Trials@uspto.gov
`571-272-7822
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` Paper 11
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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.
`
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owner.
`____________
`
`Case IPR2019-00685
`Patent 9,211,253 B2
`____________
`
`
`Before ZHENYU YANG, JACQUELINE T. HARLOW, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
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`
`
`571-272-7822
`
`
`
`
`
`
`
`
`
`
` Paper 11
`
` Entered: August 27, 2019
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`NALOX-1 PHARMACEUTICALS, LLC,
`Petitioner,
`
`v.
`
`OPIANT PHARMACEUTICALS, INC.,
`Patent Owner.
`____________
`
`Case IPR2019-00685
`Patent 9,211,253 B2
`____________
`
`
`Before ZHENYU YANG, JACQUELINE T. HARLOW, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`
`
`
`
`IPR2019-00685
`Patent 9,211,253 B2
`
`
`INTRODUCTION
`Nalox-1 Pharmaceuticals, LLC (“Petitioner”) filed a Petition (Paper 1
`(“Pet.”)), seeking an inter partes review of claims 1–29 of U.S. Patent
`9,211,253 B2 (“the ’253 patent,” Ex. 1001). Opiant Pharmaceuticals, Inc.
`(“Patent Owner”) filed a Preliminary Response. Paper 6 (“Prelim. Resp.”).
`Under the statute, an inter partes review may not be instituted unless
`the information presented in the petition and the preliminary response shows
`“there is a reasonable likelihood that the petitioner would prevail with
`respect to at least 1 of the claims challenged in the petition.” 35 U.S.C.
`§ 314(a). On April 24, 2018, the Supreme Court held that a decision under
`§ 314 may not institute review on fewer than all claims challenged in the
`petition. SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348, 1355–56 (2018).
`For the reasons provided below, we determine Petitioner has satisfied
`the threshold requirement set forth in 35 U.S.C. § 314(a). Thus, based on
`the information presented, and under SAS, we institute an inter partes review
`of claims 1–29 of the ’253 patent.
`Related Proceedings
`Petitioner concurrently filed IPR2019-00686 and IPR2019-00687,
`challenging the same claims of the ’253 patent with additional prior art.
`The ’253 patent is one of five patents listed in the Orange Book for
`intranasal naloxone sold under the brand name NARCAN. Pet. 1; Paper 8,
`1. Petitioner also filed petitions for inter partes review, challenging the
`other four patents listed. Pet. 6; Paper 5, 1–2.
`According to the parties, Patent Owner asserted all five Orange-Book-
`listed patents in Adapt Pharma Operations Ltd. v. Teva Pharmaceuticals
`USA, Inc., Case 2:16-cv-07721 (D.N.J.) (consolidated, “the Teva Case”),
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`IPR2019-00685
`Patent 9,211,253 B2
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`and Adapt Pharma Operations Ltd. v. Perrigo UK FINCO Limited
`Partnership, Case 2:18-cv-15287 (D.N.J.). Pet. 5; Paper 5, 2. Petitioner is
`not involved in those actions. Pet. 5–6.
`Background of Technology and the ’253 Patent
`Opioid overdose is a crisis in the United States. Ex. 1001, 6:34.
`Naloxone is an opioid receptor antagonist that was initially approved for use
`by injection for the reversal of opioid overdose. Id. at 2:9–10. Naloxone
`hydrochloride injection prevents or reverses the effects of opioids,
`“including respiratory depression, sedation and hypotension.” Ex. 1044,1
`1300.
`
`According to the ’253 patent, administering naloxone via injection
`requires trained medical personnel and imposes the risk of exposure to blood
`borne pathogens through needlestick injury. Ex. 1001, 6:10–22. The
`’253 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
`6:33–37.
`The ’253 patent acknowledges that nasal administration of naloxone
`was known and used by numerous medical services and health departments.
`Ex. 1001, 2:25–6:3, see also id. at 4:32–35 (“Overdose education and nasal
`naloxone distribution (OEND) programs are community-based interventions
`that educate people at risk for overdose and potential bystanders on how to
`
`
`1 Physicians’ Desk Reference 2003, entry for NARCAN (Naloxone
`Hydrochloride Injection, USP).
