Trials@uspto.gov
`571-272-7822
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`Paper No. 14
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` Entered: August 27, 2019
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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 LIMITED, and
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owners.
`____________
`
`Case IPR2019-00691
`Patent 9,561,177 B2
`____________
`
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`HARLOW, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`571-272-7822
`
`
`
`
`
`
`
`
`Paper No. 14
`
`
`
` Entered: August 27, 2019
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`ADAPT PHARMA LIMITED, and
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owners.
`____________
`
`Case IPR2019-00691
`Patent 9,561,177 B2
`____________
`
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`HARLOW, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`
`IPR2019-00691
`Patent 9,561,177 B2
`
`
`I. INTRODUCTION
`Nalox-1 Pharmaceuticals, LLC (“Petitioner”), filed a Petition
`requesting inter partes review of claims 1–30 of U.S. Patent
`No. 9,561,177 B2 (Ex. 1001, “the ’177 patent”). Paper 1 (“Pet.”). Adapt
`Pharma Limited and Opiant Pharmaceuticals, Inc. (collectively, “Patent
`Owner”) timely filed a Preliminary Response. Paper 9 (“Prelim. Resp.”).
`Under 35 U.S.C. § 314(a), an inter partes review may not be instituted
`unless the information presented in the petition “shows that there is a
`reasonable likelihood that the petitioner would prevail with respect to at
`least 1 of the claims challenged in the petition.” Having considered the
`evidence and arguments of record, we agree with Patent Owner that the prior
`art teaches away from the claimed invention, and, therefore, decline to
`institute inter partes review.
`A. Related Matters
`Claims 1–30 of the ’177 patent are also the subject of IPR2019-00692
`and IPR2019-00693, initiated by Petitioner contemporaneously with the
`instant proceeding. Paper 8, 2–3. We issue our decisions declining to
`institute inter partes review in IPR2019-00692 and IPR2019-00693
`concurrently with this Decision.
`In addition to the three petitions challenging the ’177 patent,
`Petitioner has filed 12 petitions against four patents related to the
`’177 patent. Id.; Pet. 7–8. Each of the five patents for which Petitioner
`seeks inter partes review is listed in the Orange Book for intranasal
`naloxone sold under the brand name NARCAN. Pet. 1, 7–8. These five
`patents are also the subject of pending district court litigation in Adapt
`2
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`IPR2019-00691
`Patent 9,561,177 B2
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`Pharma Operations Ltd. v. Teva Pharmaceuticals USA, Inc., Case 2:16-cv-
`07721 (D.N.J.) (consolidated, “the Teva Case”),1 and Adapt Pharma
`Operations Ltd. v. Perrigo UK FINCO Limited Partnership, Case 2:18-cv-
`15287 (D.N.J.). Pet. 7; Paper 8, 3. Petitioner is not party to the district court
`actions, however. Pet. 7.
`
`B. The ’177 Patent
`The ’177 patent, titled “Nasal Drug Products and Methods of Their
`Use” (Ex. 1001, (54)), describes “[d]rug products adapted for nasal delivery,
`comprising a pre-primed device filled with a pharmaceutical composition
`comprising an opioid receptor antagonist” (id. at Abstract), as well as
`“[m]ethods of treating opioid overdose or its symptoms with the inventive
`drug products” (id.).
`Opioid overdose is a growing public health challenge in the United
`States. Ex. 1001, 1:57–2:4. According to the ’177 patent, in 2014 alone,
`more than 28,000 people in the United States died from overdoses of heroin
`or prescription opioids, representing a nearly four-fold increase since 1999.
`Id. at 1:63–65. The patent further explains that “the increase in the rate of
`drug overdose in recent years has been driven mainly by overdoses of
`prescription [opioid] analgesics.” Id. at 2:2–4.
`The ’177 patent identifies naloxone as “an opioid receptor antagonist
`that is approved for use by injection for the reversal of opioid overdose and
`for adjunct use in the treatment of septic shock.” Ex. 1001, 2:5–7. The
`
`
`1 Patent Owner informs us that bench trial in the Teva Case is set for
`August 26, 2019. Paper 10, 1.
