Opiant Pharmaceuticals, Inc.

Patent Trials and Appeals Board

Aug 21, 2020

IPR2019-00688 (P.T.A.B. Aug. 21, 2020)

Trials@uspto.gov Paper 57
571-272-7822 Date: August 21, 2020

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

NALOX-1 PHARMACEUTICALS, LLC,
Petitioner,

v.

ADAPT PHARMA OPERATIONS LIMITED, and
OPIANT PHARMACEUTICALS, INC.,
Patent Owner.
____________

IPR2019-00688
Patent 9,468,747 B2
____________

Before ERICA A. FRANKLIN, ZHENYU YANG, and
MICHAEL A. VALEK, Administrative Patent Judges.

YANG, Administrative Patent Judge.

JUDGMENT
Final Written Decision
Determining No Challenged Claims Unpatentable
35 U.S.C. § 318(a)

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INTRODUCTION
Nalox-1 Pharmaceuticals, LLC (“Petitioner”) filed a Petition (Paper 1
(“Pet.”)), seeking an inter partes review of claims 1–45 of U.S. Patent
No. 9,468,747 B2 (“the ’747 patent,” Ex. 1001). We instituted trial to review
the challenged claims. Paper 11 (“Dec.”). Thereafter, Adapt Pharma
Operations Limited and Opiant Pharmaceuticals, Inc. (collectively, “Patent
Owner”) filed a Response to the Petition (Paper 34, “PO Resp.”), Petitioner
filed a Reply (Paper 39), and Patent Owner filed a Sur-Reply (Paper 49).
Petitioner also filed a Motion for Observations (Paper 51). An oral hearing
for this proceeding was held on May 19, 2020, and a transcript of that
hearing is of record. See Paper 53 (“Tr.”).
The Board has jurisdiction under 35 U.S.C. § 6 and issues this final
written decision pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. For
the reasons provided below, and based on the evidence and argument
presented in this proceeding, we conclude Petitioner has not established by a
preponderance of the evidence that claims 1–45 of the ’747 patent are
unpatentable.
Related Proceedings
Petitioner filed IPR2019-00689 and IPR2019-00690, challenging the
same claims of the ’747 patent with additional prior art. We denied those
petitions. IPR2019-00689, Paper 11; IPR2019-00690, Paper 11.
The ’747 patent is one of the patents listed in the Orange Book for
intranasal naloxone sold under the brand name NARCAN. Pet. 1; Paper 9, 1.
Petitioner also filed petitions for inter partes review, challenging other
patents listed in the Orange Book. Pet. 7; Paper 5, 1–2. We denied some of
those petitions but instituted reviews in IPR2019-00685 (challenging U.S.
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Patent No. 9,211,253) and IPR2019-00694 (challenging U.S. Patent
9,629,965). IPR2019-00685, Paper 11; IPR2019-00694, Paper 10.
Concurrently with this Decision, we issue a final written decision in each of
those cases.
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”),
and Adapt Pharma Operations Ltd. v. Perrigo UK FINCO Limited
Partnership, Case 2:18-cv-15287 (D.N.J.) (“the Perrigo Case”). Pet. 7;
Paper 5, 2. Petitioner is not involved in those actions. Pet. 7.
According to Patent Owner, on March 2, 2020, the Perrigo Case was
dismissed with prejudice pursuant to a consent judgment. Paper 56, 3. On
June 26, 2020, the district court entered final judgment in the Teva Case,
holding claims 7 and 9 of the ’747 patent invalid. Id. at 3–4. Patent Owner
states that its appeal from that judgment was docketed on August 3, 2020.
Id. at 4.
Background of Technology and the ’747 Patent
Opioid overdose is a crisis in the United States. Ex. 1001, 6:43.
Naloxone is an opioid receptor antagonist that was initially approved for use
by injection for the reversal of opioid overdose. Id. at 2:13–14. Naloxone
hydrochloride injection prevents or reverses the effects of opioids,
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“including respiratory depression, sedation and hypotension.” Ex. 1044,1
1300.2
According to the ’747 patent, administering naloxone via injection
requires trained medical personnel and imposes the risk of exposure to blood
borne pathogens through needlestick injury. Ex. 1001, 6:20–32. The
’747 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
6:42–46.
The ’747 patent acknowledges that nasal administration of naloxone
was known and used by numerous medical services and health departments.
Id. at 2:29–6:13, see also id. at 4:39–42 (“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
prevent, recognize and respond to an overdose.”). It points out, however,
that some studies “reported that the nasal administration of naloxone is as
effective as the intravenous route in opiate addicts,” yet 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 2:47–55.
The ’747 patent states:

1 Physicians’ Desk Reference 2003, entry for NARCAN (Naloxone
Hydrochloride Injection, USP).
2 Where applicable, we cite to the original page numbers of the exhibits, and
not the pagination added by the parties.
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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 6:52–61.
According to the ’747 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 6:63–7:2.
Illustrative Claims
Among the challenged claims, claims 1 and 30 are independent, and
are reproduced below:
1. A method of treatment of opioid overdose or a symptom
thereof, comprising nasally administering to a patient in need
thereof a dose of naloxone hydrochloride using 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 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 compound
which is at least one of a preservative, a cationic surfactant, and
a permeation enhancer;
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between about 0.1 mg and about 0.5 mg of a stabilizing agent;
and
an amount of an acid sufficient to achieve a pH of 3.5-5.5.
30. A pharmaceutical formulation for intranasal
administration comprising, in an aqueous solution of not more
than about 140 µL:
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 compound
which is at least one of a preservative, a cationic surfactant, and
a permeation enhancer;
between about 0.1 mg and about 0.5 mg of a stabilizing agent;
an amount of an acid sufficient to achieve a pH of 3.5-5.5.
Instituted Grounds of Unpatentability
We instituted trial to determine whether claims 1–45 of the
’747 patent are unpatentable based on the following grounds:
Claims Challenged 35 U.S.C. § References
1–3, 16–24, 28–45 103 Wyse,3 HPE4
4–7, 10–15, 25–27 103 Wyse, Djupesland,5 HPE
8, 9 103 Wyse, Djupesland, HPE,
the ’291 patent6
Dec. 6.

3 Wyse et al., U.S. Patent No. 9,192,570 B2, issued November 24, 2015
(Ex. 1007).
4 Handbook of Pharmaceutical Excipients, 56–60, 64–66, 78–81, 220–22,
242–44, 270–72, 441–45, 517–22, 596–98 (Rowe et al. eds., 6th ed. 2009)
(Ex. 1012).
5 Djupesland, Nasal Drug Delivery Device: Characteristics and Performance
in a Clinical Perspective - A Review, 3 DRUG DELIV. & TRANSL. RES. 42–62
(2013) (Ex. 1010).
6 Wermeling, U.S. Patent No. 8,198,291 B2, issued June 12, 2012
(Ex. 1015).
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Petitioner relies on the Declarations of Maureen D. Donovan, Ph.D.
(Exs. 1002, 1201) and Günther Hochhaus, Ph.D. (Exs. 1003, 1202). Patent
Owner relies on the Declarations of Stuart A. Jones, Ph.D. (Exs. 2201,
2300), Kenneth Williams, M.D. (Ex. 2202), Thomas Begres (Ex. 2203), Eric
Karas (Ex. 2204), Robert L. Vigil, Ph.D. (Ex. 2205), and Declan Brides
(Ex. 2207). Exhibits 2201, 2205, and 2207 were filed under seal, and Patent
Owner has provided Exhibits 2208 and 2206 as the redacted version of
Exhibits 2201 and 2205, respectively.
ANALYSIS
Principles of Law
To prevail in this inter partes review, Petitioner must prove
unpatentability by a preponderance of the evidence. 35 U.S.C. § 316(e);
37 C.F.R. § 42.1(d).
A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
differences between the claimed subject matter and the prior art are such that
the subject matter, as a whole, would have been obvious at the time the
invention was made to a person having ordinary skill in the art to which said
subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
(2007). The question of obviousness is resolved on the basis of underlying
factual determinations, including (1) the scope and content of the prior art;
(2) any differences between the claimed subject matter and the prior art;
(3) the level of skill in the art; and (4) objective evidence of nonobviousness.
Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966); KSR, 550 U.S. at 406.
A party that asserts obviousness of a claim must show that “a skilled
artisan would have been motivated to combine the teachings of the prior art
references to achieve the claimed invention, and that the skilled artisan
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would have had a reasonable expectation of success in doing so.” In re
Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed. Cir. 2016). “There
is no suggestion to combine, however, if a reference teaches away from its
combination with another source.” Tec Air, Inc. v. Denso Mfg. Mich. Inc.,
192 F.3d 1353, 1360 (Fed. Cir. 1999).
We analyze the instituted grounds of unpatentability in accordance
with these principles.
Level of Ordinary Skill in the Art
Petitioner argues that “[a]s it relates to the ’747 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. 8 (citing
Ex. 1002 ¶ 26; Ex. 1003 ¶ 22).
According to Petitioner, this team would include a “Formulator
POSA” who has “experience in preformulation testing for and selection of
excipients for a solution-based dosage form (including intranasal dosage
forms) to achieve a target pharmaceutical profile.” Id.
Petitioner asserts that:
The POSA team would also include drug development
professionals [“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 9–10.
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In our Institution Decision, we adopted Petitioner’s definition of the
level of ordinary skill, which was undisputed at the time, because it was
consistent with the level of skill reflected in the prior art of record and the
disclosure of the ’747 patent. Dec. 10; see Okajima v. Bourdeau, 261 F.3d
1350, 1355 (Fed. Cir. 2001).
Patent Owner does not contest the level of skill as adopted in our
Institution Decision, and we continue to apply that same skill level in our
analysis for this Final Written Decision.
Claim Construction
In an inter partes review, a claim term “shall be construed using the
same claim construction standard that would be used to construe the claim in
a civil action under 35 U.S.C. [§] 282(b), including construing the claim in
accordance with the ordinary and customary meaning of such claim as
understood by one of ordinary skill in the art and the prosecution history
pertaining to the patent.” 37 C.F.R. § 42.100(b);7 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,