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`IPR2019-00685
`Patent 9,211,253 B2
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`prevent, recognize and respond to an overdose.”). It points out, however,
`although some studies “reported that the nasal administration of naloxone is
`as effective as the intravenous route in opiate addicts,” others “reported that
`naloxone administered intranasally displays a relative bioavailability of 4%
`only and concluded that the IN [intranasal] absorption is rapid but does not
`maintain measurable concentrations for more than an hour.” Id. at 2:45–51.
`The ’253 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 6:43–52.
`According to the ’253 patent, its invention relates to devices adapted
`for nasal delivery of “a therapeutically effective amount of an opioid
`antagonist selected from naloxone and pharmaceutically acceptable salts
`thereof, wherein the device is pre-primed, and wherein the therapeutically
`effective amount, is equivalent to about 2 mg to about 12 mg of naloxone
`hydrochloride.” Id. at 6:54–60.
`Illustrative Claim
`Among the challenged claims, claim 1 is independent, and is
`reproduced below:
`A single-use, pre-primed device adapted for nasal delivery
`1.
`of a pharmaceutical composition to a patient by one actuation of
`said device into one nostril of said patient, having a single
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`Patent 9,211,253 B2
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`
`reservoir comprising a pharmaceutical composition which is an
`aqueous solution of about 100 µL comprising:
`about 4 mg naloxone hydrochloride or a hydrate thereof;
`between about 0.2 mg and about 1.2 mg of an isotonicity agent;
`between about 0.005 mg and about 0.015 mg of a preservative;
`about 0.2 mg of a stabilizing agent;
`an amount of an acid sufficient to achieve a pH o[f] 3.5-5.5.
`Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability:
`Claims
`Basis
`References
`1–3, 16–24, 28, 29
`§ 103(a)
`Wyse2 and HPE3
`4–7, 10–15, 25–27
`§ 103(a)
`Wyse, Djupesland,4 and HPE
`8, 9
`§ 103(a) Wyse, Djupesland, HPE, and the ’291
`patent5
`In support of its patentability challenge, Petitioner relies on the
`Declarations of Maureen D. Donovan, Ph.D. (Ex. 1002) and Günther
`Hochhaus, Ph.D. (Ex. 1003).
`
`ANALYSIS
`Discretion under § 314(a)
`Under § 314(a), the Director has discretion to deny institution of an
`inter partes review. Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131,
`2140 (2016) (“[T]he agency’s decision to deny a petition is a matter
`
`
`2 Wyse et al., U.S. Patent 9,192,570 B2, issued November 24, 2015
`(Ex. 1007).
`3 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).
`4 Djupesland, Nasal Drug Delivery Device: Characteristics and
`Performance in a Clinical Perspective - A Review, 3 DRUG DELIV. &
`TRANSL. RES. 42–62 (2013) (Ex. 1010).
`5 Wermeling, U.S. Patent 8,198,291 B2, issued June 12, 2012 (Ex. 1015).
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`Patent 9,211,253 B2
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`committed to the Patent Office’s discretion.”). Citing NHK Spring Co. v.
`Intri-Plex Techs. Inc., IPR2018-00752, Paper 8 (PTAB Sept. 12, 2018)
`(precedential), Patent Owner asks us to deny the Petition in light of the
`parallel district-court actions. Prelim. Resp. 5–15. We decline to do so for
`the following reasons.
`In NHK, the Board exercised its discretion under 35 U.S.C. §§ 314(a)
`and 325(d) to deny institution of an inter partes review. NHK,
`IPR2018-00752, Paper 8, 2. For the analysis under § 314(a), the Board
`considered “the status of the district court proceeding between the parties,”
`and concluded that “the advanced state of the district court proceeding is an
`additional factor that weighs in favor of denying the Petition under
`§ 314(a).” Id. at 19–20 (emphasis added).
`Here, Patent Owner represents that “Teva, a motivated pharmaceutical
`company who has recently obtained FDA approval for its generic intranasal
`naloxone product, filed a Paragraph IV certification challenging the same
`patents and is currently litigating the Teva Case in the District of New
`Jersey.” Prelim. Resp. 11. It is undisputed that Petitioner is not involved in
`the Teva Case. Id. at 12; Pet. 5–6.
