Trials@uspto.gov
`571-272-7822
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` Paper No. 10
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` Entered: September 11, 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 IPR2019-00694
`Patent 9,629,965 B2
`____________
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`
`VALEK, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
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`
`
`571-272-7822
`
`
`
`
`
`
`
`
`
`
` Paper No. 10
`
` Entered: September 11, 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 IPR2019-00694
`Patent 9,629,965 B2
`____________
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`
`VALEK, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`
`
`
`
`
`
`
`
`
`
`IPR2019-00694
`Patent No. 9,629,965 B2
`
`
`INTRODUCTION
`I.
`Nalox-1 Pharmaceuticals, LLC (“Petitioner”), filed a Petition (Paper 2
`(“Pet.”)), seeking an inter partes review of claims 1–30 of U.S. Patent
`No. 9,629,965 B2 (“the ’965 patent,” Ex. 1001). 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 1–30 of the ’965 patent.
`BACKGROUND
`II.
`A.
`Related Proceedings
`The ’965 patent is one of five patents listed in the Orange Book for
`intranasal naloxone sold under the brand name NARCAN. Pet. 1; Prelim.
`Resp. 1. Petitioner concurrently filed IPR2019-00695 and IPR2019-00696,
`challenging the same claims of the ’965 patent with additional prior art.
`Petitioner also filed three petitions for inter partes review challenging
`the claims of each of four other patents listed in the Orange Book for
`NARCAN. Pet. 6. Inter partes review of claims 1–29 of U.S. Patent
`
`2
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`
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`IPR2019-00694
`Patent No. 9,629,965 B2
`
`No. 9,211,253 B2 was instituted in IPR2019-00685. To date, in five other
`proceedings, the Board has denied institution of inter partes review on the
`petitions challenging these other patents. See IPR2019-00686, IPR2019-
`00687, and IPRs 2019–00691, 692, and 693.
`In addition, the parties inform us that the ’965 patent is asserted in
`Adapt Pharma Operations Ltd. v. Teva Pharmaceuticals USA, No. 2:16-cv-
`07721 (D.N.J.) (the “Teva Case”) and Adapt Pharma Operations Ltd. v.
`Perrigo UK FINCO Limited Partnership, No. 2:18-cv-15287 (D.N.J.) (the
`“Perrigo Case”). Pet. 6; Prelim. Resp. 8. Petitioner, however, is not a party
`to these litigations.
`Background of Technology and the ’965 Patent
`B.
`Naloxone is an opioid receptor antagonist that was initially approved
`for use by injection for the reversal of opioid overdose. Ex. 1001, 2:15–17.
`Naloxone hydrochloride injection prevents or reverses the effects of opioids,
`“including respiratory depression, sedation and hypotension.” Ex. 1044,1
`1300. The ’965 patent explains that “[s]ince the onset of action of naloxone
`used in opioid overdose cases should be as fast as possible, naloxone is thus
`far mainly administered intravenously or intramuscularly by emergency
`health care personnel.” Ex. 1001, 6:17–20.
`According to the ’965 patent, administering naloxone via injection
`requires trained medical personnel and imposes the risk of exposure to blood
`borne pathogens through needle-stick injury. Id. at 6:26–38. The
`’965 patent discloses that “it ha[d] been suggested that in view of the
`
`
`1 Physicians’ Desk Reference 2003, entry for NARCAN (Naloxone
`Hydrochloride Injection, USP).
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`3
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`growing opioid overdose crisis in the US, naloxone should be made
`available over-the-counter (OTC), which would require a device, such as a
`nasal spray device, that untrained consumers are able to use safely.” Id. at
`6:45–49.
`The ’965 patent acknowledges that nasal administration of naloxone
`was known and, in fact, had been used by numerous medical services and
`health departments. See generally id. at 2:32–6:54. 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 2:50–58.
`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 6:55–64.
`The ’965 patent purports to meet this need by providing devices
`adapted for nasal delivery of “a therapeutically effective amount of an opioid
`antagonist selected from naloxone and pharmaceutically acceptable salts
`thereof, wherein the device is pre-primed, and wherein the therapeutically
`effective amount, is equivalent to about 2 mg to about 12 mg of naloxone
`hydrochloride.” Id. at 6:55–7:5.