7 See Changes to the Claim Construction Standard for Interpreting Claims in
Trial Proceedings Before the Patent Trial and Appeal Board, 83 Fed. Reg.
51,340, 51,340, 51,358 (Oct. 11, 2018) (amending 37 C.F.R. § 42.100(b)
effective November 13, 2018) (now codified at 37 C.F.R. § 42.100(b)
(2019)).
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deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed.
Cir. 1994).
Petitioner proposes that we construe certain terms. Pet. 24–26. On this
record and for purposes of this Decision, we see no need to construe any
term expressly. Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.,
868 F.3d 1013, 1017 (Fed. Cir. 2017) (stating that claim terms need only be
construed to the extent necessary to resolve the controversy).
Prior-Art Disclosures
Wyse
Wyse teaches “compositions containing an opioid antagonist such as
naloxone and one or more pharmaceutically acceptable excipients. The
compositions may be used for intranasal delivery of Naloxone for the
treatment of, for example, opioid overdose in an individual in need thereof.”
Ex. 1007, Abstract.
Wyse discloses the results of preliminary formulation screening
studies for 13 naloxone formulations, each including 20 mg/ml naloxone
HCl and a different combination of excipients. Id. at 26:26–29, Table 13.
Wyse reports that the study “surprisingly showed” that, in four of the five
formulations that include benzalkonium chloride (“BAC”)8 as the
preservative, the use of BAC “resulted in an additional degradant.” Id.
at 27:29–32, Table 13. According to Wyse, apart 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.” Id. at 27:32–34.