`Additionally, the petitioner in NHK asserted “the same prior art and
`arguments” in both the district-court proceeding and the IPR petition. NHK,
`IPR2018-00752, Paper 8, 20 (emphasis added). Here, Patent Owner
`contends that the Teva Case “involves the same prior art references as those
`asserted by Petitioner in this proceeding.” Prelim. Resp. 11. Patent Owner,
`however, does not proffer evidence to show, or even assert, that the
`arguments presented by Petitioner in this proceeding are the same or
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`Patent 9,211,253 B2
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`substantially similar to those at issue in the Teva Case. Thus, the facts in
`this case are distinguishable from those in NHK.
`In addition, as explained below, Petitioner has presented evidence
`supporting its challenge of claims 1 and 16–24, including that Wyse
`discloses a range of naloxone doses that fully encompasses the dosage
`recited in claim 1, thereby establishing a presumption of obviousness. That
`presumption, coupled with the fact that the only other arguments Patent
`Owner raises to oppose institution are premised on limitations not found in
`claims 1 and 16–24, further distinguishes the facts here.
`Patent Owner also argues that “under similar circumstances to this
`Petition, where a parallel district court action was pending against a generic
`pharmaceutical company unrelated to the petitioner, the Board recently
`declined to institute a petition.” Prelim. Resp. 12 (citing Neptune Generics,
`LLC v. Aventis Generics S.A., IPR2019-00136, Paper 15 (PTAB May 6,
`2019), 35–37). “In that case,” Patent Owner continues, “like this one, the
`parallel court proceedings involved the same invention and the same prior
`art, but did not involve the IPR petitioner.” Id. The facts here are also
`distinguishable from those in Neptune.
`In Neptune, the Board exercised its discretion under § 325(d) to deny
`institution, because the prior art and arguments in that petition were
`substantially similar to those presented in a prior IPR petition challenging
`the same claims of the same patent. Neptune, IPR2019-00136, Paper 15,
`30–35. It was within this context that the Board considered the district-court
`action “as an adjunct to” its analysis under § 325(d). Id. at 35. In other
`words, the Board did not deny the petition solely based on the parallel
`district-court proceeding.
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`Patent 9,211,253 B2
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`Moreover, at the time the Board denied institution in Neptune, the
`district court had completed a bench trial and concluded that the same
`challenged claims had not been shown to be invalid. Id. at 23. That
`decision was appealed, and was ready for oral argument before the Federal
`Circuit. Id. at 25. In contrast, here, although the Teva Case is “nearing its
`final stages,” trial just started and the district court has not entered any
`judgment concerning the validity of the ’253 patent claims. Prelim.
`Resp. 11; see also Paper 10 (noting a bench trial is scheduled to begin on
`August 26, 2019). This distinction is significant because the parties to the
`Teva Case may settle, and the district court may dismiss the case without
`adjudicating the merits.
`In short, under the circumstances of this case, we decline to deny the
`Petition in view of the parallel district court actions involving the ’253
`patent.
`Consistent with the guidance provided in the July 2019 Update to the
`Office Trial Practice Guide,6 we sought and received briefing from the
`parties concerning the relative strength of and differences between the three
`parallel petitions filed by Petitioner against the ’253 patent. Papers 7–9. In
`its filing ranking the three parallel petitions, Petitioner asks that we consider
`the Petition in the instant proceeding first. Paper 8, 1. For the reasons given
`herein, we conclude in the instant proceeding that Petitioner has established
`a reasonable likelihood of prevailing in demonstrating the unpatentability of
`
`
`6 Office Patent Trial Practice Guide, July 2019 Update, 84 Fed. Reg. 33,925
`(July 16, 2019) (“Trial Practice Guide Update”),
`https://www.uspto.gov/sites/default/files/documents/trial-practice-guide-
`update3.pdf, 27 n.4.
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`IPR2019-00685
`Patent 9,211,253 B2
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`at least one claim of the ’253 patent. We address in separate decisions
`Petitioner’s less preferred petitions, IPR2019-00686 and IPR2019-00687.
`Level of Ordinary Skill in the Art
`Petitioner argues that “[a]s it relates to the ’253 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. 7 (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. at 7.
`This team, Petitioner asserts, would also include a “Pharmacologist
`POSA,” who has “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.
`For purposes of this Decision, Patent Owner does not dispute, and we
`adopt, Petitioner’s proposed definition of the level of ordinary skill.