`
`4
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`
`Illustrative Claims
`C.
`Claims 1 and 20 are independent and reproduced below.
`A pharmaceutical formulation for intranasal
`1.
`administration comprising, in an aqueous solution of not more
`than about 140 μL:
`about 4 mg naloxone hydrochloride;
`about 0.74 mg NaCl;
`about 0.01 mg benzalkonium chloride;
`about 0.2 mg disodium edetate; and
`an amount of hydrochloric acid sufficient to achieve a pH
`of 3.5–5.5.
`
`20. A single-use, pre-primed device adapted for nasal
`delivery of a pharmaceutical composition to a patient by one
`actuation of said device into one nostril of said patient, having a
`single reservoir comprising a pharmaceutical composition
`which comprises per 100 μL of aqueous solution:
`
`about 4 mg naloxone hydrochloride or a hydrate thereof;
`
`between about 0.2 mg and about 1.2 mg of an isotonicity
`agent;
`
`between about 0.005 mg and about 0.015 mg of a
`preservative;
`
`between about 0.1 mg and about 0.5 mg of a stabilizing
`agent; and
`
`an amount of acid sufficient to achieve a pH of 3.5–5.5.
`Among other differences, claim 1 differs from claim 20 in that it requires the
`presence of both benzalkonium chloride (BAC) and disodium edetate
`(EDTA) in the claimed pharmaceutical formulation, whereas claim 20
`recites a “preservative” and “stabilizing agent” generally. Dependent claims
`21 and 22 further specify that the preservative in claim 20 is BAC and that
`the stabilizing agent is EDTA. Dependent claims 23–30, however, depend
`directly from claim 20 and do not recite such limitations. Therefore, claims
`
`5
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`20 and 23–30 do not require the combination of BAC and EDTA as
`excipients, whereas the rest of the claims of the ’965 patent do.
`
`Asserted Grounds of Unpatentability
`D.
`Petitioner asserts the following grounds of unpatentability:
`Claims Challenged
`Basis
`References
`1–22, 25, 26, 29,
`§ 103
`Wyse2 and HPE3
`and 30
`Wyse, Djupesland,4 and HPE
`§ 103
`23, 24
`Wyse, HPE, and the ’291 patent5
`§ 103
`27, 28
`In support of these grounds, Petitioner relies on the Declarations of
`Maureen D. Donovan, Ph.D. (Ex. 1002) and Günther Hochhaus, Ph.D.
`(Ex. 1003).
`
`III. ANALYSIS
`A. 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
`committed to the Patent Office’s discretion.”). Citing NHK Spring Co. v.
`Intri-Plex Techs. Inc., IPR2018-00752, Paper 8 (PTAB Sept. 12, 2018)
`
`
`2 Wyse et al., U.S. Patent No. 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 No. 8,198,291 B2, issued June 12, 2012
`(Ex. 1015).
`
`6
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`(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. at 10–11. Trial in the Teva Case was set to begin on
`August 26, 2019. Id. Thus, like the district court proceeding in NHK, the
`Teva Case is at an “advanced state.”6 NHK, IPR2018-00752, Paper 8, 20.
`But, unlike NHK, Patent Owner in this case has not demonstrated the
`district court proceeding is likely to address the same issues raised in the
`Petition. In NHK, the same petitioner 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, however, Patent
`Owner does not proffer evidence to show that Petitioner’s arguments are the
`
`
`6 In contrast, there is no indication, and Patent Owner does not contend, that
`the Perrigo Case will progress to trial prior to the deadline for a final written
`decision in this proceeding.
`
`7
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`same, or even substantially similar, to those raised by Teva in the Teva Case.
`Patent Owner represents only that the Teva Case “involves the same prior art
`references” and that the district court will “consider substantially the same
`prior art as applied to the same invention as are at issue here.” Prelim. Resp.
