Trials@uspto.gov
`571-272-7822
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` Paper 55
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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.
`____________
`
`IPR2019-00694
`Patent 9,629,965 B2
`____________
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`VALEK, Administrative Patent Judge.
`
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`
`
`
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`
`571-272-7822
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`
`
`
`
`
`
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` Paper 55
`
`
` Date: August 21, 2020
`
`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.
`____________
`
`IPR2019-00694
`Patent 9,629,965 B2
`____________
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`VALEK, Administrative Patent Judge.
`
`
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`
`
`
`
`
`
`
`
`
`
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`IPR2019-00694
`Patent No. 9,629,965 B2
`
`
`INTRODUCTION
`Nalox-1 Pharmaceuticals, LLC, (“Petitioner”) filed a Petition (Paper 2
`(“Pet.”)), seeking an inter partes review of claims 1–30 of U.S. Patent
`No. 9,629,965 B2 (“the ’965 patent,” Ex. 1001). We instituted trial to review
`the challenged claims. Paper 10 (“Dec.”). Thereafter, Adapt Pharma
`Operations Limited and Opiant Pharmaceuticals, Inc. (collectively, “Patent
`Owner”) filed a Response to the Petition (Paper 32, “PO Resp.”), Petitioner
`filed a Reply (Paper 37, “Reply”), and Patent Owner filed a Sur-Reply
`(Paper 47, “Sur-Reply”). Petitioner also filed a Motion for Observations
`(Paper 49). An oral hearing for this proceeding was held on May 19, 2020,
`and a transcript of that hearing is of record. See Paper 51 (“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 1–30 of the ’965 patent are
`unpatentable.
`
`Related Proceedings
`Petitioner filed IPR2019-00695 and IPR2019-00696, challenging the
`same claims of the ’965 patent with additional prior art. We denied those
`petitions. IPR2019-00695, Paper 10; IPR2019-00696, Paper 10.
`The ’965 patent is one of the patents listed in the Orange Book for
`intranasal naloxone sold under the brand name NARCAN. Pet. 1. Petitioner
`also filed petitions for inter partes review, challenging other patents listed in
`the Orange Book. Pet. 8; Paper 4, 1–2. We denied some of those petitions
`but also instituted review in IPR2019-00685 (challenging U.S. Patent
`
`2
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`No. 9,211,253) and IPR2019-00688 (challenging U.S. Patent 9,468,747).
`IPR2019-00685, Paper 11; IPR2019-00688, Paper 11. Concurrently with
`this Decision, we issue a final written decision in each of those cases.
`According to the parties, Patent Owner asserted five of its 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.
`8; Paper 4, 2. Petitioner is not involved in those actions. Pet. 8.
`According to Patent Owner, on March 2, 2020, the Perrigo Case was
`dismissed with prejudice pursuant to a consent judgment. Paper 54, 3. On
`June 22, 2020, the district court entered final judgment in the Teva Case,
`holding claims 21, 24, and 25 of the ’965 patent invalid. Id. at 4. Patent
`Owner states that its appeal from this judgment was docketed on August 3,
`2020. Id. at 4.
`
`Background of Technology and the ’965 Patent
`Naloxone is an opioid receptor antagonist that was initially approved
`for use by injection for the reversal of opioid overdose. Id. at 2:15–17.
`Naloxone hydrochloride injection prevents or reverses the effects of opioids,
`“including respiratory depression, sedation and hypotension.” Ex. 1044,1
`1300.2 The ’965 patent explains that “[s]ince the onset of action of naloxone
`used in opioid overdose cases should be as fast as possible, naloxone is thus
`
`1 Physicians’ Desk Reference 2003, entry for NARCAN (Naloxone
`Hydrochloride Injection, USP).
`2 Where applicable, we cite to the original page number of the exhibits, and
`not the pagination added by the parties.
`3
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`far mainly administered intravenously or intramuscularly by emergency
`health care personnel.” Ex. 1001, 6:17–20.
`According to the ’965 patent, administering naloxone via injection
`requires trained medical personnel and imposes the risk of exposure to blood
`borne pathogens through needlestick injury. Ex. 1001, 6:26–38. The
`’965 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
`6:45–49.
`The ’965 patent acknowledges that nasal administration of naloxone
`was known and, in fact, had been used by numerous medical services and
`health departments. See generally id. at 2:32–6:54. The patent points out,
`however, that some studies have “reported that the nasal administration of
`naloxone is as effective as the intravenous route in opiate addicts,” yet other
`studies have “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 2:50–58. The ’965 patent states:
`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 6:55–64.