8 Benzalkonium chloride is abbreviated as BAC in the Petition, and BZK in
the Patent Owner Response.
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HPE
HPE lists pharmaceutical excipients, including BAC, benzyl alcohol,
and disodium edetate (“EDTA”). Ex. 1012. HPE describes various
information about each excipient, such as the applications in pharmaceutical
formulation as well as safety. Id.
For BAC, HPE teaches that in nasal formulations, it is used in “a
concentration of 0.002–0.02% w/v.” Id. at 56. HPE notes that BAC is
“[i]ncluded in the FDA Inactive Ingredients Database” for nasal
preparations. Id. at 57 (citation omitted).
Djupesland
Djupesland teaches that the Pfeiffer/Aptar single-dose intranasal
delivery device has been used to administer certain intranasal migraine
medications. Ex. 1010, 49. According to Djupesland, to use the device,
which “consist[s] of a vial, a piston, and a swirl chamber,” one holds it
“between the second and the third fingers with the thumb on the actuator.”
Id. Djupesland explains that “[t]o emit 100 μl, a volume of 125 μl is filled in
the device (Pfeiffer/Aptar single-dose device) used for the intranasal
migraine medications.” Id.
The ’291 Patent
The ’291 patent “compares bioavailability of a butorphanol
formulation when administered using a unit-dose or multi-dose delivery
device.” Ex. 1015, 7:61–63. The unit-dose delivery system employed is
“Unitdose Second Generation,” a commercially available disposable
intranasal applicator from Pfeiffer. Id. at 8:12–16. The ’291 patent describes
the composition and volume of the formulation sprayed. Id. at 7:63–67,
8:16–18.
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Obviousness over Wyse and HPE
Petitioner argues that claims 1–3, 16–24, and 28–45 would have been
obvious over Wyse9 and HPE. Pet. 29–49. After reviewing the entire record,
we conclude Petitioner has not shown by a preponderance of the evidence
that the combination of Wyse and HPE renders any of the challenged claims
obvious.
Each of independent claims 1 and 30 recites “between about 0.005 mg
and about 0.015 mg of a compound which is at least one of a preservative, a
cationic surfactant, and a permeation enhancer,” and “between about 0.1 mg
and about 0.5 mg of a stabilizing agent.” Each of dependent claims 2, 3, 28,
29, 32, 33, 37–39, and 43–45 specifies BAC as the preservative and EDTA
as the stabilizing agent. In this Decision, the central question turns on
whether, based on evidence of the record in this proceeding, an ordinarily
skilled artisan would have understood Wyse and HPE to teach away from
using BAC as a preservative, especially in combination with the stabilizing
agent EDTA, in an intranasal naloxone formulation. Because it is dispositive
regarding all the challenged claims, we focus our analysis on this issue only.
Regarding claim 1, Petitioner argues that Wyse teaches using an
antimicrobial agent, which is a preservative, in an amount of 0.1% to 2% by
weight of the formulation. Pet. 33 (citing Ex. 1007, 7:20–28). Because Wyse

