Neurelis, Inc.

Patent Trials and Appeals Board

Aug 6, 2020

IPR2019-00451 (P.T.A.B. Aug. 6, 2020)

Trials@uspto.gov Paper: 44
Tel: 571-272-7822 Date: August 6, 2020

UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE PATENT TRIAL AND APPEAL BOARD

AQUESTIVE THERAPEUTICS, INC.,
Petitioner,
v.
NEURELIS, INC.,
Patent Owner.

IPR2019-00451
Patent 9,763,876 B2

Before ZHENYU YANG, JON B. TORNQUIST, and JAMIE T. WISZ,
Administrative Patent Judges.

WISZ, Administrative Patent Judge.
JUDGMENT
Final Written Decision
Determining All Claims Unpatentable
Denying Petitioner’s Motion to Exclude
Denying Patent Owner’s Motion to Exclude
35 U.S.C. § 318(a); 37 C.F.R. § 42.64

IPR2019-00451
Patent 9,763,876 B2
2
I. INTRODUCTION
A. Background
Aquestive Therapeutics, Inc. (“Petitioner”) filed a Petition (Paper 3,
“Pet.”) requesting an inter partes review of claims 1–36 (“the challenged
claims”) of U.S. Patent No. 9,763,876 B2 (Ex. 1001, “the ’876 patent”).
Petitioner supported its Petition with the Declaration of Nicholas A. Peppas,
Sc.D. (Ex. 1041). Neurelis, Inc.1 (“Patent Owner”) filed a Preliminary
Response (Paper 7, “Prelim. Resp.”). Upon consideration of the Petition, the
Preliminary Response, and the preliminary evidence of record, we
determined that Petitioner had demonstrated a reasonable likelihood that it
would prevail with respect to at least one of the challenged claims of the
’876 patent (Paper 8, “Institution Decision” or “Inst. Dec.”). Thus, we
instituted review with respect to all of the challenged claims.
Following institution of trial, Patent Owner filed a Request for
Rehearing (Paper 10, “Request for Rehearing” or “Req. Reh’g”), which was
denied (Paper 14, “Decision on Request for Rehearing” or “Dec. on Req.
Reh’g”), and a request for Precedential Opinion Panel (POP) review
(Ex. 3001, “POP Request”), which was also denied (Paper 17).
Patent Owner filed a Patent Owner Response (Paper 16, “PO
Response” or “PO Resp.”) and supported its Response with the Declaration
of Sveinbjörn Gizurarson, Ph.D. (Ex. 2012). Petitioner filed a Reply (Paper