`
`4
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`The ’965 patent purports to meet this need by providing 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 6:55–7:5.
`
`Illustrative Claims
`Claims 1 and 20 are independent and reproduced below.
`A pharmaceutical formulation for intranasal
`1.
`administration comprising, in an aqueous solution of not more
`than about 140 μL:
`about 4 mg naloxone hydrochloride;
`about 0.74 mg NaCl;
`about 0.01 mg benzalkonium chloride;
`about 0.2 mg disodium edetate; and
`an amount of hydrochloric acid sufficient to achieve a pH
`of 3.5–5.5.
`
`20. 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 comprises per 100 μL of aqueous solution:
`
`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
`preservative;
`
`between about 0.1 mg and about 0.5 mg of a stabilizing
`agent; and
`
`an amount of acid sufficient to achieve a pH of 3.5–5.5.
`
`5
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`Instituted Grounds of Unpatentability
`We instituted trial to determine whether claims 1–30 of the
`’965 patent are unpatentable based on the following grounds:
`Claims Challenged 35 U.S.C. §
`References/Basis
`1–22, 25, 26, 29, 30
`103
`Wyse,3 HPE4
`23, 24
`103
`Wyse, Djupesland,5 HPE
`27, 28
`103
`Wyse, HPE, the ’291 patent6
`
`Dec. 6.
`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 A. Williams, M.D., (Exs. 2001, 2202), Thomas J. 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 a
`pending motion to seal (Paper 30), and Patent Owner has provided
`Exhibits 2208 and 2206 as the redacted version of Exhibits 2201 and 2205,
`respectively.
`
`
`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).
`
`6
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`
`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
`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).
`A reference may be said to teach 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 by the applicant.
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`A reference does not teach away, however, if it merely expresses
`a general preference for an alternative invention but does not
`criticize, discredit, or otherwise discourage investigation into the
`invention claimed.
`Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013).
`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 ’965 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. 9 (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:
`The POSA team would also include drug development
`professionals 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 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 in the
`disclosure of the ’965 patent. Dec. 11; see Okajima v. Bourdeau, 261 F.3d
`1350, 1355 (Fed. Cir. 2001).
`Patent Owner does not contest the definition of the level of skill as
`adopted in our Institution Decision, and we continue to apply that same
`definition 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.” 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)); 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,
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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 teaches that these compositions may contain both
`EDTA and an “antimicrobial agent,” such as benzyl alcohol or “[o]ther
`suitable antimicrobial agents,” as excipients. Id. at 7:17–28.
`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”)7 as the
`preservative, the use of BAC “resulted in an additional degradant.” Id.
`at 27:29–32, Table 13. According to Wyse, “[a]part from the preservative,
`
`
`7 Benzalkonium chloride is abbreviated as BAC in the Petition, and BZK in
`the Patent Owner Response.
`
`10
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`[i.e., BAC,] Formulation 7”––one of the BAC-containing formulations that
`unexpectedly resulted in degradant––“was believed to be ideal for nasal
`delivery because the excipients were expected to increase the residence time
`in the nasal cavity (HPMC), prevent oxidation (EDTA), and create a
`hyperosmotic solution that facilitates diffusion across the cell membrane.”
`Id. at 27:32–37.
`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 and safety issues. Id.
`Regarding BAC, HPE teaches that “[b]enzalkonium chloride is a
`quaternary ammonium compound used in pharmaceutical formulations as an
`antimicrobial preservative in applications similar to other cationic
`surfactants, such as cetrimide.” Ex. 1012, 56. 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
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`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.
`
`Obviousness over Wyse and HPE
`Petitioner argues that claims 1–22, 25, 26, 29, and 30 would have
`been obvious over Wyse8 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.
`Independent claim 1 recites a formulation comprising “about 0.01 mg
`benzalkonium chloride” and “about 0.2 mg disodium edetate.” Ex. 1001,
`52:66–67. Independent claim 20 recites “between about 0.005 mg and about
`0.015 mg of a preservative” and “between about 0.1 mg and about 0.5 mg of
`
`
`8 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 the challenged claims is March 16, 2015. Pet. 13–
`15. Thus, Petitioner argues that Wyse qualifies as prior art under AIA
`§ 102(a)(2). Id. at 27–28. For the purposes of this proceeding, Patent Owner
`does not dispute, and we agree with, Petitioner’s argument on this point.