`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
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`IPR2019-00685
`Patent 9,211,253 B2
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`a civil action under 35 U.S.C. [§] 282(b), including construing the claim in
`accordance with the ordinary and customary meaning of such claim as
`understood by one of ordinary skill in the art and the prosecution history
`pertaining to the patent.” 37 C.F.R. § 42.100(b); 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,
`deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed.
`Cir. 1994).
`Petitioner proposes that we construe certain terms. Pet. 22–23. 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).
`Obviousness over Wyse and HPE
`Petitioner argues that claims 1–3, 16–24, 28, and 29 would have been
`obvious over Wyse and HPE. Pet. 28–45. Based on this record, we
`determine Petitioner has established a reasonable likelihood that it would
`prevail in this assertion, at least with regard to claims 1 and 16–24.
`Wyse issued on November 24, 2015, from an application filed on
`December 19, 2014. Ex. 1007, (22), (45). Petitioner asserts that the earliest
`priority date for challenged claims is March 16, 2015. Pet. 10–12. Thus,
`Petitioner argues that Wyse qualifies as prior art under AIA § 102(a)(2). Id.
`
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`IPR2019-00685
`Patent 9,211,253 B2
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`at 24. For the purposes of this proceeding, Patent Owner does not dispute,
`and we agree with, Petitioner’s argument on this point. Paper 9, 1.
`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. HPE lists pharmaceutical excipients, including
`benzalkonium chloride,7 benzyl alcohol, and disodium edetate (EDTA).
`Ex. 1012. HPE describes various information of each excipient, such as the
`applications in pharmaceutical formulation as well as safety. Id.
`Claims 1 and 16–24
`Regarding challenged claim 1, Petitioner argues that Wyse teaches all
`but one limitation (Pet. 28–34), and HPE teaches that missing limitation:
`“between about 0.005 mg and about 0.015 mg of a preservative” (id. at 31–
`33). Patent Owner relies on, among other evidence, the Declaration of
`Kenneth A. Williams, M.D. (Ex. 2001), and focuses its rebuttal on the
`limitation requiring “about 4 mg naloxone hydrochloride or a hydrate
`thereof,” arguing that Wyse does not teach, and an ordinary artisan would
`not have been motivated to use, intranasal naloxone in a single dose of 4 mg.
`Prelim. Resp. 17–48. Based on the current record, and for the following
`reasons, we find Petitioner’s arguments more persuasive. Patent Owner
`does not dispute that the combination of Wyse and HPE teaches or suggests
`the other limitations of claim 1. Because we find Petitioner has met its
`
`
`7 Benzalkonium chloride is abbreviated as BAC in the Petition, and BZK in
`the Preliminary Response.
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`IPR2019-00685
`Patent 9,211,253 B2
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`burden at this stage of the proceeding with respect to those limitations, we
`focus our discussion on the limitation of dosage amount.
`In an IPR, an overlap between the ranges of a claimed composition
`and those disclosed in the prior art creates a presumption of obviousness.
`E.I. DuPont de Nemours & Co. v. Synvina C.V., 904 F.3d 996, 1006 (Fed.
`Cir. 2018). In this case, Wyse teaches “compositions comprising naloxone
`for intranasal delivery.” Ex. 1007, 3:41–42. As Petitioner points out, Wyse
`states that “the disclosed compositions may comprise from about 5 mg/mL
`to about 50 mg/mL . . . of an opioid antagonist.” Pet. 30 (citing Ex. 1007,
`6:50–65). According to Wyse, “[t]he opioid antagonist may be naloxone or
`a pharmaceutically acceptable salt thereof.” Ex. 1007, 6:59–60, see also id.
`at 6:62–65 (defining “naloxone” as “refer[ring] to naloxone, naloxone HCl,
`naloxone HCl dihydrate, any pharmaceutically acceptable salt of naloxone,
`or combinations thereof”). Wyse also teaches the Aptar/Pfeiffer Unitdose
`delivery device, which delivers a volume of about 100 µL per spray, may be
`used to deliver the intranasal naloxone composition. Id. at 10:53–56. Thus,
`we agree with Petitioner that “Wyse discloses an amount of about 0.5 mg to
`5 mg naloxone hydrochloride or naloxone hydrochloride dihydrate in
`100 μL of solution.” See Pet. 30–31 (citing Ex. 1002 ¶ 126). This range
`fully encompasses the dosage of “about 4 mg naloxone hydrochloride or a
`hydrate thereof” in challenged claim 1. As a result, we are persuaded that
`there is a presumption of obviousness.
