Trials@uspto.gov
`571-272-7822
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`Paper No. 13
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` Entered: October 16, 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.
`___________
`
`IPR2019-00699
`Patent 9,775,838 B2
`____________
`
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`571-272-7822
`
`
`
`
`
`
`
`
`Paper No. 13
`
`
`
` Entered: October 16, 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.
`___________
`
`IPR2019-00699
`Patent 9,775,838 B2
`____________
`
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`JACQUELINE T. HARLOW, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`
`IPR2019-00699
`Patent 9,775,838 B2
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`I. INTRODUCTION
`Nalox-1 Pharmaceuticals, LLC (“Petitioner”), filed a Petition
`requesting inter partes review of claims 1–46 (“the challenged claims”) of
`U.S. Patent No. 9,775,838 B2 (Ex. 1001, “the ’838 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
`The parties identify the following district court cases involving the
`’838 patent: Adapt Pharma Operations Ltd. v. Teva Pharmaceuticals USA,
`No. 2:16-cv-07721 (D.N.J.); Adapt Pharma Operations Ltd. v. Perrigo UK
`FINCO Limited Partnership, No. 2:18-cv-15287 (D.N.J.). Pet. 6; Paper 6, 2.
`Petitioner is not a party in either of those cases. Petitioner additionally
`challenges claims 1–46 of the ’838 patent in two other petitions concurrently
`filed in IPR2019-00697 and IPR2019-00698.
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`The ’838 patent is one of five patents listed in the Orange Book for
`intranasal naloxone sold under the brand name NARCAN. Pet. 1; Paper 9,
`1. Petitioner has also filed petitions for inter partes review of claims of each
`of those other four patents. Paper 6, 1–2.
`B. The ’838 Patent
`The ’838 patent is directed to “pharmaceutical compositions
`comprising an opioid receptor antagonist, medical devices for delivery of the
`pharmaceutical compositions, and methods of using the compositions and
`the medical devices.” Ex. 1001, 1:35–39. In particular, the Specification
`discloses what is described as an “improved single-use, pre-primed device
`adapted for nasal delivery of a pharmaceutical solution to a patient”
`comprising naloxone hydrochloride or a hydrate thereof. Id. at 2:66–3:2.
`Naloxone is an opioid receptor antagonist approved for use by injection for
`the reversal of opioid overdose. Id. at 2:9. According to the Specification,
`the improvement derives from administering naloxone nasally with a device
`being adapted to spray a round plume with an ovality ratio less than about
`two. Id. at 3:3–5. Additionally, the Specification explains that nasal
`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, 10:52–58.
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`The disclosed compositions comprise benzalkonium chloride
`(“BAC”). Id. at 13:67–14:16. The Specification explains that 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. at 14:16–19.
`C. Illustrative Claim
`Claims 1 and 41 are the only independent claims of the ’838 patent.
`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,
`wherein the spray delivers between about 4 mg and about 10 mg
` naloxone, an isotonicity agent, and between about 0.005% and
` about 0.015% (w/v) of benzalkonium chloride.
`
`
`Ex. 1001, 63:5–13 (emphasis added).
`Independent claim 41 recites a method of treating narcotic-induced
`respiratory depression, wherein the method similarly requires the spray of a
`pharmaceutical solution from a pre-primed device into a nostril of a patient
`to deliver between about 4 mg and about 10 mg naloxone, an isotonicity
`agent, and “between about 0.005% and about 0.015% (w/v) of benzalkonium
`chloride.” Id. at 65:16–19.
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`D. Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of claims 1–46 under 35 U.S.C.
`§ 103 on the following grounds:
`
`References
`Claim(s)
`1–2, 4, 18–23, 30–31, 39–40 Davies1 and HPE2
`3, 32–34
`Davies, HPE, Bahal,3 and Kushwaha4
`5–12
`Davies, HPE, and Wang5
`Davies, HPE, Djupesland6, and the
`13–17
`’291 patent7
`24, 35, 37
`Davies, HPE, and Djupesland
`25–29, 36
`Davies, HPE, and Wyse8
`Davies, HPE, Djupesland, and Zomig
`38
`Review9
`Davies, HPE, Djupesland, Wyse, and the
`’291 patent
`
`41–46
`
`
`1 Davies et al., PCT Publication No. WO 00/62757, published Oct. 26, 2000
`(“Davies”) (Ex. 1009).
`2 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)
`(“HPE”) (Ex. 1012).
