Trials@uspto.gov
`571-272-7822
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` Paper 57
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` Date: August 21, 2020
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ADAPT PHARMA OPERATIONS LIMITED, and
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owner.
`____________
`
`IPR2019-00688
`Patent 9,468,747 B2
`____________
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`
`YANG, Administrative Patent Judge.
`
`
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`
`
`
`
`
`
`
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`
`

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`IPR2019-00688
`Patent No. 9,468,747 B2
`
`
`INTRODUCTION
`Nalox-1 Pharmaceuticals, LLC (“Petitioner”) filed a Petition (Paper 1
`(“Pet.”)), seeking an inter partes review of claims 1–45 of U.S. Patent
`No. 9,468,747 B2 (“the ’747 patent,” Ex. 1001). We instituted trial to review
`the challenged claims. Paper 11 (“Dec.”). Thereafter, Adapt Pharma
`Operations Limited and Opiant Pharmaceuticals, Inc. (collectively, “Patent
`Owner”) filed a Response to the Petition (Paper 34, “PO Resp.”), Petitioner
`filed a Reply (Paper 39), and Patent Owner filed a Sur-Reply (Paper 49).
`Petitioner also filed a Motion for Observations (Paper 51). An oral hearing
`for this proceeding was held on May 19, 2020, and a transcript of that
`hearing is of record. See Paper 53 (“Tr.”).
`The Board has jurisdiction under 35 U.S.C. § 6 and issues this final
`written decision pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. For
`the reasons provided below, and based on the evidence and argument
`presented in this proceeding, we conclude Petitioner has not established by a
`preponderance of the evidence that claims 1–45 of the ’747 patent are
`unpatentable.
`
`Related Proceedings
`Petitioner filed IPR2019-00689 and IPR2019-00690, challenging the
`same claims of the ’747 patent with additional prior art. We denied those
`petitions. IPR2019-00689, Paper 11; IPR2019-00690, Paper 11.
`The ’747 patent is one of the patents listed in the Orange Book for
`intranasal naloxone sold under the brand name NARCAN. Pet. 1; Paper 9, 1.
`Petitioner also filed petitions for inter partes review, challenging other
`patents listed in the Orange Book. Pet. 7; Paper 5, 1–2. We denied some of
`those petitions but instituted reviews in IPR2019-00685 (challenging U.S.
`
`2
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`IPR2019-00688
`Patent No. 9,468,747 B2
`
`Patent No. 9,211,253) and IPR2019-00694 (challenging U.S. Patent
`9,629,965). IPR2019-00685, Paper 11; IPR2019-00694, Paper 10.
`Concurrently with this Decision, we issue a final written decision in each of
`those cases.
`According to the parties, Patent Owner asserted all five Orange-Book-
`listed patents in Adapt Pharma Operations Ltd. v. Teva Pharmaceuticals
`USA, Inc., Case 2:16-cv-07721 (D.N.J.) (consolidated, “the Teva Case”),
`and Adapt Pharma Operations Ltd. v. Perrigo UK FINCO Limited
`Partnership, Case 2:18-cv-15287 (D.N.J.) (“the Perrigo Case”). Pet. 7;
`Paper 5, 2. Petitioner is not involved in those actions. Pet. 7.
`According to Patent Owner, on March 2, 2020, the Perrigo Case was
`dismissed with prejudice pursuant to a consent judgment. Paper 56, 3. On
`June 26, 2020, the district court entered final judgment in the Teva Case,
`holding claims 7 and 9 of the ’747 patent invalid. Id. at 3–4. Patent Owner
`states that its appeal from that judgment was docketed on August 3, 2020.
`Id. at 4.
`
`Background of Technology and the ’747 Patent
`Opioid overdose is a crisis in the United States. Ex. 1001, 6:43.