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`3
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`Patent 9,561,177 B2
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`patent states that intranasal (“IN”) delivery of naloxone is “considered an
`attractive route for needle-free, systemic drug delivery, especially when
`rapid absorption and effect are desired. In addition, nasal delivery may help
`address issues related to poor bioavailability, slow absorption, drug
`degradation, and adverse events (AEs) in the gastrointestinal tract and avoids
`the first-pass metabolism in the liver.” Ex. 1001, 10:50–56. The patent also
`notes that several intranasal naloxone formulations of have been elsewhere
`described. Id. at 2:15–49. For example, the ’177 patent states that
`reports pharmaceutical
`to Davies2
`WO 00/62757
`compositions for IN or oral (PO) administration which comprise
`an opioid antagonist, such as naloxone for application by spray
`in the reversal of opioid depression for treatment of patients
`suffering from opioid over-dosage, wherein the spray applicator
`is capable of delivering single or multiple doses and suitable
`dosage units are in the range of 0.2 to 5 mg.
`Ex. 1001, 2:28–34. The patent goes on to explain, however, that “[t]he use
`of nasal naloxone is not without controversy.” Id. at 2:35. In this regard, the
`’177 patent represents that a study by Dowling3 “reported that naloxone
`administered intranasally displays a relative bioavailability of 4% only and
`concluded that the IN absorption is rapid but does not maintain measurable
`
`
`2 Davies et al., PCT Publication No. WO 00/62757, published Oct. 26, 2000
`(Ex. 1009).
`3 Dowling et al., Population Pharmacokinetics of Intravenous,
`Intramuscular, and Intranasal Naloxone in Human Volunteers, 30(4) THER.
`DRUG. MONIT. 490–96 (2008) (Ex. 1027).
`4
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`Patent 9,561,177 B2
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`concentrations for more than an hour.” Id. at 2:37–41. Moreover, and of
`particular relevance here, the ’177 patent observes that
`U.S. Pat. No. 9,192,570 to Wyse4 reports naloxone
`formulations for intranasal administration. Wyse reports
`(column 27, lines 29–37) that benzalkonium chloride [(“BAC”)
`or (“BZE”)] is not suitable in such formulations, because it
`facilitates unacceptable degradation of the naloxone. Wyse
`recommends (lines 41–43) benzyl alcohol and paraben
`preservatives in place of benzalkonium chloride.
`Id. at 2:42–48.
`According to the ’177 patent, therefore, “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.” Ex. 1001, 2:49–53. The patent goes on to explain that “[t]he
`therapeutically effective dose should be sufficient to obviate the need for the
`untrained individual to administer an alternative medical intervention to the
`patient, and to stabilize the patient until professional medical care becomes
`available.” Id.at 2:53–57.
`To meet these needs, the ’177 patent discloses devices adapted for
`nasal delivery of “a therapeutically effective amount of an opioid antagonist
`selected from naloxone and pharmaceutically acceptable salts thereof,
`wherein said device is pre-primed, and wherein said therapeutically effective
`amount, is equivalent to about 2 mg to about 12 mg of naloxone
`
`
`4 Wyse et al., U.S. Patent No. 9,192,570 B2, issued Nov. 24, 2015
`(Ex. 1007).
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`Patent 9,561,177 B2
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`hydrochloride.” Id. at 12:57–64. The ’177 patent further discloses, despite
`the contrary recommendation of Wyse, the inclusion of BAC in the opioid
`antagonist-containing composition. Id. at 14:11–15. According to the
`’177 patent, BAC “can function as a preservative (even in low amounts), a
`permeation/penetration enhancer, and/or a cationic surfactant (typically at a
`higher amount for these latter two).” Id.
`C. Illustrative Claim
`Claims 1, 12, and 22 of the ’177 patent are independent. Claim 1,
`reproduced below, is illustrative of the claimed subject matter.
`1.
`A method of treating opioid overdose, the method
`comprising:
`delivering a 25–200 μL spray of a pharmaceutical solution
`from a pre-primed device into a nostril of a patient, wherein the
`device
`is adapted for nasal delivery, and wherein
`the
`pharmaceutical solution comprises about 4 mg naloxone
`hydrochloride or a hydrate thereof, between about 0.005% and
`about 0.015% (w/v) of benzalkonium chloride, and an isotonicity
`agent.