1 Patent Owner informs us that, subsequent to the filing of the Petition, Hale
Biopharma Ventures, LLC, the originally named Patent Owner in this case,
assigned its rights in the ’876 patent to Neurelis, Inc. Paper 6, 2 (citing Reel
048271; Frame 0304).
IPR2019-00451
Patent 9,763,876 B2
3
21, “Reply”) with a Declaration of Daniel P. Wermeling, Pharm.D.
(Ex. 1150). Patent Owner filed a Sur-Reply (Paper 28, “PO Sur-Reply”).
Petitioner and Patent Owner each separately filed Motions to Exclude
regarding certain evidence of record (Paper 34, “Pet. MTE”; Paper 35, “PO
MTE”). We address each of these Motions in this Decision.
An oral hearing was held on May 14, 2020, and a transcript of the
hearing is included in the record (Paper 43, “Tr.”).
We have jurisdiction under 35 U.S.C. § 6. After considering the
parties’ arguments and supporting evidence, we conclude that Petitioner has
proven by a preponderance of the evidence that claims 1–36 of the ’876
patent are unpatentable. 35 U.S.C. § 316(e).
B. Real Parties-in-Interest
Petitioner identifies Aquestive Therapeutics, Inc. (formerly Monosol
Rx, LLC) as the real party-in-interest. Pet. 1. Patent Owner identifies
Neurelis, Inc. as the real party-in-interest. Paper 6, 2.
C. Related Proceedings
The ’876 patent was challenged by Petitioner in IPR2019-00449 and
IPR2019-00450. Institution of inter partes review in both cases was denied.
IPR2019-00449, Paper 7; IPR2019-00450, Paper 8.
Patent Owner also indicates that it filed a tort suit against Petitioner in
which it cited Petitioner’s IPR petitions “as evidence of a pattern of tortious
behavior” against Patent Owner. Paper 29, 2 (citing Neurelis, Inc. v.
Aquestive Therapeutics, Inc., No. 37-00064665-CU-BT-CTL (Super. Ct.
Cal., San Diego)).
IPR2019-00451
Patent 9,763,876 B2
4
D. The ’876 Patent
The ’876 patent is directed to nasally administered pharmaceutical
solutions containing one or more benzodiazepine drugs. Ex. 1001, 9:14–17.
The ’876 patent explains that solubility challenges associated with
benzodiazepine drugs previously hindered the development of formulations
intended for oral, rectal, or parenteral administration. Id. at 1:53–57, 19:12–
15. According to the’876 patent, it was discovered, however, that vitamin E
(which includes tocopherols and tocotrienols) is an effective carrier for
benzodiazepine drugs, as these compounds are soluble, or at least partially
soluble, in vitamin E. Id. at 33:8–13, 33:42–45. The ’876 patent also
reports that vitamin E “can have the added benefit of either avoiding
irritation of sensitive mucosal membranes and/or soothing irritated mucosal
membranes.” Id. at 33:47–49.
The ’876 patent discloses that one or more lower alcohols, such as
ethanol and benzyl alcohol, may be used in the formulation. Ex. 1001, 2:57–
64, 33:55–67 (noting that to “avoid the drawbacks of emulsions,” the
disclosed solutions contain vitamin E and “one or more lower alkyl
alcohols”). In addition, an alkyl glycoside may be added to the formulation
to act as a penetration enhancer. Id. at 34:2–9.
E. Illustrative Claim
Petitioner challenges claims 1–36 of the ’876 patent. Claim 1, which
is the only independent claim of the ’876 patent, is illustrative of the
challenged claims, and is reproduced below:
1. A method of treating a patient with a disorder which is
treatable with a benzodiazepine drug, comprising:
IPR2019-00451
Patent 9,763,876 B2
5
administering to one or more nasal mucosal membranes of
a patient a pharmaceutical solution for nasal administration
consisting of
a benzodiazepine drug,
one or more natural or synthetic tocopherols or
tocotrienols, or any combinations thereof, in an amount
from about 30% to about 95% (w/w);
ethanol and benzyl alcohol in a combined amount
from about 10% to about 70% (w/w); and
an alkyl glycoside.
Ex. 1001, 63:26–34 (formatting added). Challenged claims 2–36
depend from claim 1, either directly or indirectly.
F. Instituted Grounds of Unpatentability
We instituted trial to determine whether claims 1–36 of the ’876
patent are unpatentable based on the following grounds:
Claims Challenged 35 U.S.C. § References/Basis
1–16, 24–36 103(a) Gwozdz,2 Meezan ’9623
17–23 103(a) Gwozdz, Meezan ’962, Cartt
’7844
Inst. Dec. 5.