`Naloxone is an opioid receptor antagonist that was initially approved for use
`by injection for the reversal of opioid overdose. Id. at 2:13–14. Naloxone
`hydrochloride injection prevents or reverses the effects of opioids,
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`IPR2019-00688
`Patent No. 9,468,747 B2
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`“including respiratory depression, sedation and hypotension.” Ex. 1044,1
`1300.2
`According to the ’747 patent, administering naloxone via injection
`requires trained medical personnel and imposes the risk of exposure to blood
`borne pathogens through needlestick injury. Ex. 1001, 6:20–32. The
`’747 patent discloses that “it ha[d] been suggested that in view of the
`growing opioid overdose crisis in the US, naloxone should be made
`available over-the-counter (OTC), which would require a device, such as a
`nasal spray device, that untrained consumers are able to use safely.” Id. at
`6:42–46.
`The ’747 patent acknowledges that nasal administration of naloxone
`was known and used by numerous medical services and health departments.
`Id. at 2:29–6:13, see also id. at 4:39–42 (“Overdose education and nasal
`naloxone distribution (OEND) programs are community-based interventions
`that educate people at risk for overdose and potential bystanders on how to
`prevent, recognize and respond to an overdose.”). It points out, however,
`that some studies “reported that the nasal administration of naloxone is as
`effective as the intravenous route in opiate addicts,” yet others “reported that
`naloxone administered intranasally displays a relative bioavailability of 4%
`only and concluded that the IN [intranasal] absorption is rapid but does not
`maintain measurable concentrations for more than an hour.” Id. at 2:47–55.
`The ’747 patent states:
`
`
`1 Physicians’ Desk Reference 2003, entry for NARCAN (Naloxone
`Hydrochloride Injection, USP).
`2 Where applicable, we cite to the original page numbers of the exhibits, and
`not the pagination added by the parties.
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`IPR2019-00688
`Patent No. 9,468,747 B2
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`
`Thus, there remains a need for durable, easy-to-use, needleless
`devices with storage-stable formulations, that can enable
`untrained individuals to quickly deliver a therapeutically
`effective dose of a rapid-acting opioid antagonist to an opioid
`overdose patient. The therapeutically effective dose should be
`sufficient to obviate the need for the untrained individual to
`administer either a second dose of opioid antagonist or an
`alternative medical intervention to the patient, and to stabilize the
`patient until professional medical care becomes available.
`Id. at 6:52–61.
`According to the ’747 patent, its invention relates to devices adapted
`for nasal delivery of “a therapeutically effective amount of an opioid
`antagonist selected from naloxone and pharmaceutically acceptable salts
`thereof, wherein the device is pre-primed, and wherein the therapeutically
`effective amount, is equivalent to about 2 mg to about 12 mg of naloxone
`hydrochloride.” Id. at 6:63–7:2.
`Illustrative Claims
`Among the challenged claims, claims 1 and 30 are independent, and
`are reproduced below:
`A method of treatment of opioid overdose or a symptom
`1.
`thereof, comprising nasally administering to a patient in need
`thereof a dose of naloxone hydrochloride using a single-use, pre-
`primed device adapted for nasal delivery of a pharmaceutical
`composition to a patient by one actuation of said device into one
`nostril of said patient, having a single reservoir comprising a
`pharmaceutical composition which is an aqueous solution of
`about 100 µL comprising:
`about 4 mg naloxone hydrochloride or a hydrate thereof;
`between about 0.2 mg and about 1.2 mg of an isotonicity agent;
`between about 0.005 mg and about 0.015 mg of a compound
`which is at least one of a preservative, a cationic surfactant, and
`a permeation enhancer;
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`IPR2019-00688
`Patent No. 9,468,747 B2
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`
`between about 0.1 mg and about 0.5 mg of a stabilizing agent;
`and
`an amount of an acid sufficient to achieve a pH of 3.5-5.5.
`30. A
`pharmaceutical
`formulation
`for
`intranasal
`administration comprising, in an aqueous solution of not more
`than about 140 µL:
`about 4 mg naloxone hydrochloride or a hydrate thereof;
`between about 0.2 mg and about 1.2 mg of an isotonicity agent;
`between about 0.005 mg and about 0.015 mg of a compound
`which is at least one of a preservative, a cationic surfactant, and
`a permeation enhancer;
`between about 0.1 mg and about 0.5 mg of a stabilizing agent;
`an amount of an acid sufficient to achieve a pH of 3.5-5.5.