`11. What is not clear is the extent to which, if at all, we are being asked to
`analyze the same issues as is the district court in the Teva Case. For
`example, there is no indication which claims of the ’965 patent are asserted
`against Teva, much less that Teva is, in fact, challenging as obvious all of
`the claims of the ’965 patent as does Petitioner here. Nor has Patent Owner
`shown that Teva presents Petitioner’s references in the same, or even
`similar, combinations to those in the Petition. As such, the facts in this case
`are distinguishable from those in NHK.
`In addition, the merits of Petitioner’s challenge to claims 20 and 23–
`30 further distinguish NHK. As explained below, Wyse discloses a range of
`naloxone doses that fully encompasses the dosage recited in claim 1, thereby
`establishing a presumption that supports the obviousness challenge here.
`E.I. DuPont de Nemours & Co. v. Synvina C.V., 904 F.3d 996, 1006 (Fed.
`Cir. 2018). Moreover, unlike NHK where a weighing of the § 325(d) factors
`premised on the arguments and findings during prosecution was “alone . . .
`sufficient to support an exercise of our discretion to deny institution,” the
`Examiner’s stated reason for allowing the ’965 patent claims over Wyse
`does not apply to claims 20 and 23–30. NHK, IPR2018-00752, Paper 8, 18.
`The Examiner found that Wyse “teach[es] away from the instantly claimed
`composition” because it “expressly exclude[s] the use of benzalkonium
`chloride” by stating that BAC “results in increased degradation of the
`naloxone active” and instead teaches the use of a different preservative,
`
`8
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`benzyl alcohol. Ex. 1063, 9. But claims 20 and 23–30 are not limited to
`BAC. And Patent Owner does not, at least in its Preliminary Response,
`dispute that benzyl alcohol is a “preservative” within the meaning of those
`claims. Thus, Examiner’s teaching away determination, as well as the
`teaching away arguments that Patent Owner presently advances (see Prelim.
`Resp. 48–58), are inapplicable to a number of the challenged claims.
`Patent Owner further 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 Pharma S.A., IPR2019-00136, Paper 15 (PTAB May 6,
`2019), 35–37). The facts of this case are also distinguishable from those in
`Neptune.
`In Neptune, the Board exercised discretion to deny institution under
`§ 325(d) because the prior art and arguments in that petition were
`substantially similar to those presented in a prior IPR petition challenging
`the same patent claims that were denied institution. Neptune,
`IPR2019-00136, Paper 15, 30–35. It was in that context the Board
`considered the district-court action “as an adjunct to” its analysis under
`§ 325(d). Id. at 35. In other words, the Board there did not exercise
`discretion to deny the petition based solely on the advanced state of a
`parallel district court proceeding.
`Moreover, at the time the Board denied institution in Neptune, the
`district court had completed a bench trial and entered a judgment finding
`that the challenged claims had not been shown to be invalid. Id. at 23. That
`decision was appealed and was pending oral argument before the Federal
`
`9
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`Circuit. Id. at 25. In contrast, here, the district court has not yet entered
`judgment concerning the validity of the ’965 patent claims. This distinction
`is significant because, even assuming the Teva Case presents a challenge to
`the same patent claims on the same prior art grounds as the Petition here, the
`district court may not enter a judgment on those issues if, e.g., the parties to
`the Teva Case settle and stipulate to a dismissal.
`In sum, given the particular circumstances of this case, we decline to
`deny the Petition in view of the parallel district court actions involving the
`’965 patent.
`
`Petitioner’s Parallel Petitions
`B.
`Consistent with the guidance provided in the July 2019 Update to the
`Office Trial Practice Guide,7 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 ’965 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
`at least one claim of the ’965 patent. We will address Petitioner’s less-
`preferred petitions, IPR2019-00695 and IPR2019-00696, in separate
`decisions.
`
`
`7 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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`10
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`
`Level of Ordinary Skill in the Art
`C.
`Petitioner argues that “[a]s it relates to the ’965 patent, a person of
`ordinary skill in the art (‘POSA’) would comprise a team of individuals
`having experience in drug development, and specifically the development of
`solution-based dosage forms such as intranasal dosage forms.” Pet. 9 (citing
`Ex. 1002 ¶ 26; Ex. 1003 ¶ 22).