`3 Bahal, et al., U.S. Patent No. 5,866,154, issued Feb. 2, 1999 (“Bahal”)
`(Ex. 1014).
`4 Kushwaha, et al., Advances in Nasal Trans-Mucosal Drug Delivery,
`(1)7 J. APPLIED PHARM. SCI. 21–28 (2011) (“Kushwaha”) (Ex. 1013)
`5 Wang et al., Chinese Patent Publication No. CN 1575795 A, published
`February 9, 2005 (“Wang”) (Ex. 1008).
`6 Djupesland, Nasal Drug Delivery Device: Characteristics and
`Performance in a Clinical Perspective - A Review, 3 DRUG DELIV. &
`TRANSL. RES. 42–62 (2013) (“Djupesland”) (Ex. 1010).
`7 Wermeling, U.S. Patent No. 8,198,291 B2, issued June 12, 2012 (“the ’291
`patent”) (Ex. 1015).
`8 Wyse et al., U.S. Patent No. 9,192,570 B2, issued Nov. 24, 2015 (“Wyse”)
`(Ex. 1007).
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`Petitioner also relies on the Declarations of Maureen D. Donovan,
`Ph.D. (Ex. 1002) and Günther Hochhaus, Ph.D. (Ex. 1003) to support its
`challenge.
`
`II. ANALYSIS
`A. Claim Construction
`In an inter partes review based on a petition filed after November 13,
`2018, such as the present Petition, the Board interprets a claim term by
`applying “the standard used in federal courts, in other words, the claim
`construction standard that would be used to construe the claim in a civil
`action under 35 U.S.C. [§] 282(b), which is articulated in Phillips.”10 83
`Fed. Reg. 51,340, 51,343. Under that standard, 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.” Phillips v. AWH Corp., 415 F.3d 1303, 1312–13 (Fed.
`Cir. 2005) (en banc) (citations omitted). Any special definitions for claim
`terms must be set forth with reasonable clarity, deliberateness, and precision.
`In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`
`9 CDC, NDA No. 21-450 Clinical Pharmacology & Biopharmaceutics
`Review (2002) (“Zomig Review”) (Ex. 1024).
`10 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, 51,344 (Oct. 11, 2018) (to be codified at 37 C.F.R.
`pt. 42).
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`Petitioner proposes constructions for certain claim terms and phrases.
`Pet. 23–25. Patent Owner does not address Petitioner’s proposed claim
`constructions or offer its own in the Preliminary Response. Based upon our
`review, there is no controversy regarding the construction of any claim term.
`For purposes of this Decision, we interpret the challenged claims according
`to their ordinary meaning as understood by one skilled in the art at the time
`of invention. Thus, we do not find it necessary to provide any express claim
`constructions. Further, we note that this 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., 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’”)
`(quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
`(Fed. Cir. 1999)).
`
`B. Level of Ordinary Skill in the Art
`The level of ordinary skill in the art is a factual determination that
`provides a primary guarantee of objectivity in an obviousness analysis. Al-
`Site Corp. v. VSI Int’l Inc., 174 F.3d 1308, 1324 (Fed. Cir. 1999) (citing
`Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966); Ryko Mfg. Co. v. Nu-
`Star, Inc., 950 F.2d 714, 718 (Fed. Cir. 1991)).
`According to Petitioner, a person with ordinary skill in the art
`(“POSA”) at the time of the invention of the ’838 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. 7 (citing Ex. 1002 ¶ 35; Ex. 1003 ¶ 22). Petitioner asserts that
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`this team would include a “Formulator POSA” as well as a “Pharmacologist
`POSA.” Pet. 7–9. 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. at 7 (citing Ex. 1002 ¶ 35). Petitioner
`explains that the Pharmacologist POSA 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
`and/or evaluating issues of safety and efficacy, and evaluating
`the regulatory requirements of a new dosage form.
`Id. at 8 (citing Ex. 1003 ¶ 22).
`For purposes of this Decision, we adopt Petitioner’s definition of the
`level of ordinary skill in the art, as it is supported by declaration testimony,
`undisputed by Patent Owner in the Preliminary Response, and 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).
`C. Obviousness
`Each ground presented in the Petition challenges claims of the ’838
`patent as obvious over various combinations of prior art references. Pet. 3.