9 Wyse issued on November 24, 2015, from an application filed on
December 19, 2014. Ex. 1007, codes (22), (45). Petitioner asserts that the
earliest priority date for challenged claims is March 16, 2015. Pet. 12–14.
Thus, Petitioner argues that Wyse qualifies as prior art under AIA
§ 102(a)(2). Id. at 26. For the purposes of this proceeding, Patent Owner
does not dispute, and we agree with, Petitioner’s argument on this point.
Paper 10, 1.
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does not specify “the types of antimicrobial agents that may be used,”
Petitioner asserts a Formulator POSA would have consulted HPE to choose
the antimicrobial agents in appropriate amounts based on their potencies. Id.
(citing Ex. 1002 ¶¶ 140, 141).
According to Petitioner, “Wyse discloses using quantities of
preservative between 0.1% w/v and 2% w/v” based on benzyl alcohol, the
preservative exemplified in Wyse. Id. at 34. Petitioner argues that benzyl
alcohol “is usually used at concentrations such as 5 mg/mL (0.5% w/v)
because it is only moderately active against Gram-positive organisms and
less active against Gram-negative bacteria.” Id. at 34 (citing Ex. 1012, 64).
In contrast, Petitioner asserts, BAC “is a commonly used
antimicrobial preservative in FDA-approved nasal formulations [that] has a
broad range of antimicrobial activities at low concentrations, such as 0.002–
0.02% w/v.” Id. at 33–34 (citing Ex. 1002 ¶¶ 65, 143; Ex. 1012, 56–60).
Thus, Petitioner concludes, “[a] POSA would have been particularly
motivated to use BAC as a preservative in such a nasal spray,” in the amount
of 0.002–0.02 mg (at the concentration of 0.002–0.02% w/v in the volume of
100 μL), which fully encompasses the 0.005–0.015 mg range recited in
challenged claim 1. Id. at 33–34 (citing Ex. 1002 ¶ 142; Ex. 1012, 56). In
other words, as Patent Owner points out, Petitioner’s “arguments for
obviousness of the recited preservative amounts hinge on establishing that
the POSA would have used [BAC].” PO Resp. 5.
In our Institution Decision, we agreed with Patent Owner that both
Wyse and HPE taught away from using BAC as the preservative, especially
in combination with the stabilizing agent EDTA, in formulating intranasal
naloxone. Dec. 19–23. Although we focused on certain dependent claims
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when discussing the teaching-away issue at institution, after considering the
full record developed through trial, we agree with Patent Owner that the
teaching-away argument applies to all challenged claims. We highlight
relevant arguments and evidence in the following discussion.
In its preliminary formulation screening studies, Wyse evaluated 13
excipient combinations. Ex. 1007, 26:26–27. According to Wyse, the results
“surprisingly showed that the use of benzalkonium chloride, a common nasal
product preservative, resulted in an additional degradant in formulations 7,
9, 14, and 14A.” Id. at 27:29–32. Wyse concluded that “benzyl alcohol and
paraben preservatives were acceptable, but benzalkonium chloride was not,
due to increased observed degradation.” Id. at 27:42–44, see also id. at
28:23–27 (“Applicant found that, surprisingly, commonly used excipients
including . . . benzylalkonium chloride, were found to increase degradation
of naloxone.”).
Petitioner acknowledges Wyse’s disclosure on this issue (Pet. 58–59
(citing Ex. 1007, 27:30–34, 41–44)), but emphasizes that “[n]o other prior
art cited by [Patent Owner] would have directed a POSA away from using
BAC in an intranasal naloxone formulation.” Reply 9–10. We are not
persuaded by this argument.
As Petitioner acknowledges, an ordinarily skilled artisan “would have
been concerned about naloxone degradation,” and would have “been
motivated to choose ingredients to render the formulation chemically and
microbiologically stable.” Pet. 20; 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;
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and the solution would have been free of microbial growth or ingress.”
(citing Ex. 1002 ¶ 51)).
In this proceeding, Wyse is the only reference of record that compares
naloxone formulations having different excipient combinations, and
provides stability data for intranasal naloxone formulations. Thus, we find
that, contrary to Petitioner’s assertion that “a POSA would not have granted
[Wyse’s] statements much merit” (Pet. 59), an ordinarily skilled artisan,
when “determin[ing] what antimicrobial agents he or she should consider in
developing a nasal formulation of naloxone” (id. at 33), would have taken
into consideration, and indeed, would have given significant weight, to the
only naloxone formulation stability data disclosed in Wyse.
Petitioner contends that ordinarily skilled artisans “reading the
disclosure of Wyse have concluded that it does not teach away” from using
BAC. Pet. 59–60. As support, Petitioner cites Glende,10 “a Norwegian
graduate thesis published in 2016.” Id. Acknowledging that Glende is not
prior art, Petitioner nevertheless points out that Glende “reviewed the WIPO
publication equivalent of Wyse [and] not[ed] that the disclosure should not
be understood to disparage the use of BAC, as the criticism of its use may be
incorrectly based.” Id. (citing Ex. 1031, 76). Glende, however, reached this
conclusion after also reviewing the WIPO publication equivalent of a parent
application of the challenged ’747 patent (Ex. 1031, 54), which disclosed
BAC-containing formulations were “storage-stable” (id. at 54, 64). Thus, we