`Ex. 1001, 62:34–42 (emphasis added).
`Independent claims 12 and 22 likewise require compositions including
`naloxone and BAC. Claim 12 recites, in pertinent part, “[a] mist delivered
`from a pre-primed device,” the droplets of which mist “comprise, in
`aggregate, about 4 mg of naloxone hydrochloride or a hydrate thereof, [and]
`between about 0.005% and about 1% (w/v) of benzalkonium chloride.”
`63:14–18. Claim 22 similarly recites, in relevant part, “[a] method of
`treating narcotic-induced respiratory depression” through the delivery of a
`pharmaceutical solution in a spray, “wherein the spray comprises about 4 mg
`
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`Patent 9,561,177 B2
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`naloxone hydrochloride or a hydrate thereof, [and] between about 0.005%
`and about 0.015% (w/[v]) ref benza[l]konium chloride.” Id. at 63:43–64:7.
`D. Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability (Pet. 3):
`
`Claim(s)
`1–5, 10–11
`6–9
`12–27, 29
`
`28
`
`30
`
`References
`
`Basis
`§ 103(a) Wyse and HPE5
`§ 103(a) Wyse, HPE, and Djupesland6
`§ 103(a) Wyse, HPE, and the ’291 patent7
`Wyse, HPE, the ’291 patent, and Wang8 and
`the knowledge of a pharmacologist of
`ordinary skill in the art, or Wermeling 20139
`§ 103(a) Wyse, HPE, the ’291 patent, Djupesland, and
`Zomig Review10
`
`§ 103(a)
`
`Petitioner relies on the Declarations of Maureen D. Donovan, Ph.D.
`(Ex. 1002) and Günther Hochhaus, Ph.D. (Ex. 1003) to support its challenge.
`
`
`5 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).
`6 Djupesland, Nasal Drug Delivery Device: Characteristics and
`Performance in a Clinical Perspective - A Review, 3 DRUG DELIV. &
`TRANSL. RES. 42–62 (2013) (Ex. 1010).
`7 Wermeling, U.S. Patent No. 8,198,291 B2, issued June 12, 2012
`(Ex. 1015).
`8 Wang et al., Chinese Patent No. 1,575,795, published Feb. 9, 2005
`(certified translation) (Ex. 1008).
`9 Wermeling, A Response to the Opioid Overdose Epidemic: Naloxone
`Nasal Spray, 3 DRUG DELIV. & TRANSL. RES. 63–74 (2013) (Ex. 1016).
`10 CDC, NDA No. 21-450 Clinical Pharmacology & Biopharmaceutics
`Review (2002) (Ex. 1024).
`
`7
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`IPR2019-00691
`Patent 9,561,177 B2
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`
`II. ANALYSIS
`A. Level of Ordinary Skill in the Art
`In determining the level of ordinary skill in the art, various factors
`may be considered, including the “type of problems encountered in the art;
`prior art solutions to those problems; rapidity with which innovations are
`made; sophistication of the technology; and educational level of active
`workers in the field.” In re GPAC, Inc., 57 F.3d 1573, 1579 (Fed. Cir. 1995)
`(citation omitted). In that regard, Petitioner, citing its declarants,
`Drs. Donovan and Hochhaus, submits that a person with ordinary skill in the
`art (“POSA”) at the time of the invention of the ’177 patent “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 ¶ 38; Ex. 1003 ¶ 22).
`According to Petitioner, this team would include a “Formulator
`POSA” as well as a “Pharmacologist POSA.” Pet. 9–10. Petitioner explains
`that the Formulator POSA would have “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.
`(citing Ex. 1002 ¶ 38). The Pharmacologist POSA, in contrast, would have
`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
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`Patent 9,561,177 B2
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`and/or evaluating issues of safety and efficacy, and evaluating
`the regulatory requirements of a new dosage form.
`Id. at 10 (citing Ex. 1003 ¶ 22).
`For purposes of this Decision, we adopt Petitioner’s presently
`undisputed definition of the level of ordinary skill in the art, as it is
`consistent with the level of skill in the art reflected in the prior art of record.