`In particular, Petitioner includes Wyse as a basis for two of those grounds
`and asserts, regarding all grounds, that Wyse does not teach away from the
`claimed invention. Pet. 3, 62–66. Patent Owner disagrees. Prelim. Resp. 3,
`47–52. As that assertion is potentially dispositive of each ground, we begin
`
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`our obviousness analysis by addressing the teachings of the prior art, and,
`specifically, determining whether Wyse teaches away from the claimed
`inventions.
`
`1. Davies
`Davies describes a spray applicator “for administering an opioid
`antagonist selected from naloxone and/or naltrexone.” Ex. 1009, Abstract.
`Davies also discloses “[a] pharmaceutical composition for nasal or oral
`administration” comprising “an opioid antagonist, such as naloxone and/or
`naltrexone” and “a water-susceptible solid carrier admixed with the opioid
`antagonist.” Id. Example 1 of Davies describes a “[s]prayable aqueous
`liquid composition for a nasal application.” Id. at 3:28. According to
`Davies,
`[n]aloxone hydrochloride was dissolved in a solution of purified
`water to form a solution containing 0.8% weight/volume of the
`naloxone.
` Benzalkonium chloride was added
`to
`the
`hydrochloride solution in an amount of 0.025% weight/volume
`as a preservative. The solution may be buffered to a pH of about
`6.5 using a phosphate buffer (sodium or potassium hydrogen
`phosphate). The solution was packaged into a dispenser as
`shown in the accompanying drawing, giving a shot volume of
`50μl (microlitre) which is equivalent to a unit dose of 400μg
`(microgram) per shot.
`Id. at 3:29–4:5.
`
`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
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`formulations, BAC is used in “a concentration of 0.002–0.02% w/v.” Id.
`HPE notes that BAC is “[i]ncluded in the FDA Inactive Ingredients
`Database” for nasal preparations. Id. at 57 (citation omitted).
`3. Bahal
`Bahal describes stabilized injectable naloxone formulations.
`Ex. 1014, Abstract. In particular, Bahal teaches that “addition of a chelating
`agent, such as sodium edetate, to the commercial formulation prevents
`naloxone degradation.” Id. at 1:45–57. Bahal further discloses that
`“[p]referred concentrations of the stabilizing agents are 0.0001 to 1%.” Id.
`at 2:65–67.
`
`4. Kushwaha
`Kushwaha is a review of advances in intranasal drug delivery.
`Ex. 1013, Abstract. Kushwaha teaches the use of EDTA as a permeation
`enhancer or chelating agent in intranasal pharmaceutical formulations. Id. at
`25–26, Table 1. Kushwaha also discloses that BAC is a commonly used
`preservative in intranasal formulations. Id. at 24.
`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
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`present invention is selected from methyl, ethyl, propyl, or butyl
`para-hydroxybenzoate, sorbic acid, benzoic acid, sodium benzoate, benzyl
`alcohol, benzalkonium chloride, benzalkonium bromide, chlorobutanol,
`resorcinol, sodium ethylenediamine tetraacetate and the like.” Id.
`6. 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.
`7. 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.
`
`8. 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
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`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––
`“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 explains 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.
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`9. 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.
`10. Analysis
`Having considered the record before us, we are not persuaded that
`Petitioner has demonstrated a reasonable likelihood of prevailing in
`establishing that at least one of the challenged claims is unpatentable. Each
`independent claim of the ’838 patent requires a naloxone formulation that
`comprises BAC. For the reasons set forth below, we find that Wyse teaches
`away from the use of BAC in intranasal naloxone formulations, and,
`therefore, we determine that Petitioner has not demonstrated sufficiently for
`institution that a person of ordinary skill in the art would have had a
`reasonable expectation of successfully using BAC in an intranasal naloxone
`formulation, in view of Wyse.
`Petitioner contends that the combination of Davies and HPE teaches
`or suggests the inclusion of BAC in an intranasal formulation in an amount
`falling within the ranges specified by independent claims 1 and 41. Pet. 31–
`32, 58.11 According to Petitioner, “Davies discloses, in Example 1, a
`
`
`11 Petitioner points to the analysis of Davies 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 by independent claim 41. Pet. 58. 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.
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`sprayable aqueous liquid composition of naloxone hydrochloride for a nasal
`applicator in which ‘[b]enzalkonium chloride was added to the
`hydrochloride solution in an amount of 0.025% weight/volume as a
`preservative.’” Pet. 31–32 (quoting Ex. 1009, 3:30–4:2). Petitioner reasons
`that an ordinarily skilled artisan
`reviewing Davies would have been motivated to review the
`HPE’s monograph regarding BAC from Davies’s disclosure of
`its use in a nasal formulation, and would have been motivated to
`reduce the concentration of BAC accordingly for any number of
`reasons (including cost savings, making the formulation appear
`more acceptable to regulatory authorities, or others).