`Instituted Grounds of Unpatentability
`We instituted trial to determine whether claims 1–45 of the
`’747 patent are unpatentable based on the following grounds:
`Claims Challenged 35 U.S.C. §
`References
`1–3, 16–24, 28–45
`103
`Wyse,3 HPE4
`4–7, 10–15, 25–27
`103
`Wyse, Djupesland,5 HPE
`8, 9
`103
`Wyse, Djupesland, HPE,
`the ’291 patent6
`
`Dec. 6.
`
`
`3 Wyse et al., U.S. Patent No. 9,192,570 B2, issued November 24, 2015
`(Ex. 1007).
`4 Handbook of Pharmaceutical Excipients, 56–60, 64–66, 78–81, 220–22,
`242–44, 270–72, 441–45, 517–22, 596–98 (Rowe et al. eds., 6th ed. 2009)
`(Ex. 1012).
`5 Djupesland, Nasal Drug Delivery Device: Characteristics and Performance
`in a Clinical Perspective - A Review, 3 DRUG DELIV. & TRANSL. RES. 42–62
`(2013) (Ex. 1010).
`6 Wermeling, U.S. Patent No. 8,198,291 B2, issued June 12, 2012
`(Ex. 1015).
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`Patent No. 9,468,747 B2
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`
`Petitioner relies on the Declarations of Maureen D. Donovan, Ph.D.
`(Exs. 1002, 1201) and Günther Hochhaus, Ph.D. (Exs. 1003, 1202). Patent
`Owner relies on the Declarations of Stuart A. Jones, Ph.D. (Exs. 2201,
`2300), Kenneth Williams, M.D. (Ex. 2202), Thomas Begres (Ex. 2203), Eric
`Karas (Ex. 2204), Robert L. Vigil, Ph.D. (Ex. 2205), and Declan Brides
`(Ex. 2207). Exhibits 2201, 2205, and 2207 were filed under seal, and Patent
`Owner has provided Exhibits 2208 and 2206 as the redacted version of
`Exhibits 2201 and 2205, respectively.
`
`ANALYSIS
`Principles of Law
`To prevail in this inter partes review, Petitioner must prove
`unpatentability by a preponderance of the evidence. 35 U.S.C. § 316(e);
`37 C.F.R. § 42.1(d).
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are such that
`the subject matter, as a whole, would have been obvious at the time the
`invention was made to a person having ordinary skill in the art to which said
`subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`(2007). The question of obviousness is resolved on the basis of underlying
`factual determinations, including (1) the scope and content of the prior art;
`(2) any differences between the claimed subject matter and the prior art;
`(3) the level of skill in the art; and (4) objective evidence of nonobviousness.
`Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966); KSR, 550 U.S. at 406.
`A party that asserts obviousness of a claim must show that “a skilled
`artisan would have been motivated to combine the teachings of the prior art
`references to achieve the claimed invention, and that the skilled artisan
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`Patent No. 9,468,747 B2
`
`would have had a reasonable expectation of success in doing so.” In re
`Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed. Cir. 2016). “There
`is no suggestion to combine, however, if a reference teaches away from its
`combination with another source.” Tec Air, Inc. v. Denso Mfg. Mich. Inc.,
`192 F.3d 1353, 1360 (Fed. Cir. 1999).
`We analyze the instituted grounds of unpatentability in accordance
`with these principles.
`
`Level of Ordinary Skill in the Art
`Petitioner argues that “[a]s it relates to the ’747 patent, a person of
`ordinary skill in the art (‘POSA’) would comprise a team of individuals
`having experience in drug development, and specifically the development of
`solution-based dosage forms such as intranasal dosage forms.” Pet. 8 (citing
`Ex. 1002 ¶ 26; Ex. 1003 ¶ 22).