`See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001).
`B. Claim Construction
`In this inter partes review proceeding, the claims of the patent are
`construed using the same standard used in federal district court, including
`construing each claim in accordance with the ordinary and customary
`meaning of the 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) (2018);
`83 Fed. Reg. 51358 (Oct. 11, 2018) (amending the claim construction
`standard for trial proceedings before the Board).
`Petitioner proposes constructions for several terms (Pet. 25–29),
`which Patent Owner does not presently dispute (see generally Prelim.
`Resp.). In addition, as Patent Owner notes (id. at 11), the district court has
`issued a claim construction decision in the Teva Case (Ex. 2025). The
`district court provides interpretations for certain claim terms set forth in
`patents related to the ’177 patent, but explains that the parties resolved their
`disputes concerning terms recited in the ’177 patent itself. Ex. 2025, 1 n.1.
`For purposes of this Decision, we interpret the challenged claims in
`accord with their ordinary meaning to one skilled in the art at the time of
`invention in light of the teachings of the specification and the prosecution
`
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`Patent 9,561,177 B2
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`history, and do not find it necessary to provide any express claim
`constructions. In reaching this conclusion, we observe that the parties do not
`dispute the meaning of the challenged claims, and our decision declining to
`institute trial does not turn on the adoption of any particular claim
`construction. See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.
`Ltd., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (noting that “we need only
`construe terms ‘that are in controversy, and only to the extent necessary to
`resolve the controversy’”) (citing Vivid Techs., Inc. v. Am. Sci. & Eng’g,
`Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
`C. References Relied Upon
`1. 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.
`Of particular relevance here, 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.
`Ex. 1007, 26:26–29, Table 13. BAC was present in five of the formulations
`tested. Id. at Table 13. Wyse reports that the study “surprisingly showed”
`that the use of BAC “resulted in an additional degradant” in four of those
`formulations. Id. at 27:29–32. In this regard, Wyse remarks that “[a]part
`from the preservative [i.e., BAC,] Formulation 7”––one of the
`BAC-containing formulations that unexpectedly resulted in degradant––
`10
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`Patent 9,561,177 B2
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`“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.
`Wyse goes on to explain that “[i]n this initial study, the preliminary
`conclusion was that benzyl alcohol and paraben preservatives were
`acceptable, but benzalkonium chloride was not, due to increased observed
`degradation.” Id. at 27:41–44. Wyse concludes:
`Net, Applicant found that, surprisingly, commonly used
`excipients
`including one or more
`[of] ascorbic acid,
`hypromellose, propylene glycol 400, sorbitol, glycerine,
`polypropylene
`glycol, methylparaben,
`propylparaben,
`benzylalkonium chloride, were found to increase degradation of
`naloxone.
` While some of
`the excipients might work
`individually, the combination of many of these was found to be
`unacceptable for various reasons as outlined above. Equally
`surprising was that the disclosed compositions, which lack
`commonly used excipients and combinations of commonly used
`excipients, had superior stability as compared to more complex
`formulations and remained stable for a period of up to 36 months
`under ambient conditions.
`Id. at 28:23–35.
`
`2. HPE
`HPE discloses 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. According to HPE, in nasal
`formulations, BAC is used in “a concentration of 0.002–0.02% w/v.” Id.
`
`11
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`HPE notes that BAC is “[i]ncluded in the FDA Inactive Ingredients
`Database” for nasal preparations. Id. at 57 (citation omitted).
`3. Djupesland
`Djupesland describes the Pfeiffer/Aptar single-dose intranasal
`delivery device used to administer certain migraine medications. Ex. 1010,
`49. 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 Imitrex (sumatriptan) and Zomig (zolmitriptan).” Id.
`4. The ’291 Patent
`The ’291 patent discloses the spray pattern function for an intranasal
`butorphanol composition when sprayed from the Pfeiffer Unitdose Second
`Generation device onto an impaction plate from various distances.
`Ex. 1015, 11:46–12:15. For example, the ’291 patent describes the spray
`diameter, ovality, and droplet size distribution observed at several spray
`distances. Id.
`
`5. Wang
`Wang describes a naloxone hydrochloride nasal spray. Ex. 1008, 7.