`Patent Owner asserts that “the range of ‘from about 5 mg/mL to about
`50 mg/mL’ does not refer specifically to naloxone.” Prelim. Resp. 40. We
`disagree. Wyse claims a nasal spray composition comprising “from about
`5 mg/mL to about 50 mg/mL of naloxone.” Ex. 1007, claims 1 and 15, see
`
`12
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`IPR2019-00685
`Patent 9,211,253 B2
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`also id. at 8:54–58 (disclosing an aseptic composition comprising “from
`5 mg/mL to 50 mg/mL of an opioid antagonist selected from naloxone,
`naloxone HCl, naloxone HCl dihydrate, or a combination thereof”).
`Patent Owner also contends that “the teaching of ‘from about
`5 mg/mL to about 50 mg/mL’ refers to a concentration, not to a dose and
`that disclosure is not tied to a volume of 100 μL, or for that matter, any
`particular volume.” Prelim. Resp. 40. Patent Owner points out that Wyse
`teaches modifying the nasal spray device to deliver “between 50 μL to about
`200 μL spray.” Id. at 40–41 (citing Ex. 1007, 10:39–41). According to
`Patent Owner, 50 μL of spray with a concentration of 50 mg/mL would lead
`to 2.5 mg, and not 4 mg, naloxone. Id. Arithmetically, Patent Owner is
`correct. But, the modified volume range emphasized by Patent Owner only
`broadens the dosage range from “0.5 to 5 mg” argued by Petitioner to
`“0.25 mg (50 μL of 5 mg/mL) to 10 mg (200 μL of 50 mg/mL),” which
`would still encompass the claimed “about 4 mg” dosage, and thus, create a
`presumption of obviousness.
`According to Patent Owner, “Petitioner’s error is compounded,
`moreover, by Wyse’s express teaching that the volume could be
`administered as ‘half doses’ to two nostrils.” Prelim. Resp. 41 (citing
`Ex. 1007, 11:16–17). Wyse teaches:
`In another aspect, the unit dose comprises about 200 µL of a
`disclosed composition, where the unit dose may be divided into
`two half doses. Each half dose may comprise about 100 µL of a
`disclosed composition, such that administration of the two half
`doses results in a total administration of about 200 µL of the
`composition.
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`Patent 9,211,253 B2
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`Ex. 1007, 11:15–20. When read in context, each half dose is 100 µL, the
`volume Petitioner relies on to calculate the dosage amount. Thus, the
`passage Patent Owner relies on does not support its position.
`In view of Wyse’s teaching of a nasal spray composition comprising
`from about 5 mg/mL to about 50 mg/mL of naloxone, delivered in a 100 µL
`unit dose, we determine Petitioner has established a presumption of
`obviousness of challenged claim 1. Patent Owner argues that Petitioner has
`not carried its burden to show that a concentration of 40 mg/mL is desirable
`for naloxone itself. Prelim. Resp. 40. We are not persuaded by this
`argument. As explained above, Wyse claims a nasal spray composition
`comprising “from about 5 mg/mL to about 50 mg/mL of naloxone.”
`Moreover,
`[W]here there is a range disclosed in the prior art, and the claimed
`invention falls within that range, the burden of production falls
`upon the patentee to come forward with evidence that (1) the
`prior art taught away from the claimed invention; (2) there were
`new and unexpected results relative to the prior art; or (3) there
`are other pertinent secondary considerations.
`Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 737–38 (Fed.
`Cir. 2013). A patentee may also rebut the presumption of obviousness
`created by an overlapping range by showing that “a change to a parameter
`may be patentable if the parameter was not recognized as ‘result-effective,’”
`or that range disclosed in the prior art is especially broad. DuPont, 904 F.3d
`at 1006.