`According to Petitioner, this team would include a “Formulator
`POSA” who has “experience in preformulation testing for and selection of
`excipients for a solution-based dosage form (including intranasal dosage
`forms) to achieve a target pharmaceutical profile.” Id.
`Petitioner asserts that:
`The POSA team would also include drug development
`professionals [“Pharmacologist POSA”] with clinical, clinical
`pharmacology, and regulatory expertise relevant to the design
`and performance of a drug development strategy for solution-
`based dosage forms such as intranasal dosage forms, including
`testing and/or evaluating the fate of the drug in the body (i.e.,
`pharmacokinetics,
`including
`the
`physiological
`and
`biopharmaceutical aspects of nasal drug absorption), testing
`and/or evaluating issues of safety and efficacy, and evaluating
`the regulatory requirements of a new dosage form.
`Id. at 9–10.
`
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`
`In our Institution Decision, we adopted Petitioner’s definition of the
`level of ordinary skill, which was undisputed at the time, because it was
`consistent with the level of skill reflected in the prior art of record and the
`disclosure of the ’747 patent. Dec. 10; see Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001).
`Patent Owner does not contest the level of skill as adopted in our
`Institution Decision, and we continue to apply that same skill level in our
`analysis for this Final Written Decision.
`Claim Construction
`In an inter partes review, a claim term “shall be 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), including construing the claim in
`accordance with the ordinary and customary meaning of such claim as
`understood by one of ordinary skill in the art and the prosecution history
`pertaining to the patent.” 37 C.F.R. § 42.100(b);7 see also Phillips v. AWH
`Corp., 415 F.3d 1303, 1312–13 (Fed. Cir. 2005) (en banc) (holding that the
`words of a claim “are generally given their ordinary and customary
`meaning,” which is “the meaning that the term would have to a person of
`ordinary skill in the art in question at the time of the invention, i.e., as of the
`effective filing date of the patent application”) (citations omitted). Any
`special definitions for claim terms must be set forth with reasonable clarity,
`
`
`7 See Changes to the Claim Construction Standard for Interpreting Claims in
`Trial Proceedings Before the Patent Trial and Appeal Board, 83 Fed. Reg.
`51,340, 51,340, 51,358 (Oct. 11, 2018) (amending 37 C.F.R. § 42.100(b)
`effective November 13, 2018) (now codified at 37 C.F.R. § 42.100(b)
`(2019)).
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`Patent No. 9,468,747 B2
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`deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed.
`Cir. 1994).
`Petitioner proposes that we construe certain terms. Pet. 24–26. On this
`record and for purposes of this Decision, we see no need to construe any
`term expressly. Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.,
`868 F.3d 1013, 1017 (Fed. Cir. 2017) (stating that claim terms need only be
`construed to the extent necessary to resolve the controversy).
`Prior-Art Disclosures
`
`Wyse
`
`Wyse teaches “compositions containing an opioid antagonist such as
`naloxone and one or more pharmaceutically acceptable excipients. The
`compositions may be used for intranasal delivery of Naloxone for the
`treatment of, for example, opioid overdose in an individual in need thereof.”
`Ex. 1007, Abstract.
`Wyse discloses the results of preliminary formulation screening
`studies for 13 naloxone formulations, each including 20 mg/ml naloxone
`HCl and a different combination of excipients. Id. at 26:26–29, Table 13.
`Wyse reports that the study “surprisingly showed” that, in four of the five
`formulations that include benzalkonium chloride (“BAC”)8 as the
`preservative, the use of BAC “resulted in an additional degradant.” Id.
`at 27:29–32, Table 13. According to Wyse, apart from the preservative, i.e.,
`BAC, “Formulation 7,” one of the BAC-containing formulations that
`unexpectedly resulted in degradant, “was believed to be ideal for nasal
`delivery.” Id. at 27:32–34.
`
`8 Benzalkonium chloride is abbreviated as BAC in the Petition, and BZK in
`the Patent Owner Response.