`According to Petitioner, this team would include a “Formulator
`POSA” who has “experience in preformulation testing for and selection of
`excipients for a solution-based dosage form (including intranasal dosage
`forms) to achieve a target pharmaceutical profile.” Id. at 9.
`Petitioner asserts that this team would also include a “Pharmacologist
`POSA,” with “clinical, clinical pharmacology, and regulatory expertise
`relevant to the design and performance of a drug development strategy for
`solution-based dosage forms such as intranasal dosage forms, including
`testing and/or evaluating the fate of the drug in the body (i.e.,
`pharmacokinetics, including the physiological and biopharmaceutical
`aspects of nasal drug absorption), testing and/or evaluating issues of safety
`and efficacy, and evaluating the regulatory requirements of a new dosage
`form.” Id. at 10.
`Patent Owner offers no evidence to the contrary and does not dispute
`Petitioner’s proposed definition of the level of ordinary skill, at least in its
`Preliminary Response. Accordingly, for purposes of this Decision, we adopt
`Petitioner’s proposed definition.
`D. 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
`
`11
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`IPR2019-00694
`Patent No. 9,629,965 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 in the specification 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. 24–27. On
`this record and for purposes of this Decision, we see no need to expressly
`construe any term. In reaching this conclusion, we observe that the parties
`do not dispute the meaning of the challenged claims, nor does our decision
`instituting trial turn on the adoption of any particular claim construction.
`See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Matal, 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)).
`E.
`1. Wyse
`Wyse issued on November 24, 2015, from an application filed on
`December 19, 2014. Ex. 1007, (22), (45). Petitioner asserts that the earliest
`
`References Relied Upon
`
`12
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`priority date for challenged claims is March 16, 2015. Pet. 13–15. Thus,
`Petitioner argues that Wyse qualifies as prior art under AIA § 102(a)(2). Id.
`at 28. For the purposes of this proceeding, Patent Owner does not dispute,
`and we agree with, Petitioner’s argument on this point. Paper 9, 1.
`Wyse teaches “compositions containing an opioid antagonist such as
`naloxone and one or more pharmaceutically acceptable excipients. The
`compositions may be used for intranasal delivery of Naloxone for the
`treatment of, for example, opioid overdose in an individual in need thereof.”
`Ex. 1007, Abstract. Wyse teaches that these compositions may contain both
`EDTA and an “antimicrobial agent,” such as benzyl alcohol or “[o]ther
`suitable antimicrobial agents,” as excipients. Id. at 7:17–28.
`Wyse describes results from a pharmacokinetic study comparing
`“naloxone administered by using conventional FDA-approved products,
`routes of delivery and doses . . . to a naloxone nasal spray drug product.” Id.
`at 15:19–22. Various PK parameters from this study are reported in Table 4.
`Id. at 16 (Table 4).
`In addition, 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. Wyse further states 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
`
`13
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`IPR2019-00694
`Patent No. 9,629,965 B2
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`in the nasal cavity (HPMC), prevent oxidation (EDTA), and create a
`hyperosmotic solution that facilitates diffusion across the cell membrane.”
`Id. at 27:32–37.
`HPE
`2.
`HPE lists pharmaceutical excipients, including BAC, benzyl alcohol,
`and EDTA. Ex. 1012. HPE describes various information regarding these
`excipients, such as the applications in pharmaceutical formulation as well as
`safety. Id.
`Regarding BAC, HPE teaches that “[b]enzalkonium chloride is a
`quaternary ammonium compound used in pharmaceutical formulations as an
`antimicrobial preservative in applications similar to other cationic
`surfactants, such as cetrimide.” Ex. 1012, 56. According to HPE, in nasal
`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).
`Djupesland
`3.
`Djupesland describes the Pfeiffer/Aptar single-dose intranasal
`delivery device used to administer certain migraine medications. Ex. 1010,
`49. Djupesland states 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.
`The ’291 patent
`4.
`The ’291 patent discloses data for a butorphanol formulation
`administered in a Pfeiffer Unitdose Second Generation spray device.