2 PCT Pub. No. WO 2009/120933 A2, published October 1, 2009 (Ex. 1014,
“Gwozdz”).
3 U.S. Pub. No. 2006/0046962 A1, published March 2, 2006 (Ex. 1011,
“Meezan ’962”).
4 U.S. Pub. No. 2008/0279784 A1, published November 13, 2008 (Ex. 1015,
“Cartt ’784”).
IPR2019-00451
Patent 9,763,876 B2
6
II. ANALYSIS
We have reviewed the parties’ respective briefs as well as the relevant
evidence discussed in those papers. For the reasons discussed in detail
below, we determine that Petitioner has shown by a preponderance of the
evidence that claims 1–36 of the ’876 patent are unpatentable under 35
U.S.C. § 103 as having been obvious.
A. Principles of Law
To prevail in its challenges to the patentability of all claims of the
’876 patent, Petitioner must demonstrate by a preponderance of the evidence
that the claims are unpatentable. 35 U.S.C. § 316(e) (2018); 37 C.F.R.
§ 42.1(d) (2019). “In an [inter partes review], the petitioner has the burden
from the onset to show with particularity why the patent it challenges is
unpatentable.” Harmonic Inc. v. Avid. Tech., Inc., 815 F.3d 1356, 1363
(Fed. Cir. 2016); see also 35 U.S.C. § 312(a)(3) (requiring inter partes
review petitions to identify “with particularity . . . the evidence that supports
the grounds for the challenge to each claim”). That burden of persuasion
never shifts to Patent Owner. Dynamic Drinkware, LLC v. Nat’l Graphics,
Inc., 800 F.3d 1375, 1378 (Fed. Cir. 2015); see also In re Magnum Oil Tools
Int’l, Ltd., 829 F.3d 1364, 1375–78 (Fed. Cir. 2016) (discussing the burden
of proof in inter partes review).
Regarding obviousness, the Supreme Court in KSR International Co.
v. Teleflex Inc., 550 U.S. 398 (2007), reaffirmed the framework for
determining obviousness as set forth in Graham v. John Deere Co., 383 U.S.
1 (1966). The KSR Court summarized the four factual inquiries set forth in
Graham (383 U.S. at 17–18) that are applied in determining whether a claim
is reasonably likely to be unpatentable as obvious under 35 U.S.C. § 103(a)
IPR2019-00451
Patent 9,763,876 B2
7
as: (1) determining the scope and content of the prior art; (2) ascertaining the
differences between the prior art and the claims at issue; (3) resolving the
level of ordinary skill in the pertinent art; and (4) considering objective
evidence indicating obviousness or non-obviousness. KSR, 550 U.S. at 406.
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR, 550 U.S. at 416. “[W]hen the question is whether a patent claiming
the combination of elements of prior art is obvious,” the answer depends on
“whether the improvement is more than the predictable use of prior art
elements according to their established functions.” Id. at 417. It is generally
obvious to those skilled in the art to substitute one known equivalent for
another. See In re Omeprazole Patent Litigation, 483 F.3d 1364, 1374 (Fed.
Cir. 2007) (“[T]his court finds no . . . error in [the] conclusion that it would
have been obvious to one skilled in the art to substitute one ARC [alkaline
reactive compound] for another.”); see also Wm. Wrigley Jr. Co. v. Cadbury
Adams USA LLC, 683 F.3d 1356, 1364 (Fed. Cir. 2012) (the combination of
known elements and substitution of one well known agent for another is
obvious).
When there is a range disclosed in the prior art, and the claimed
invention falls within that range, or the disclosed range overlaps with the
claimed range, there is a presumption of obviousness. Iron Grip Barbell Co.
v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004); In re Peterson,
315 F.3d 1325, 1329 (Fed. Cir. 2003) (“In cases involving overlapping
ranges, we and our predecessor court have consistently held that even a
slight overlap in range establishes a prima facie case of obviousness.”); see
also In re Geisler, 116 F.3d 1465, 1469 (Fed. Cir. 1997) (noting that a
IPR2019-00451
Patent 9,763,876 B2
8
claimed range overlaps with a prior art range if the two ranges share a
common endpoint (e.g., claim range of 50–100 Å overlaps with prior art
range of 100–600 Å)). This presumption may be rebutted by showing the
criticality of the claimed range, that the prior art taught away from the
claimed range, or that the parameter was not recognized as “result-
effective.” E.I. DuPont de Nemours & Company v. Synvina C.V., 904 F.3d
996, 1006 (Fed. Cir. 2018); Iron Grip, 392 F.3d 1322.
We analyze Petitioner’s asserted grounds of unpatentability in
accordance with the above-stated principles.
B. Level of Ordinary Skill in the Art
We consider the asserted grounds of unpatentability in view of the