`Wang states that
`[t]he inventors have found through intensive studies that a novel
`nasal spray administration dosage form is formed by mixing
`naloxone hydrochloride with an optional preservative, osmotic
`pressure regulator, penetration enhancer and water. The
`preparation has a single-dose and multi-dose nasal spray with
`rapid absorption, high bioavailability and low irritation. The
`preparation is suitable for scale production and storage.
`Id. According to Wang, “the preservative used in the nasal spray of the
`present invention is selected from methyl, ethyl, propyl, or butyl
`12
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`para-hydroxybenzoate, sorbic acid, benzoic acid, sodium benzoate, benzyl
`alcohol, benzalkonium chloride, benzalkonium bromide, chlorobutanol,
`resorcinol, sodium ethylenediamine tetraacetate and the like.” Id.
`6. Wermeling 2013
`Wermeling 2013 describes the “scientific basis for design and study of
`an intranasal naloxone product.” Ex. 1016, Abstract. Wermeling 2013
`reasons that an intranasal naloxone dose “must have sufficient solubility to
`be administered in approximately 100–200 μL (one spray per naris) of
`solution” (id. at 65), and estimates that “[a] 2 mg nasal [naloxone] solution
`dose will likely have a Cmax of 3–5 ng/mL and a tmax of approximately
`20 min, similar to naltrexone and hydromorphone” (id. at 66).
`7. Zomig Review
`Zomig Review discloses a unit dose delivery device designed to
`administer zolmitriptan, a selective 5-HT 1B/1D receptor agonist for the
`acute treatment of migraine headaches, to the nasal cavity. Ex. 1024, 4, 5.
`D. The Examiner Found that Wyse Teaches Away
`from the Claimed Invention
`Teaching away by Wyse from the use of BAC in intranasal naloxone
`formulations was a central issue addressed during prosecution of the
`’177 patent. The Examiner initially rejected numerous claims in the
`application for the ’177 patent as obvious over Wyse and Djupesland, two of
`the references Petitioner relies on here. Ex. 1004, 10–15.11 In response, the
`
`
`11 Consistent with the convention adopted by the parties, our citations to the
`prosecution history for the ’177 patent (Ex. 1004–1006) refer to the
`pagination added by Petitioner.
`
`13
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`Applicant amended each proposed independent claim to require 4 mg of
`naloxone and an amount of BAC falling with a specified range (about
`0.005% to about 0.015% w/v for claims 1 and 24, and about 0.005% to
`about 1% for claim 14). Ex. 1005, 3–6. The Applicant then argued (id. at
`11–12), and the Examiner agreed (Ex. 1006, 13), that Wyse teaches away
`from the claims as amended because, inter alia, Wyse teaches away from the
`use of BAC in an intranasal naloxone formulation.
`In the Reasons for Allowance, the Examiner explained that Wyse
`is considered to expressly exclude the use of benzalkonium
`chloride stating that benzalkonium chloride, a common nasal
`product preservative, results in increased degradation of the
`naloxone active and teaches outright that apart from the
`preservative (i.e., benzalkonium chloride) the formulation of
`Example 7 is suitable for nasal administration (see col. 27, lines
`18–37). This is considered to be a direct departure from the
`instantly claimed composition. Thus, despite the teaching of
`Wynne et al. at claim 11 teaching benzalkonium chloride and
`benzyl alcohol as functionally equivalent preservatives (pg. 7,
`lines 1–5), motivation to combine and or modify such teachings
`are considered to be overcome by the teachings of Wyse.
`Ex. 1006, 13 (emphasis omitted).
`E. Petitioner Has Not Adequately Established that a Skilled Artisan Would
`Have Had a Reasonable Expectation of Successfully Using BAC
`in an Intranasal Naloxone Formulation
`In view of the record before us, we are not persuaded by Petitioner’s
`arguments and evidence attempting to show that there is a reasonable
`likelihood that it would prevail in establishing that at least one of claims 1–
`30 of the ’177 patent is unpatentable.