`
`10
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`IPR2019-00688
`Patent No. 9,468,747 B2
`
`HPE
`
`HPE lists pharmaceutical excipients, including BAC, benzyl alcohol,
`and disodium edetate (“EDTA”). Ex. 1012. HPE describes various
`information about each excipient, such as the applications in pharmaceutical
`formulation as well as safety. Id.
`For BAC, HPE teaches that in nasal formulations, it is used in “a
`concentration of 0.002–0.02% w/v.” Id. at 56. HPE notes that BAC is
`“[i]ncluded in the FDA Inactive Ingredients Database” for nasal
`preparations. Id. at 57 (citation omitted).
`Djupesland
`Djupesland teaches that the Pfeiffer/Aptar single-dose intranasal
`delivery device has been used to administer certain intranasal migraine
`medications. Ex. 1010, 49. According to Djupesland, to use the device,
`which “consist[s] of a vial, a piston, and a swirl chamber,” one holds it
`“between the second and the third fingers with the thumb on the actuator.”
`Id. Djupesland explains that “[t]o emit 100 μl, a volume of 125 μl is filled in
`the device (Pfeiffer/Aptar single-dose device) used for the intranasal
`migraine medications.” Id.
`The ’291 Patent
`The ’291 patent “compares bioavailability of a butorphanol
`formulation when administered using a unit-dose or multi-dose delivery
`device.” Ex. 1015, 7:61–63. The unit-dose delivery system employed is
`“Unitdose Second Generation,” a commercially available disposable
`intranasal applicator from Pfeiffer. Id. at 8:12–16. The ’291 patent describes
`the composition and volume of the formulation sprayed. Id. at 7:63–67,
`8:16–18.
`
`11
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`IPR2019-00688
`Patent No. 9,468,747 B2
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`
`Obviousness over Wyse and HPE
`Petitioner argues that claims 1–3, 16–24, and 28–45 would have been
`obvious over Wyse9 and HPE. Pet. 29–49. After reviewing the entire record,
`we conclude Petitioner has not shown by a preponderance of the evidence
`that the combination of Wyse and HPE renders any of the challenged claims
`obvious.
`Each of independent claims 1 and 30 recites “between about 0.005 mg
`and about 0.015 mg of a compound which is at least one of a preservative, a
`cationic surfactant, and a permeation enhancer,” and “between about 0.1 mg
`and about 0.5 mg of a stabilizing agent.” Each of dependent claims 2, 3, 28,
`29, 32, 33, 37–39, and 43–45 specifies BAC as the preservative and EDTA
`as the stabilizing agent. In this Decision, the central question turns on
`whether, based on evidence of the record in this proceeding, an ordinarily
`skilled artisan would have understood Wyse and HPE to teach away from
`using BAC as a preservative, especially in combination with the stabilizing
`agent EDTA, in an intranasal naloxone formulation. Because it is dispositive
`regarding all the challenged claims, we focus our analysis on this issue only.
`Regarding claim 1, Petitioner argues that Wyse teaches using an
`antimicrobial agent, which is a preservative, in an amount of 0.1% to 2% by
`weight of the formulation. Pet. 33 (citing Ex. 1007, 7:20–28). Because Wyse
`
`
`9 Wyse issued on November 24, 2015, from an application filed on
`December 19, 2014. Ex. 1007, codes (22), (45). Petitioner asserts that the
`earliest priority date for challenged claims is March 16, 2015. Pet. 12–14.
`Thus, Petitioner argues that Wyse qualifies as prior art under AIA
`§ 102(a)(2). Id. at 26. For the purposes of this proceeding, Patent Owner
`does not dispute, and we agree with, Petitioner’s argument on this point.
`Paper 10, 1.
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`IPR2019-00688
`Patent No. 9,468,747 B2
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`does not specify “the types of antimicrobial agents that may be used,”
`Petitioner asserts a Formulator POSA would have consulted HPE to choose
`the antimicrobial agents in appropriate amounts based on their potencies. Id.
`(citing Ex. 1002 ¶¶ 140, 141).