`Here, Patent Owner has presented certain evidence and arguments that
`amount to an effort to rebut the presumption. For example, Patent Owner
`argues that an ordinary artisan would not have been motivated to use a single
`intranasal naloxone dose of 4 mg. Prelim. Resp. 17–48. According to
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`Patent Owner, higher doses of naloxone risked withdrawal symptoms and
`other negative effects. Id. at 26–37 (citing Ex. 2001 ¶¶ 26–36). Although
`we recognize “[t]he concerns about withdrawal . . . are not mere conjecture”
`(id. at 35), it appears “opiate withdrawal is not a medical emergency,” and is
`described as “moderate to severe flu-like illness, subjectively severe but
`objectively mild” (Ex. 1049, 60:3–6). Meanwhile, “[s]erious complications
`(seizure, pulmonary oedema, asystole, cardiac arrest) after naloxone
`administration are reportedly rare (0.3 and 1.6%).” Ex. 1035, 381.
`Patent Owner also contends that an ordinary artisan would not have
`been motivated to use an initial intranasal dose of 4 mg because the prior art
`taught that 2 mg or less was therapeutically effective. Prelim. Resp. 20–23.
`According to Patent Owner, “all of the lengthy list of clinical references
`with which the POSA would have been familiar—many of which Petitioner
`cited, see, e.g., Pet. at 14–15—involved doses of 2 mg naloxone or less.” Id.
`at 21 (citing Ex. 2001 ¶ 38). Patent Owner’s argument is not unreasonable.
`But, although it appears these references all involved the administration of
`an initial dose of 2 mg or less, it is unclear whether any “criticize[d],
`discredit[ed], or otherwise discourage[d]” increasing that dose to above
`2 mg. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). Moreover, at
`least one of the references reports that twice as many of the patients who
`received an initial dose of intranasal naloxone (IN) “were given second
`doses” as compared to patients who received intravenous naloxone (IV), and
`suggests “this finding may represent the need for a higher naloxone dose
`when given IN, rather than IV.” Ex. 1040, 8.
`Patent Owner also challenges “[t]he purported motivation to
`administer a 4 mg dose aris[ing] from a calculation that Petitioner performs
`
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`using pharmacokinetic data disclosed in Table 4 of Wyse.” Prelim.
`Resp. 45. For that calculation, Petitioner argues “prior art concentrated
`intranasal naloxone formulations had bioavailability of about 40% as
`compared to injectable naloxone.” Pet. 18 (citing Ex. 1002 ¶ 53; Ex. 1003
`¶ 59; Ex. 1007, Table 4). Relying on the FDA’s requirement that “an
`intranasal naloxone formulation to meet or exceed the exposure levels of an
`approved dose of the injection,” Petitioner argues that an ordinary artisan
`would have, “[b]ased on simple math,” arrived at an intranasal formulation
`with 4–6 mg naloxone to match the exposure levels of 2 mg, the highest
`FDA-approved initial injection dosage. Id. at 18–19 (citing Ex. 1002 ¶ 56;
`Ex. 1003 ¶ 61; Ex. 1032, 8, 14–15; Ex. 1049, 166, 169–70, 172).
`Patent Owner does not dispute that, in 2012, the FDA required “an
`intranasal naloxone formulation for community use match or exceed the
`exposure of an FDA-approved parenteral product.” Prelim. Resp. 34. Patent
`Owner, however, again contends that before the ’253 patent, an ordinary
`artisan would not have chosen the highest FDA-approved intravenous
`naloxone dose because of concerns about withdrawal. Id. at 43. In addition,
`Patent Owner appears to question Petitioner’s approach in calculating the
`bioavailability of intranasal naloxone. See id. at 45 (“Petitioner’s experts
`assume dose-linearity and then appear to have used the ‘AUC’ (area-under-
`the-curve) data for these three formulations to calculate intranasal
`bioavailability of about 36% for 1 mg IN and about 42% for 2 mg IN.”)
`(citing Ex. 1003 ¶ 59).
`We share Patent Owner’s doubt over Petitioner’s assertion that the
`relative bioavailability of intranasal naloxone is 40%. Indeed, several
`references Petitioner relies on show “i.n. route to have similar
`
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`pharmacokinetics to the i.v. route with 100% bioavailability.” Ex. 1035,
`382; see also Ex. 1021, 267 (“After intranasal mucosal administration,
`naloxone exhibits opiate antagonist effects almost as rapidly as the i.v. route
`with a bioavailability and clinical response approaching 100% in animal and
`human studies.”). These numbers conflict with Petitioner’s calculated
`bioavailability of 40%.