10 Glende, O., Development of Non-Injectable Naloxone for Pre-Hospital
Reversal of Opioid Overdose: A Norwegian Project and a Review of
International Status (May 2016) (unpublished M.A. thesis, Norwegian
University of Science and Technology).
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agree with Patent Owner that “Glende’s conclusion was based on knowledge
of the patented invention which disclosed the stability of the patentee’s
formulations, not what the POSA would have understood from the prior art.”
See PO Resp. 12.
Regarding the teachings of Wyse, Petitioner argues that an ordinarily
skilled artisan “would not have properly concluded that Wyse taught away
from using BAC with naloxone.” Pet. 58. 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. at 59; see also Reply 6 (“Wyse
discloses that his prototyping studies, in which combinations of excipients
were tested together, would not permit a conclusion that any one ingredient
in the combinations was responsible for naloxone degradation.”). We are not
persuaded by this argument either.
In its screening tests, Wyse tested benzyl alcohol, paraben, and BAC
preservatives. Ex. 1007, Table 13. Of special note is that formulations 13
and 13A contain benzyl alcohol as the preservative, whereas formulations 14
and 14A contain BAC as the preservative. Id., Table 13. Wyse observed an
additional degradant in formulations 14 and 14A (id. at 27:29–32) even
though, but for the preservative, formulation 14 is identical to formulation
13, and formulation 14A is identical to formulation 13A (id., Table 13).
Based on these results, Wyse concluded that “benzyl alcohol and paraben
preservatives were acceptable, but benzalkonium chloride [BAC] was not,
due to increased observed degradation.” Id. at 27:42–44. On this record,
Petitioner has not shown this conclusion was unreasonable, or that an
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ordinarily skilled artisan, based on knowledge possessed at the time of the
invention, would have otherwise doubted Wyse’s express teaching that BAC
was not an acceptable preservative because it caused the increased
degradation that Wyse observed in its tests.
Petitioner also questions whether, in Wyse, BAC “specifically
resulted in additional naloxone degradation, rather than degradation of
another component.” Pet. 59. We disagree. Wyse specified that BAC
increases “degradation of naloxone.” Id. at 28:23–27, see also id. at 26:32–
34 (explaining “Naloxone RP-HPLC assay for purity”), 27:19–21
(discussing the “stability of naloxone HCl” and “degradation of naloxone
HCl”).
Petitioner further argues that “if the ‘additional degradant’ was a
naloxone degradant, it would likely be an oxidation degradant.” Reply 5.
According to Petitioner, “a POSA would have known that BAC could not
have been responsible for the production of any oxidative degradants.” Id.
The evidence of the record does not support Petitioner’s position.
Petitioner relies on the Donovan Declaration to support its argument
that the additional degradant reported by Wyse “would likely be an oxidation
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degradant.”11 Reply 5 (citing Ex. 1201 ¶¶ 13, 15, emphasis added).
Dr. Donovan’s testimony on this point, however, is much more tentative:
I think a person of ordinary skill in the art would hold open the
possibility that it was an oxidative degradant because that’s what
Wyse was trying to accomplish, but they wouldn’t have any
reason to believe it was a particular form of an -- of the oxidative
degradants known or unknown and, yes, they, again, couldn’t
anticipate what that material was without additional information
but certainly oxidative degradants would be in keeping with what
a POSA would postulate might show up in these mixtures.
Ex. 2215, 502:14–503:2 (emphases added). In view of such equivocal
testimony, we are not persuaded by Petitioner’s argument that an ordinarily
skilled artisan would have attributed the “additional degradant” disclosed in
Wyse to oxidative degradation, and thus would have subsequently deduced
that BAC could not have caused such degradation.
Petitioner argues that “the evidence does not show that BAC is
incompatible with naloxone, and thus does not teach away from its inclusion
in a naloxone formulation.” Pet. 59. According to Petitioner, “[a] POSA
would have known that in order to conclude that BAC and naloxone were
incompatible, one would need to study the individual combination of the two
compounds.” Reply 7, see also id. (“To determine the root cause of any