`According to Petitioner, “Wyse discloses using quantities of
`preservative between 0.1% w/v and 2% w/v” based on benzyl alcohol, the
`preservative exemplified in Wyse. Id. at 34. Petitioner argues that benzyl
`alcohol “is usually used at concentrations such as 5 mg/mL (0.5% w/v)
`because it is only moderately active against Gram-positive organisms and
`less active against Gram-negative bacteria.” Id. at 34 (citing Ex. 1012, 64).
` In contrast, Petitioner asserts, BAC “is a commonly used
`antimicrobial preservative in FDA-approved nasal formulations [that] has a
`broad range of antimicrobial activities at low concentrations, such as 0.002–
`0.02% w/v.” Id. at 33–34 (citing Ex. 1002 ¶¶ 65, 143; Ex. 1012, 56–60).
`Thus, Petitioner concludes, “[a] POSA would have been particularly
`motivated to use BAC as a preservative in such a nasal spray,” in the amount
`of 0.002–0.02 mg (at the concentration of 0.002–0.02% w/v in the volume of
`100 μL), which fully encompasses the 0.005–0.015 mg range recited in
`challenged claim 1. Id. at 33–34 (citing Ex. 1002 ¶ 142; Ex. 1012, 56). In
`other words, as Patent Owner points out, Petitioner’s “arguments for
`obviousness of the recited preservative amounts hinge on establishing that
`the POSA would have used [BAC].” PO Resp. 5.
`In our Institution Decision, we agreed with Patent Owner that both
`Wyse and HPE taught away from using BAC as the preservative, especially
`in combination with the stabilizing agent EDTA, in formulating intranasal
`naloxone. Dec. 19–23. Although we focused on certain dependent claims
`
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`Patent No. 9,468,747 B2
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`when discussing the teaching-away issue at institution, after considering the
`full record developed through trial, we agree with Patent Owner that the
`teaching-away argument applies to all challenged claims. We highlight
`relevant arguments and evidence in the following discussion.
`In its preliminary formulation screening studies, Wyse evaluated 13
`excipient combinations. Ex. 1007, 26:26–27. According to Wyse, the results
`“surprisingly showed that the use of benzalkonium chloride, a common nasal
`product preservative, resulted in an additional degradant in formulations 7,
`9, 14, and 14A.” Id. at 27:29–32. Wyse concluded that “benzyl alcohol and
`paraben preservatives were acceptable, but benzalkonium chloride was not,
`due to increased observed degradation.” Id. at 27:42–44, see also id. at
`28:23–27 (“Applicant found that, surprisingly, commonly used excipients
`including . . . benzylalkonium chloride, were found to increase degradation
`of naloxone.”).
`Petitioner acknowledges Wyse’s disclosure on this issue (Pet. 58–59
`(citing Ex. 1007, 27:30–34, 41–44)), but emphasizes that “[n]o other prior
`art cited by [Patent Owner] would have directed a POSA away from using
`BAC in an intranasal naloxone formulation.” Reply 9–10. We are not
`persuaded by this argument.
`As Petitioner acknowledges, an ordinarily skilled artisan “would have
`been concerned about naloxone degradation,” and would have “been
`motivated to choose ingredients to render the formulation chemically and
`microbiologically stable.” Pet. 20; see also id. (“Ideally, nearly all of the
`naloxone active ingredient would remain present after storage; the solution
`would have resisted any changes in color or formation of particulate matter;
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`IPR2019-00688
`Patent No. 9,468,747 B2
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`and the solution would have been free of microbial growth or ingress.”
`(citing Ex. 1002 ¶ 51)).
`In this proceeding, Wyse is the only reference of record that compares
`naloxone formulations having different excipient combinations, and
`provides stability data for intranasal naloxone formulations. Thus, we find
`that, contrary to Petitioner’s assertion that “a POSA would not have granted
`[Wyse’s] statements much merit” (Pet. 59), an ordinarily skilled artisan,
`when “determin[ing] what antimicrobial agents he or she should consider in
`developing a nasal formulation of naloxone” (id. at 33), would have taken
`into consideration, and indeed, would have given significant weight, to the
`only naloxone formulation stability data disclosed in Wyse.
