPO proceedings referenced by Petitioner, the pending claims
`were being rejected over the Cartt ’865 application.9 See id. at 274–277,
`296–299. The disclosure relied on by the EPO Examiner in Cartt ’865 to
`reject the claims was very similar to the disclosure from Gwozdz relied on
`by Petitioner here. See id. at 274 (citing Ex. 1010 ¶¶ 10, 16–17, 39).
`Compare Ex. 1001 ¶¶ 10, 16–17, 39, with Ex. 1014, 4:19–21, 6:16–19,
`7:10–11.
`However, in its Petition, Petitioner fails to address that during
`subsequent prosecution of this application, the applicants asserted to the
`EPO that “the co-solvent system of 1-25% ethanol and 1-25% benzyl
`alcohol provides an unexpected increase in bioavailability over and above
`the increase in bioavailability from” the alkyl glycoside. Ex. 1040, 377.
`
`
`9 U.S. Pub. No. 2009/0258865 A1, published October 15, 2009 (Ex. 1010,
`“Cartt ’865”).
`
`18
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`IPR2019-00451
`Patent 9,763,876 B2
`Moreover, upon review of Cartt ’865, the recited evidence, and the
`applicant’s unexpected results arguments, the EPO withdrew its pending
`rejection and issued claims that are nearly identical to challenged claims 8
`and 15 of the ’876 patent. Compare Ex. 1001, claims 8, 15, with Ex. 1040,
`512–513 (claims 1, 6).
`Given that (1) Patent Owner has successfully argued to another
`tribunal that the claimed amounts of ethanol and benzyl alcohol provide
`unexpected results, (2) nearly identical claims were issued by that tribunal
`over a similar disclosure to that of Gwozdz, and (3) the ’876 patent contains
`the same disclosures relied upon by the EPO to establish unexpected results
`(compare Ex. 1040, 316 (pointing to Figures 1–3 and Table 11-3 in support
`of its unexpected effects argument), 377–79 (also relying on Table 4-1 and
`Tables 11-1, 11-2, 11-3 in support of its “unexpected effect” argument), 520
`(cancelling oral proceedings and granting applicants main request), with
`Ex. 1001, Figs. 1–3, Tables 4-1, 11-1, 11-2, 11-3), Petitioner’s assertion that
`Patent Owner never showed any unexpected results is not sufficiently
`supported by the evidence of record. Pet. 45.
`In view of the foregoing, we are somewhat skeptical as to whether one
`of ordinary skill in the art would have found it obvious to use a solution with
`1 to 25% (w/v) ethanol and 1 to 25% (w/v) benzyl alcohol or 10 to 22.5%
`(w/v) ethanol and 7.5 to 12.5% (w/v) benzyl alcohol with a reasonable
`expectation of success. Pursuant to SAS and PGS, however, when instituting
`on the basis that Petitioner has demonstrated a reasonable likelihood with
`respect to at least one challenged claim, we must institute on all claims and
`all grounds challenged in the Petition. See SAS, 138 S. Ct. at 1359–60; PGS,
`
`19
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`IPR2019-00451
`Patent 9,763,876 B2
`891 F.3d at 1360. Thus, this issue will be resolved on a complete trial
`record.
`
`g. Claims 9–10
`Claim 9 depends from claim 8 and requires that the “benzodiazepine
`drug is present in the pharmaceutical solution in a concentration from about
`10 mg/mL to about 250 mg/mL.” Ex. 1001, 63:62–64. Claim 10 depends
`from claim 9 and requires that the benzodiazepine drug concentration is
`“f
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