`Paper 9, 1.
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`a stabilizing agent.” Id. at 54:18–22. Claims 21 and 22, which depend from
`claim 20, specify BAC as the preservative and EDTA as the stabilizing
`agent. Id. at 54:23–36.
`Here, Petitioner’s obviousness allegation 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 in this Decision on this issue
`alone.
`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, 7:21–28). Because Wyse
`“does not specifically identify in this passage 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. at 33–34 (citing Ex. 1002 ¶¶ 138, 139).
`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. (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–
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`0.02% w/v.” Id. (citing Ex. 1002 ¶¶ 64, 138; Ex. 1012, 56). Thus, Petitioner
`concludes, “[a] POSA would have been particularly motivated to use BAC
`as a preservative in such a nasal spray,” because it “will function at lower
`concentrations of between 0.002% w/v and 0.02% w/v (i.e., 0.002 mg/100
`μL to 0.02 mg/100 μL) in nasal sprays,” which encompasses the amounts
`recited in independent claims 1 and 20. Id. at 34–35 (citing Ex. 1002 ¶¶64,
`138; Ex. 1012, 56), 42–43 (relying on Petitioner’s arguments for claims 1
`and 2 for claim 20). In other words, as Patent Owner points out, Petitioner’s
`“obviousness argument for all the claims . . . 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. Our discussion of the teaching away issue at institution focused on
`certain claims. Dec. 22–26. After reviewing the full record developed at
`trial, we determine that the preponderance of the evidence supports that
`same teaching away applies to Petitioner’s arguments concerning all of the
`challenged claims. Indeed, Petitioner has not advanced any separate
`argument for other excipient combinations. We highlight the arguments and
`evidence relating to this issue 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,
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`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 (see Pet. 51
`(citing Ex. 1007, 27:30–32)), but urges 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 (emphasis omitted). 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. 21; 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,
`and the solution would have been free of microbial growth or ingress.”
`(citing Ex. 1002 ¶ 50)).
`Wyse is the only reference of record in this proceeding 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. 51), an ordinarily skilled artisan,
`when “determin[ing] what antimicrobial agents he or she should consider in
`developing a nasal formulation of naloxone” (id. at 34), would have taken
`into consideration, and indeed, would have given significant weight, to the
`naloxone formulation stability data in Wyse.
`
`15
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`
`Petitioner contends that “others reading the disclosure of Wyse have
`concluded that it does not teach away from using BAC.” Pet. 52. As support
`for this contention, Petitioner cites Glende,9 “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, considered
`the WIPO publication equivalent of Wyse in light of the WIPO publication
`equivalent of a parent application to the ’965 patent,10 which disclosed
`BAC-containing formulations that were “storage-stable.” Ex. 1031, 52, 64.
`Thus, we 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. 51. 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
`
`
`9 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) (Ex. 1031).
`10 Crystal, et al., PCT Publication No. WO/2015/136373, published Sept. 17,
`2015.
`
`16
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`IPR2019-00694
`Patent No. 9,629,965 B2
`
`issues in the disclosed formulation.” Id. at 51 (citing Ex. 1002 ¶¶ 71–73); 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
`ordinarily skilled artisan, based on the 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, Wyse taught that BAC “specifically
`resulted in additional naloxone degradation, rather than degradation of
`another component.” Pet. 52. 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
`
`17
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`IPR2019-00694
`Patent No. 9,629,965 B2
`
`(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
`degradant.”11 Reply 5 (citing Ex. 1201 ¶¶ 13, 15, emphasis added).
`However, under cross examination, Dr. Donovan’s testimony on this point
`was 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.
`
`
`11 Petitioner also asserts that “the ‘additional degradant’ in these
`formulations was identified in a separate document as Impurity E—i.e., 2,2’-
`binaloxone—the primary oxidation degradation product of naloxone.”
`Reply 5 (citing Ex. 2188). As support, Petitioner relies on Exhibit 2188,
`“Indivior NDA Module 3.2.P.2.” Paper 46, 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 30, 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.
`
`18
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`IPR2019-00694
`Patent No. 9,629,965 B2
`
`Ex. 2215, 502:11–503:2 (emphases added). In view of such equivocal
`testimony, we are not persuaded 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 as urged by Petitioner.
`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. 52. 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
`problems, a POSA would have to evaluate each excipient and experimental
`condition individually and potentially evaluate other factors, including the
`presence of oxygen or materials used in containers during the storage period,
`to determine the cause of the observed problem.”). 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
`p
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