`Petitioner contends that ordinarily skilled artisans “reading the
`disclosure of Wyse have concluded that it does not teach away” from using
`BAC. Pet. 59–60. As support, Petitioner cites Glende,10 “a Norwegian
`graduate thesis published in 2016.” Id. Acknowledging that Glende is not
`prior art, Petitioner nevertheless points out that Glende “reviewed the WIPO
`publication equivalent of Wyse [and] not[ed] that the disclosure should not
`be understood to disparage the use of BAC, as the criticism of its use may be
`incorrectly based.” Id. (citing Ex. 1031, 76). Glende, however, reached this
`conclusion after also reviewing the WIPO publication equivalent of a parent
`application of the challenged ’747 patent (Ex. 1031, 54), which disclosed
`BAC-containing formulations were “storage-stable” (id. at 54, 64). Thus, we
`
`
`10 Glende, O., Development of Non-Injectable Naloxone for Pre-Hospital
`Reversal of Opioid Overdose: A Norwegian Project and a Review of
`International Status (May 2016) (unpublished M.A. thesis, Norwegian
`University of Science and Technology).
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`Patent No. 9,468,747 B2
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`agree with Patent Owner that “Glende’s conclusion was based on knowledge
`of the patented invention which disclosed the stability of the patentee’s
`formulations, not what the POSA would have understood from the prior art.”
`See PO Resp. 12.
`Regarding the teachings of Wyse, Petitioner argues that an ordinarily
`skilled artisan “would not have properly concluded that Wyse taught away
`from using BAC with naloxone.” Pet. 58. According to Petitioner, because
`“Wyse performed degradation testing on multiple different formulations
`combining multiple different excipients, it cannot be conclusively
`determined that any individual excipient was responsible for any instability
`issues in the disclosed formulation.” Id. at 59; see also Reply 6 (“Wyse
`discloses that his prototyping studies, in which combinations of excipients
`were tested together, would not permit a conclusion that any one ingredient
`in the combinations was responsible for naloxone degradation.”). We are not
`persuaded by this argument either.
`In its screening tests, Wyse tested benzyl alcohol, paraben, and BAC
`preservatives. Ex. 1007, Table 13. Of special note is that formulations 13
`and 13A contain benzyl alcohol as the preservative, whereas formulations 14
`and 14A contain BAC as the preservative. Id., Table 13. Wyse observed an
`additional degradant in formulations 14 and 14A (id. at 27:29–32) even
`though, but for the preservative, formulation 14 is identical to formulation
`13, and formulation 14A is identical to formulation 13A (id., Table 13).
`Based on these results, Wyse concluded that “benzyl alcohol and paraben
`preservatives were acceptable, but benzalkonium chloride [BAC] was not,
`due to increased observed degradation.” Id. at 27:42–44. On this record,
`Petitioner has not shown this conclusion was unreasonable, or that an
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`ordinarily skilled artisan, based on knowledge possessed at the time of the
`invention, would have otherwise doubted Wyse’s express teaching that BAC
`was not an acceptable preservative because it caused the increased
`degradation that Wyse observed in its tests.
`Petitioner also questions whether, in Wyse, BAC “specifically
`resulted in additional naloxone degradation, rather than degradation of
`another component.” Pet. 59. We disagree. Wyse specified that BAC
`increases “degradation of naloxone.” Id. at 28:23–27, see also id. at 26:32–
`34 (explaining “Naloxone RP-HPLC assay for purity”), 27:19–21
`(discussing the “stability of naloxone HCl” and “degradation of naloxone
`HCl”).
`Petitioner further argues that “if the ‘additional degradant’ was a
`naloxone degradant, it would likely be an oxidation degradant.” Reply 5.
`According to Petitioner, “a POSA would have known that BAC could not
`have been responsible for the production of any oxidative degradants.” Id.
`The evidence of the record does not support Petitioner’s position.