`Moreover, as Patent Owner points out, Petitioner admits that “as
`expected from the prior art, a more concentrated intranasal naloxone solution
`has been shown to have a higher bioavailability.” Prelim. Resp. 25 (quoting
`Ex. 1003 ¶ 59). Based on that logic, even if Petitioner is correct that the
`relative bioavailability of intranasal naloxone at 10 mg/ml is 40%, a more
`concentrated naloxone solution would also have higher bioavailability. This
`casts further doubt over the premise for Petitioner’s “simple math” in
`calculating intranasal naloxone of 4–6 mg. Nevertheless, these factual
`issues, together with evidence of secondary considerations, are better suited
`for evaluation after the parties fully develop the record during trial.
`Petitioner also argues that claims 16–24 would have been obvious
`over Wyse and HPE. Pet. 39–43. Patent Owner does not address these
`claims separately. After considering the Petition, the Preliminary Response,
`and accompanying evidence, we are persuaded that, for purposes of this
`Decision, Petitioner has made a sufficient showing regarding the
`unpatentability of those claims.8
`
`
`8 Patent Owner asserts that “[c]laims 2–15 and 17–29—in other words all
`except two of the claims in the ’253 patent—require” benzalkonium chloride
`as a preservative and EDTA as a stabilizing agent. Prelim. Resp. 49. Patent
`Owner is mistaken. Claims 17–24 do not require so.
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`Having determined that Petitioner has demonstrated a reasonable
`likelihood of showing the unpatentability of claims 1 and 16–24, we institute
`an inter partes review as to all claims challenged in the Petition. See SAS,
`138 S. Ct. at 1355–56; see also PGS Geophysical AS v. Iancu, 891 F.3d
`1354, 1360 (Fed. Cir. 2018) (interpreting the statute to require “a simple yes-
`or-no institution choice respecting a petition, embracing all challenges
`included in the petition”). We nevertheless offer the following observations
`on Petitioner’s challenges of the other claims.
`Claims 2, 3, 28, and 29
`Claim 2 depends from claim 1, and further recites “the isotonicity
`agent is NaCl; the preservative is benzalkonium chloride; the stabilizing
`agent is disodium edetate; and the acid is hydrochloric acid.” Claims 3, 28,
`and 29 depend, directly or indirectly, from claim 2. Petitioner argues that
`Wyse teaches using NaCl, EDTA, and hydrochloric acid. Pet. 35–36.
`Relying on HPE, Petitioner also asserts that an ordinary artisan “would have
`been particularly motivated to use benzalkonium chloride (‘BAC’) as a
`preservative in such a nasal spray, as it is a commonly used antimicrobial
`preservative in FDA-approved nasal formulations that has a broad range of
`antimicrobial activities at low concentrations, such as 0.002-0.02 % w/v.”
`Id. at 33 (citing Ex. 1012, 56; Ex. 1002 ¶¶ 64, 137), 35 (the same). Patent
`Owner counters that the prior art teaches away from using the combination
`of benzalkonium chloride and EDTA. Prelim. 49–59. We find Patent
`Owner’s arguments more persuasive.
`“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
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`the path that was taken by the applicant.” In re Gurley, 27 F.3d 551, 553
`(Fed. Cir. 1994). In its preliminary formulation screening studies, Wyse
`evaluated 13 excipient combinations. Ex. 1007, 26:26–27. According to
`Wyse, the results “surprisingly showed that the use of benzalkonium
`chloride, a common nasal product preservative, resulted in an additional
`degradant in formulations 7, 9, 14, and 14A.” Id. at 27:29–32. Wyse
`concluded that “benzyl alcohol and paraben preservatives were acceptable,
`but benzalkonium chloride was not, due to increased observed degradation.”
`Id. at 27:42–44. This explicit statement ––despite Petitioner’s contention
`that Wyse did not “conclusively determine[] that any individual excipient
`was responsible for any instability issues in the disclosed formulation”
`(Pet. 55)––appears to directly “criticize, discredit, or otherwise discourage
`the solution claimed.” See In re Fulton, 391 F.3d at
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