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`Each independent claim of the ’177 patent requires a naloxone
`formulation that includes BAC. Specifically, claim 1 recites “[a] method of
`treating opioid overdose” through the intranasal delivery of a
`“pharmaceutical solution compris[ing] about 4 mg naloxone hydrochloride
`or a hydrate thereof, between about 0.005% and about 0.015% (w/v) of
`benzalkonium chloride, and an isotonicity agent.” Ex. 1001, 62:34–42.
`Claim 22 similarly recites “[a] method of treating narcotic-induced
`respiratory depression” through the intranasal delivery of a pharmaceutical
`solution in a spray having the same amounts of naloxone and BAC specified
`in claim 1 and an isotonicity agent. Id. at 63:43–64:9. Claim 12 is directed
`to a product rather than a method of treatment, but likewise requires a
`formulation including naloxone and BAC. In particular, claim 12 recites
`“[a] mist delivered from a pre-primed device, wherein the mist comprises
`droplets, wherein the droplets comprise, in aggregate, about 4 mg of
`naloxone hydrochloride or a hydrate thereof, between about 0.005% and
`about 1% (w/v) of benzalkonium chloride, and an isotonicity agent.” Id. at
`63:14–20.
`For the reasons set forth below, we find that the prior art teaches away
`from the use of BAC in intranasal naloxone formulations, and, therefore,
`determine that Petitioner has not established a reasonable likelihood of
`prevailing as to any of the challenged claims.
`1. Petitioner’s Contentions
`Despite the Examiner’s contrary finding, discussed above, Petitioner
`contends that the combination of Wyse and HPE teaches the inclusion of
`BAC in an intranasal formulation in an amount falling within the ranges
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`specified by claims 1, 12, and 22. Pet. 35–36, 47, 54–55.12 According to
`Petitioner, Wyse discloses that an intranasal naloxone formulation “can
`contain an antimicrobial agent—i.e., a preservative—in an amount of 0.1%
`to 2% by weight of the formulation.” Id. at 35 (citing Ex. 1007, 21–28).
`Petitioner recognizes that Wyse discloses the use of benzyl alcohol as a
`preservative, but points out that Wyse also teaches that “[o]ther suitable
`antimicrobial agents may be readily understood by one of ordinary skill in
`the art.” Id. (citing Ex. 1007, 7:26–28). Petitioner, therefore, reasons that
`such an artisan “would have looked to pharmaceutical compendiums like
`HPE to determine what other antimicrobial agents would be acceptable;
`BAC would have been one such antimicrobial agent.” Id. (citing Ex. 1012,
`56–57). Specifically, according to Petitioner, an ordinarily skilled artisan
`would have selected BAC for use in an intranasal naloxone formulation
`because it has a wide range of antimicrobial activity at low concentrations, is
`FDA-approved for, and commonly used in nasal sprays, and is more
`effective than other nasal spray preservatives against certain bacteria and
`fungi. Pet. 36 (citing Ex. 1002 ¶¶ 75–76, 78).
`Petitioner acknowledges Wyse’s teaching that BAC is not acceptable
`for inclusion in intranasal naloxone formulations due to increased observed
`
`
`12 Petitioner points to the analysis of Wyse and HPE set forth in its
`discussion of the patentability of claim 1 to support its contention that the
`prior art teaches or suggests including BAC in a naloxone formulation in the
`amounts recited in claims 12 and 22. Pet. 47, 54–55. Because Petitioner
`focuses its analysis on claim 1 with regard to the BAC requirement set forth
`in each challenged independent claim, we do the same.
`16
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`IPR2019-00691
`Patent 9,561,177 B2
`
`degradation. Pet. 61 (citing Ex. 1007, 27:30–34, 27:41–44). Petitioner
`asserts, however, that an ordinarily skilled artisan would not have given
`Wyse’s statements disparaging the use of BAC “much merit.” Pet. 61–62.
`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.” Pet. 62
`(citing Ex. 1002 ¶¶ 83–85). In addition, Petitioner argues that Wyse does
`not indicate that the inclusion of BAC “specifically resulted in additional
`naloxone degradation, rather than degradation of another component” (id.