`Petitioner relies on the Donovan Declaration to support its argument
`that the additional degradant reported by Wyse “would likely be an oxidation
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`degradant.”11 Reply 5 (citing Ex. 1201 ¶¶ 13, 15, emphasis added).
`Dr. Donovan’s testimony on this point, however, is much more tentative:
`I think a person of ordinary skill in the art would hold open the
`possibility that it was an oxidative degradant because that’s what
`Wyse was trying to accomplish, but they wouldn’t have any
`reason to believe it was a particular form of an -- of the oxidative
`degradants known or unknown and, yes, they, again, couldn’t
`anticipate what that material was without additional information
`but certainly oxidative degradants would be in keeping with what
`a POSA would postulate might show up in these mixtures.
`Ex. 2215, 502:14–503:2 (emphases added). In view of such equivocal
`testimony, we are not persuaded by Petitioner’s argument that an ordinarily
`skilled artisan would have attributed the “additional degradant” disclosed in
`Wyse to oxidative degradation, and thus would have subsequently deduced
`that BAC could not have caused such degradation.
`Petitioner argues that “the evidence does not show that BAC is
`incompatible with naloxone, and thus does not teach away from its inclusion
`in a naloxone formulation.” Pet. 59. According to Petitioner, “[a] POSA
`would have known that in order to conclude that BAC and naloxone were
`incompatible, one would need to study the individual combination of the two
`compounds.” Reply 7, see also id. (“To determine the root cause of any
`
`11 Petitioner also asserts that “the ‘additional degradant’ in these
`formulations was apparently identified as Impurity E—i.e., 2,2’-
`binaloxone—the primary oxidation degradation product of naloxone.”
`Reply 5. As support, Petitioner relies on Exhibit 2188, “Indivior NDA
`Module 3.2.P.2.” Id. (citing Ex. 2188); Paper 48, 23. Exhibit 2188, however,
`is a third-party confidential document that is not alleged to be in the prior art
`and was, and remains, under seal. Paper 32, 3. Thus, Petitioner has not
`shown that an ordinarily skilled artisan, at the priority date of the claimed
`invention, would have understood that the “additional degradant” in Wyse is
`Impurity E.
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`problems, a POSA would have to evaluate each excipient and experimental
`condition individually and potentially evaluate other factors.”). Petitioner
`overstates the standard for evaluating whether a reference teaches away.
`A reference teaches away “if it suggests that the line of development
`flowing from the reference’s disclosure is unlikely to be productive of the
`result sought by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir.
`1994). Wyse explicitly and unambiguously discourages the use of BAC in
`intranasal naloxone formulations. Wyse found BAC “increase[d]
`degradation of naloxone” (Ex. 1007, 28:26–27), and excluded BAC from the
`naloxone formulations chosen for further study (id. at 28:41–47, Table 14).
`As explained above, on the record presented in this proceeding, we are not
`persuaded by Petitioner’s arguments that an ordinarily skilled artisan would
`have interpreted Wyse’s teachings differently.
`Accordingly, Wyse teaches away from using BAC as the preservative
`because it directly “criticize[s], discredit[s], or otherwise discourage[s] the
`solution claimed.” See In re Fulton, 391 F.3d at 1201. This is so despite the
`fact that, as Petitioner emphasizes, one of the five BAC-including
`formulations tested by Wyse did not result in additional degradants. Pet. 59.
`After all, a reference teaches away “when a person of ordinary skill, upon
`reading the reference, would be discouraged from following the path set out
`in the reference, or would be led in a direction divergent from the path that
`was taken” in the challenged claim. Gurley, 27 F.3d at 553.
`Here, Wyse does both. It not only presents results showing that BAC
`is not acceptable for use in intranasal naloxone formulations, but also
`provides data demonstrating that other preservatives, such as benzyl alcohol,
`are stable in such formulations. Id. at 27:41–44, 28:41–29:27. Indeed, Wyse
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`teaches that the BAC-containing version of an otherwise “ideal” naloxone
`nasal formulation produced an additional degradant, whereas the benzyl
`alcohol-containing version of that form