11 Petitioner also asserts that “the ‘additional degradant’ in these
formulations was apparently identified as Impurity E—i.e., 2,2’-
binaloxone—the primary oxidation degradation product of naloxone.”
Reply 5. As support, Petitioner relies on Exhibit 2188, “Indivior NDA
Module 3.2.P.2.” Id. (citing Ex. 2188); Paper 48, 23. Exhibit 2188, however,
is a third-party confidential document that is not alleged to be in the prior art
and was, and remains, under seal. Paper 32, 3. Thus, Petitioner has not
shown that an ordinarily skilled artisan, at the priority date of the claimed
invention, would have understood that the “additional degradant” in Wyse is
Impurity E.
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problems, a POSA would have to evaluate each excipient and experimental
condition individually and potentially evaluate other factors.”). Petitioner
overstates the standard for evaluating whether a reference teaches away.
A reference teaches away “if it suggests that the line of development
flowing from the reference’s disclosure is unlikely to be productive of the
result sought by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir.
1994). Wyse explicitly and unambiguously discourages the use of BAC in
intranasal naloxone formulations. Wyse found BAC “increase[d]
degradation of naloxone” (Ex. 1007, 28:26–27), and excluded BAC from the
naloxone formulations chosen for further study (id. at 28:41–47, Table 14).
As explained above, on the record presented in this proceeding, we are not
persuaded by Petitioner’s arguments that an ordinarily skilled artisan would
have interpreted Wyse’s teachings differently.
Accordingly, Wyse teaches away from using BAC as the preservative
because it directly “criticize[s], discredit[s], or otherwise discourage[s] the
solution claimed.” See In re Fulton, 391 F.3d at 1201. This is so despite the
fact that, as Petitioner emphasizes, one of the five BAC-including
formulations tested by Wyse did not result in additional degradants. Pet. 59.
After all, 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 challenged claim. Gurley, 27 F.3d at 553.
Here, Wyse does both. It not only presents results showing that BAC
is not acceptable for use in intranasal naloxone formulations, but also
provides data demonstrating that other preservatives, such as benzyl alcohol,
are stable in such formulations. Id. at 27:41–44, 28:41–29:27. Indeed, Wyse
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teaches that the BAC-containing version of an otherwise “ideal” naloxone
nasal formulation produced an additional degradant, whereas the benzyl
alcohol-containing version of that formulation was stable. Id. at 27:29–37,
Tables 14, 15. Wyse ultimately determined that two formulations using
benzyl alcohol, and excluding BAC, as the preservative were stable and
warranted further development. Id. at 29:19–21, Table 15.
We recognize the general teaching of prior art, including HPE, that
BAC is an antimicrobial preservative that may be used in, and is FDA
approved for, nasal formulations. Pet. 33, 36; Reply 11; see also Ex. 1012,
56–57 (showing BAC is in the FDA’s inactive ingredients database for nasal
preparations). This, however, is insufficient to defeat Wyse’s teaching away.
As explained above, in this proceeding, Wyse is the only prior-art reference
of record that specifically addresses the effect of BAC on the stability of
intranasal naloxone formulations. Thus, even if an ordinarily skilled artisan
might have generally contemplated including BAC because it was a
preservative known for use in nasal formulations, such an artisan would
have been dissuaded from doing so because Wyse expressly teaches that
BAC is unacceptable for use in intranasal naloxone formulations.
In sum, based on the evidence and arguments presented in this
proceeding, we find Wyse teaches away from using BAC in intranasal
naloxone formulations. Although independent claims 1 and 30 do not require
BAC as the preservative, they recite a specific range, “between about 0.005
mg and about 0.015 mg,” for the amount of the preservative. To account for
this limitation, Petitioner solely relies on the potency and the commonly
used concentrations of BAC. Pet. 33–34; see also Tr. 18:9-22 (Petitioner
acknowledging that “all of our argument has been tailored to the
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Patent No. 9,468,747 B2