`Id. at 32 (citing Ex. 1002 ¶ 560).
`In the Petition, Petitioner acknowledges that Wyse teaches that BAC
`is not acceptable for inclusion in intranasal naloxone formulations due to
`increased observed degradation. Pet. 63 (citing Ex. 1007, 27:30–32, 27:41–
`44). Petitioner asserts, however, that an ordinarily skilled artisan would not
`have given Wyse’s teachings regarding the unacceptable use of BAC with
`naloxone “much merit.” Id. 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. (citing Ex. 1002 ¶¶ 80–82). 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 ¶ 83), and points
`out that out that one of the five BAC-including formulations tested by Wyse
`did not result in additional degradants, id. (citing Ex. 1002 ¶¶ 84–87).
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`Further, Petitioner contends that an unpublished Norwegian graduate
`thesis by Glende,12 that is not prior art, discusses the “WIPO publication
`equivalent of Wyse” and explains that “others reading the disclosure of
`Wyse have concluded that it does not teach away from using BAC.” Id. at
`64 (citing Ex. 1031, 76; Ex. 1002 ¶¶ 76–87).
`We are not persuaded by Petitioner’s contentions, as Wyse explicitly
`discourages the use of BAC in intranasal naloxone formulations. Petitioner
`has not demonstrated persuasively for institution that an ordinarily skilled
`artisan seeking to develop an intranasal naloxone formulation would not
`have taken heed of Wyse’s teaching that BAC is unacceptable for use as an
`excipient in such a formulation. Indeed, 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. 19; 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 ¶ 59)).
`Moreover, because Wyse provides the only data of record concerning
`the use of excipients in intranasal naloxone formulations, an ordinarily
`skilled artisan seeking further information regarding BAC and interested in
`
`
`12 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) (“Glende”) (Ex. 1031).
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`“making [Davies’s] formulation appear more acceptable to regulatory
`authorities, or others,” Pet. 32, as Petitioner asserts would have been the
`motivation for such an artisan to refer to HPE, id., would have looked to the
`naloxone formulation stability data disclosed by Wyse to clarify the
`Davies’s general disclosure.
`We further find that an ordinarily skilled artisan would have given
`greater weight to Wyse’s experimental data demonstrating that BAC was
`“found to increase degradation of naloxone,” Ex. 1007, 28:23–27 (emphasis
`added), and teaching that BAC was not acceptable for use in intranasal
`naloxone formulations, id. at 27:41–44, than to the general identification of
`BAC in Davies as a preservative that might be useful in a naloxone
`formulation, Ex. 1008, 6:6–10, 7:34–38. Additionally, we note that, in view
`of the unsuccessful results achieved with BAC, Wyse teaches using other
`antimicrobial preservatives, such as benzyl alcohol, which is stable in
`combination with naloxone. Ex. 1007, 27:29–37, 28:41–29:27, Tables 14–
`15.
`
`In view of Wyse’s more comprehensive teachings concerning the
`instability and non-viability of BAC-containing intranasal naloxone
`formulations, and the stability and utility of benzyl alcohol-containing
`formulations, we find that the prior art as a whole would have discouraged
`an ordinarily skilled artisan from using BAC in such a formulation. See
`Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1305–1306 (Fed. Cir. 2015)
`(affirming a finding of teaching away even though the claimed amounts of
`active and preservative fell within ranges disclosed by a prior art reference
`
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`because the prior art as a whole taught that the amount of the claimed
`preservative should be minimized to avoid safety problems).
`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. 63–64,
`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 states that BAC was “found to increase degradation of
`naloxone,” Ex. 1007, 28:23–27 (emphasis added), and explains that BAC is
`not acceptable for use in intranasal naloxone formulations, id. at 27:41–44.
`In other words, Wyse discourages an artisan from adding BAC to an
`intranasal naloxone formulation by demonstrating how doing so results in an
`unstable formulation. Indeed, Wyse expressly excluded BAC from the
`naloxone formulations chosen for further study. Ex. 1007, 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
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`IPR2019-00699
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`preliminary screening study, while the benzyl alcohol-containing version of
`that formulation was stable. Id. at 27:29–32, 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.