understanding of a person of ordinary skill in the art (“POSA” or
“POSITA”), and thus begin with the level of ordinary skill in the art. The
level of ordinary skill in the art is “a prism or lens through which . . . the
Board views the prior art and claimed invention” to prevent hindsight bias.
Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001).
The parties dispute the level of ordinary skill in the art. Petitioner
asserts that, as of the earliest priority date, a person of ordinary skill in the
art would have been:
a medicinal chemist, pharmaceutical chemist, chemist, or
biologist involved in the research and development of
pharmaceutical formulations and/or delivery. The POSITA
would have at least a bachelor’s degree in chemical, biological,
or pharmaceutical sciences or a medical degree, and several
years of experience in the field of transmucosal (including
intranasal, rectal, vaginal, ocular, lacrimal, nasolacrimal,
buccal, sublingual, urethral, inhalation, and auricular)
pharmaceutical formulation development and/or delivery, the
amount of post-graduate experience depending upon the level
IPR2019-00451
Patent 9,763,876 B2
9
of formal education. The individual would also have some
experience in design and testing of formulations for mucosal
delivery (and particularly in intranasal formulations) of
systemic-acting drugs.
Pet. 4. Dr. Peppas also recites this definition in his Declaration. Ex. 1041
¶ 74.
In response, Patent Owner disputes certain aspects of Petitioner’s
description of the level of ordinary skill in the art. See PO Resp. 15–17.
First, Patent Owner, with supporting testimony from Dr. Gizurarson, asserts
that “the formulation of a benzodiazepine for intranasal administration is a
difficult and complex science requiring a higher skill set and knowledge than
a POSA with a bachelor’s degree ‘with several years of experience.’” Id. at
15 (citing Ex. 2012 ¶¶ 28–29). Specifically, according to Patent Owner and
Dr. Gizurarson, “the POSA would be working against physiological
constraints of active ingredient uptake due to the nasal anatomy, as well as
the very low solubility of benzodiazepines in formulating the pharmaceutical
composition disclosed in the ’876 patent.” Id. at 15–16 (citing Ex. 2012
¶¶ 28–29). Therefore, Patent Owner asserts that “a POSA would at least
have held a Master’s degree with many years of experience, or a Ph.D. or
Pharm.D[.] degree with several years of experience, or its equivalent
research experience.” Id. at 16 (citing Ex. 2012 ¶ 29).
Second, Patent Owner contends that a person of ordinary skill in the
art would not include a medicinal chemist because “[c]hemists are primarily
concerned with chemical structures and synthesizing new chemical
compounds” and it is not clear “what role a medicinal chemist would play in
the research and development of benzodiazepine pharmaceutical
formulations for intranasal administration – especially where, as here, the
IPR2019-00451
Patent 9,763,876 B2
10
chemical structures were all known.” PO Resp. 16 (citing Ex. 2012 ¶ 30).
Instead, according to Patent Owner, “a POSA would have had knowledge of
benzodiazepine structure and function, including solubility issues with
benzodiazepines in general.” Id. (citing Ex. 2012 ¶ 31). Patent Owner also
asserts that the “POSA would further have knowledge and practical
experience working with intranasal formulations, including knowledge of
the physiology and anatomy of the nasal cavity, with relevant experience in
developing intranasal formulations.” Id. at 16–17 (citing Ex. 2012 ¶ 31).
Patent Owner further contends that “[Petitioner] and Dr. Peppas’
description of a POSA having experience in ‘rectal, vaginal, ocular,
lacrimal, nasolacrimal, buccal, sublingual, urethral, inhalation, and auricular’
delivery as ‘related fields’ does not take into consideration the differences in
formulating an intranasal product and complexities of the intranasal
pathway.” PO Resp. 17 (citing Ex. 2012 ¶ 32; Ex. 2011, 118:18–120:19).
Petitioner disagrees with Patent Owner’s definition of a person of
ordinary skill in the art and contends that such a person would also have
experience working with “transmembrane” formulations in addition to
“intranasal” formulations. Reply 12 (citing Ex. 2012 ¶¶ 31, 32; Ex. 11505
¶¶ 20–22).
In determining the level of ordinary skill, various factors may be
considered, including “(1) the educational level of the inventor; (2) type of
problems encountered in the art; (3) prior art solutions to those problems; (4)