`(citing Ex. 1002 ¶ 86), and points out that out that one of the five
`BAC-including formulations tested by Wyse did not result in additional
`degradant (id. (citing Ex. 1002 ¶¶ 87–90)). Finally, Petitioner contends that
`an unpublished Norwegian graduate thesis by Glende13 that discusses the
`“WIPO publication equivalent of Wyse,” but undisputedly does not qualify
`as prior art, demonstrates that “others reading the disclosure of Wyse have
`concluded that it does not teach away from using BAC.” Id. at 62–63 (citing
`Ex. 1031, 76; Ex. 1002 ¶¶ 79–90).
`
`
`13 Glende, 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).
`17
`
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`IPR2019-00691
`Patent 9,561,177 B2
`
`
`2. Wyse Teaches Away from Using BAC in
`Intranasal Naloxone Formulations
`We agree with Patent Owner––and the Examiner––that Wyse
`unambiguously discourages the use of BAC in intranasal naloxone
`formulations. An ordinarily skilled artisan seeking to develop an intranasal
`naloxone formulation would have taken heed of Wyse’s teaching that BAC
`is not acceptable for use as an excipient in such a formulation because, as
`Petitioner acknowledges, such an 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. 22; 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 ¶ 69)).
`Wyse is the sole reference of record that compares naloxone
`formulations having different excipient combinations, and is the only one
`that provides stability data for intranasal naloxone formulations. See
`Part II.C. (summarizing the asserted references), supra. Because it is the
`only data of record concerning the use of excipients in intranasal naloxone
`formulations, an ordinarily skilled artisan interested in determining what
`“antimicrobial agents would be acceptable,” i.e., successful, in a naloxone
`formulation (Pet. 35) would have given significant weight to the naloxone
`formulation stability data disclosed by Wyse.
`
`18
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`IPR2019-00691
`Patent 9,561,177 B2
`
`
`Petitioner’s argument that Wyse cannot be said to teach away because
`it does not “conclusively” establish that BAC causes naloxone degradation
`or demonstrate that BAC is “incompatible with naloxone” (Pet. 62)
`misapprehends the standard for evaluating whether a reference teaches
`away. 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 claim. Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d
`731, 738 (Fed. Cir. 2013). “[I]n general, a reference will teach 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 meets that standard here. For example, Wyse reports that BAC
`was “found to increase degradation of naloxone” (Ex. 1007, 28:23–25
`(emphasis added)), and that BAC was not acceptable for use in intranasal
`naloxone formulations (id. at 27:41–44). In addition to teaching that
`BAC-containing naloxone formulations are unstable (id. at 28:23–25), Wyse
`also discloses that other antimicrobial preservatives, such as benzyl alcohol,
`are stable in combination with naloxone. Ex. 1007, 27:29–37, 28:41–29:27,
`Tables 14–15. These disclosures expressly teach away from the use of BAC
`in intranasal naloxone formulations, and directly counter Petitioner’s
`assertion that Wyse does not sufficiently specify the nature or importance of
`the observed BAC-associated degradant (Pet. 61).
`Wyse’s rejection of BAC as a viable excipient for use in naloxone
`formulations is further underscored by the fact that Wyse expressly excluded
`19
`
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`IPR2019-00691
`Patent 9,561,177 B2
`
`BAC from the naloxone formulations chosen for further study. Id. at 28:41–
`47, Table 14. Significantly, Wyse reports that the use of BAC as a
`preservative rendered an otherwise “ideal” naloxone formulation unstable.
`Id. at 27:29–37, 28:41–29:27, Tables 14–15. In particular, the
`BAC-containing version of the otherwise “ideal” formulation produced
`undesirable degradant in a preliminary screening study (id. at 27:29–32),
`while the benzyl alcohol-containing version of that formulation was stable
`(id. at Table 15). In addition, Wyse ultimately determined that two
`formulations using benzyl alcohol (and excluding BAC) as a preservative
`were stable and warranted further development. Id. at 29:18–40, Tables 15–
`16.
`
`That Wyse’s naloxone formulations combined “multiple different
`excipients,” and that one out of the five of the BAC-containing naloxone
`formulations tested did not show additional degradant (Pet. 62) does not
`undermine Wyse’s teaching away. As explained above, teaching away need
`not be established by irrefutable proof or scientific certainty; it is sufficient
`that a
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