21
obviousness of using BAC” and that it has not presented additional
arguments or evidence for those claims not expressly limited to BAC). As a
result, we conclude that Petitioner has not shown by a preponderance of the
evidence that all claims challenged under this ground would have been
obvious over Wyse and HPE.
In addition, each of dependent claims 2, 3, 28, 29, 32, 33, 37–39, and
43–45 recites BAC as the preservative and EDTA as the stabilizing agent.
HPE specifically teaches that “[n]asal formulations containing benzalkonium
chloride [BAC] and disodium edetate [EDTA], both known to be local
irritants, were shown to produce an inflammatory reaction, and microscopic
examination showed an extended infiltration of the mucosa by eosinophils,
and pronounced atrophy and disorganization of the epithelium.” Ex. 1012,
243.
As Petitioner acknowledges, “minimizing irritation” is an important
consideration in selecting excipients for intranasal naloxone formulation.
Pet. 22. Thus, we agree with Patent Owner that HPE’s teaching that both
BAC and EDTA are “known to be local irritants,” and that using them
together with would “produce an inflammatory reaction” would have
discouraged an ordinary artisan from doing so. See PO Resp. 14; Dec. 22–
23. As a result, we find HPE further teaches away from using BAC together
with EDTA in intranasal formulations. For this additional reason, we
conclude that Petitioner has not shown by a preponderance of the evidence
that claims 2, 3, 28, 29, 32, 33, 37–39, and 43–45 would have been obvious
over Wyse and HPE.
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Other Grounds
Petitioner argues that claims 4–7, 10–15, and 25–27 would have been
obvious over Wyse, Djupesland, and HPE, and claims 8 and 9 would have
been obvious over Wyse, Djupesland, HPE, and the ’291 patent. Pet. 49–58.
Each of these claims depends, directly or indirectly, from claim 2, which
requires the combination of BAC and EDTA.
Petitioner relies on Djupesland and the ’291 patent for teaching the
additional limitations in the claims challenged under these two grounds, but
relies only on the same teachings of Wyse and HPE as discussed above for
the limitation they incorporate by dependency from claim 2. Id. As
explained above, Wyse teaches away from using BAC in intranasal naloxone
formulations, and HPE teaches away from using BAC together with EDTA
in such formulations. Thus, we conclude that Petitioner has not shown by a
preponderance of the evidence that the claims challenged under these two
grounds would have been obvious as asserted in the Petition.12

12 We recognize that the district court held claims 7 and 9 of the ’747 patent
invalid in the Teva Case. Adapt Pharma Operations Ltd. v. Teva
Pharmaceuticals USA, Inc., Case 2:16-cv-07721, 2020 WL 3428078, *47
(D.N.J. June 22, 2020). There, the court found that, “taken as a whole, the
prior art did not teach away from using [BAC].” We reach a different
conclusion here, but note that the record before us appears to be substantially
different from that considered by the court in the Teva Case. For example,
Petitioner here relies on Wyse as the primary reference, whereas the district
court’s obviousness determination was based on combinations of art that do
not include Wyse. Id. at *29–*31. In addition, the district court relies on
expert testimony and other evidence concerning BAC-containing prior-art
naloxone formulations, which are not part of the record before us. Id. at
*31–*32.
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CONCLUSION
Petitioner has not demonstrated by a preponderance of the evidence
that claims 1–45 of the ’747 patent would have been obvious based on the
challenges presented in the Petition.
In summary:
ORDER
Accordingly, it is
ORDERED that Petitioner has not demonstrated by a preponderance
of the evidence that claims 1–45 of the ’747 patent are unpatentable; and
FURTHER ORDERED that, because this is a Final Written Decision,
parties to this proceeding seeking judicial review of our Decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.

Claims

35
U.S.C.
§
References Claims
Shown
Unpatentable
Claims Not
shown
Unpatentable
1–3, 16–24,
28–45
103 Wyse, HPE 1–3, 16–24,
28–45
4–7, 10–15,
25–27
103 Wyse, Djupesland,
HPE
4–7, 10–15,
25–27
8, 9 103 Wyse, Djupesland,
HPE, the ’291
patent
8, 9
Overall
Outcome
1–45
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Patent No. 9,468,747 B2

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For PETITIONER:
Yelee Kim
Richard Berman
Christopher Yaen
Janine Carlan
Bradford Frese
ARENT FOX
Yelee.kim@arentfox.com
Richard.berman@arentfox.com
Christopher.yaen@arentfox.com
Janine.carlan@arentfox.com
Bradford.frese@arentfox.com

For PATENT OWNER:
Jessica Mackay
Ann Kotze
GREEN GRIFFITH & BORG-BREEN, LLP
jmackay@greengriffith.com
akotze@greengriffith.com

Jessamyn Berniker
David Krinsky
Anthony Sheh
WILLIAMS AND CONNOLLY LLP
jberniker@wc.com
dkrinsky@wc.com
asheh@wc.com