`Ex. 1015, col. 7 (Ex. 1). According to the ’291 patent, when “charged with
`sufficient liquid to deliver a 0.1 mL dose” comprising 0.2 grams of the
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`Patent No. 9,629,965 B2
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`active, the Pfeiffer Unitdose Second Generation device had a 95%
`confidence interval of (0.203, 0.209). Id. at 8:16–9:19.
`Analysis of Asserted Grounds
`F.
`Claims 20 and 23–30
`1.
`We first address Petitioner’s grounds as they apply to those claims
`that do not require the presence of BAC and EDTA. Claims 20 and 23–30
`recite a “single-use, pre-primed device adapted for nasal delivery of a
`pharmaceutical composition” comprising, inter alia, “4 mg naloxone
`hydrochloride or a hydrate thereof,” a “preservative,” and a “stabilizing
`agent” in a specified range. Regarding claims 20, 25, 26, 29, and 30,
`Petitioner argues that Wyse teaches all of the claim limitations (Pet. 42–47
`(incorporating discussion for claims 1 and 2 at Pet. 31–36)) including an
`intranasal naloxone formulation containing both a preservative and EDTA in
`single-dose, pre-primed device (i.e., the Aptar device), but acknowledges
`that the amount of preservative taught in Wyse exceeds the claimed range of
`“between about 0.005 to 0.015 mg” (id. at 33–35). Petitioner urges that HPE
`teaches the use of a preservative in lower amounts that fall within the
`claimed range (id. at 33–35) and thus these claims would have been obvious
`over the combination of Wyse and HPE.8 For claims 23 and 24, Petitioner
`additionally relies on Djupesland for its teaching that the Aptar device is
`actuatable with one hand and that a volume of 125 μL is filled in the Aptar
`device to deliver a 100 μL spray volume. Id. at 47–48. Finally, for claims
`
`
`8 Petitioner also contends that HPE teaches that BAC is a suitable
`antimicrobial agent. Pet. 33. We address that contention, as well as Patent
`Owner’s responsive arguments, below in our analysis of the claims that
`require BAC.
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`27 and 28, Petitioner contends that the confidence interval limitations added
`by those claims are taught by the ’291 patent and thus those claims would
`have been obvious over the combination of Wyse, HPE and the ’291 patent.
`Id. at 49–50.
`Patent Owner focuses its rebuttal on the limitation requiring “about
`4 mg naloxone hydrochloride or a hydrate thereof.” Patent Owner argues
`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 are sufficiently supported for institution. Patent
`Owner does not dispute that the combination of Wyse and HPE teaches or
`suggests the other limitations of claims 20 and 23–30. Because we find
`Petitioner has met its burden at this stage of the proceeding with respect to
`those limitations, we focus our discussion on the dosage limitation.
`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, 904 F.3d at 1006. In this case, Wyse teaches “compositions
`comprising naloxone for intranasal delivery.” Ex. 1007, 3:41–42. As
`Petitioner points out, Wyse “discloses desirable solutions for intranasal
`administration containing between 5 mg/mL and 50 mg/mL of an opioid
`antagonist.” Pet. 31–32 (citing Ex. 1007, 6:50–65, 9:17–21). 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
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`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 appropriate 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. 39. 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
`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” per 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
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`would still encompass the claimed “about 4 mg” dosage, and thus, even
`under Patent Owner’s interpretation, Wyse’s dosage range still presents 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). Specifically, 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.
`Ex. 1007, 11:15–20. But when read in context, each half dose is 100 µL, the
`volume Petitioner relies on to calculate the dosage amount. Accordingly, the
`passage Patent Owner relies on does not support its position.
`Thus, 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 100 µL unit dose, we determine Petitioner has established a presumption
`of obviousness for claim 20. 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,
`where 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
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`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)
`(citation omitted). 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 (citation omitted).
`Here, Patent Owner presents evidence and arguments in an attempt 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. 16–48. According to 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), the
`evidence of record supports that “opiate withdrawal is not a medical
`emergency,” describing it as “moderate to severe flu-like illness,
`subjectively severe but objectively mild” (Ex. 1049, 60:3–6). Moreover,
`“[s]erious complications (seizure, pulmonary oedema, asystole, cardia
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