`Contrary to Petitioner’s assertion, the explicit teaching away in Wyse
`is not undermined by its disclosure of naloxone formulations comprising
`combinations of “multiple different excipients,” or by its disclosure that one
`out of the five of the BAC-containing naloxone formulations tested did not
`show additional degradant. See Pet. 63. As explained above, a teaching
`away need not be established by irrefutable proof or scientific certainty; it is
`sufficient that a reference discourages the skilled artisan from one path, or
`leads her down a divergent one. Galderma, 737 F.3d at 738. Here, Wyse
`does both. Specifically, Wyse presents experimental results demonstrating
`that BAC is unacceptable for use in naloxone formulations, Ex. 1007,
`27:41–44, 28:23–25, and provides data indicating that other preservatives, in
`particular, benzyl alcohol, are stable, and, thus, useful, in such formulations,
`id. at 29:18–40, Tables 15–16.
`Accordingly, even if an ordinarily skilled artisan might have
`contemplated including BAC in an intranasal naloxone formulation because
`it was a preservative known for use in nasal formulations, see Ex. 1012, 56–
`57, such an artisan would have been dissuaded from using BAC based on
`Wyse’s express teachings that BAC is unacceptable for use in intranasal
`naloxone formulations. See Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293,
`1305–1306 (Fed. Cir. 2015) (affirming a finding of teaching away even
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`though the claimed amounts of active and preservative fell within ranges
`disclosed by a prior art reference because the prior art as a whole taught that
`the amount of the claimed preservative should be minimized to avoid safety
`problems). In other words, based on the teachings of Wyse, a person of
`ordinary skill in the art would not have had a reasonable expectation of
`successfully using BAC in such an intranasal naloxone formulation.
`Petitioner’s reliance on Glende does change that result. To begin, as
`Petitioner acknowledges, Glende is not prior art. Pet. 64. Additionally,
`Petitioner’s reliance on Glende as suggesting that an ordinarily skilled
`artisan would have disregarded Wyse’s teaching away is circular. Glende
`considered the WIPO publication equivalent of Wyse (“Wyse PCT”)13 in
`light of the WIPO publication equivalent of the parent to the ’838 patent
`(“the ’373 PCT”).14,15 Ex. 1031, 52; see also Prelim. Resp. 51–52
`(explaining the relationship between the WIPO publications discussed by
`Glende and their U.S. counterparts). Glende recognizes that the Wyse PCT
`teaches that BAC “was found to further increase . . . degradation” of
`intranasal naloxone formulations. Ex. 1031, 63. Glende subsequently
`observes, however, that the ’373 PCT discloses that BAC-containing
`formulations were “storage-stable.” Id. at 64. After reviewing the thesis, we
`
`
`13 Dehart and Wyse, PCT Publication No. WO/2015/095644, published June
`25, 2015.
`14 Crystal, et al., PCT Publication No. WO/2015/136373, published Sept. 17,
`2015.
`15 The ’838 patent is a continuation-in-part of U.S. Patent No. 9,211,253 B2.
`Ex. 1001, code (63).
`
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`agree with Patent Owner that “Glende’s statement that BZK ‘should not be
`depreciated based on [Wyse] solely,’ id. at 76—the very point for which
`Petitioner tries to use it—was thus based on knowledge of the patented
`invention.” Prelim. Resp. 52.
`We are also unpersuaded, for institution, by Petitioner’s reliance on
`HPE to overcome Wyse’s teaching away. Unlike HPE, Wyse discloses the
`results of stability studies on BAC-containing intranasal naloxone
`formulations. HPE’s general teaching that BAC is an antimicrobial that may
`be used in, and is FDA-approved for, nasally administered pharmaceutical
`formulations in general, Ex. 1002, 56–57, is insufficient to defeat Wyse’s
`teaching away because HPE does not address the use of BAC in intranasal
`naloxone formulations, much less the effect of BAC on the stability of such
`formulations. See Tec Air, Inc. v. Denso Mfg. Mich. Inc., 192 F.3d 1353,
`1360 (Fed. Cir. 1999) (“There is no suggestion to combine, however, if a
`reference teaches away from its combination with another source.”). Indeed,
`HPE also teaches that the antimicrobial preservative benzyl alcohol—used in
`lieu of BAC in the formulations identified by Wyse as stable and appropriate
`for further development (Ex. 1007, Table 15)—is safe, effective, and
`commonly used in pharmaceutical formulations. Ex. 1012, 10–11.
`Accordingly, based on the record before us, we fi
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