5 Throughout the Reply, Petitioner sometimes refers to Ex. 1100 when citing
to the Declaration of Dr. Wermeling. Because there is no Ex. 1100 in the
record and because the Declaration of Dr. Wermeling is Ex. 1150, we have
used Ex. 1150 to indicate Petitioner’s citations to the Wermeling
Declaration.
IPR2019-00451
Patent 9,763,876 B2
11
rapidity with which innovations are made; (5) sophistication of the
technology; and (6) educational level of active workers in the field.” Daiichi
Sankyo Co. v. Apotex, Inc., 501 F.3d 1254, 1256 (Fed. Cir. 2007). These
factors are “merely a guide,” and the weight or significance ascribed to each
depends on the particular case. Id.
Based on our consideration of the full record, we find that, overall,
Patent Owner’s definition is more specifically tailored to the claimed subject
matter of the ’876 patent. We also find that the factors recited above,
overall, demonstrate that knowledge of and experience with transmembrane
formulations, as suggested by Petitioner, would also be relevant. See
Ex. 1014, 8:32–9:18; Ex. 1011 ¶¶ 9–13. Therefore, we find that such a
person of ordinary skill in the art would have been a pharmaceutical chemist,
chemist, or biologist involved in the research and development of
pharmaceutical formulations and/or delivery. We also find that the person
of ordinary skill in the art would have at least a Master’s degree with many
years of experience, or a Ph.D. or Pharm.D. degree with several years of
experience. In addition, the person of ordinary skill in the art would have
had knowledge of benzodiazepine structure and function and would further
have knowledge and practical experience working with intranasal and
transmembrane formulations, including knowledge of the physiology and
anatomy of the nasal cavity, with relevant experience in developing
intranasal and transmembrane formulations.
Although we agree with and have primarily adopted Patent Owner’s
definition for an ordinarily skilled artisan in this proceeding, our analysis
and conclusions herein would not change even under Petitioner’s definition.
The parties also do not appear to indicate that the outcome would differ
IPR2019-00451
Patent 9,763,876 B2
12
based on the definition of the person of ordinary skill in the art. See Pet. 4;
PO Resp. 15–17; Reply 12.
C. Claim Construction
Having defined the ordinarily skilled artisan, we now turn to claim
construction. In this inter partes review, claim terms are 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). 37 C.F.R. § 42.100(b). Under this
claim construction standard, claim terms are given their ordinary and
customary meaning as would have been understood by one of ordinary skill
in the art at the time of the invention. See id; Phillips v. AWH Corp., 415
F.3d 1303, 1313 (Fed. Cir. 2005) (en banc). A patentee may define a claim
term in a manner that differs from its ordinary and customary meaning;
however, any special definitions must be set forth in the specification with
reasonable clarity, deliberateness, and precision. See In re Paulsen, 30 F.3d
1475, 1480 (Fed. Cir. 1994).
In the Petition, Petitioner provides proposed constructions for the
terms “vitamin E,” “bioavailability,” “% (w/w),” “% (w/v),” and “about
56.47% (w/v) vitamin E.” Pet. 11–14. Patent Owner does not propose its
own construction for these terms.
In the Patent Owner Response, Patent Owner proposes constructions
for the terms “consisting of” and “in a combined amount.” PO Resp. 12–15.
Petitioner disagrees with Patent Owner’s construction of “consisting of” and
does not provide any comments on the proposed construction of “in a
combined amount.” Reply 9–11. Furthermore, Petitioner proposes a
construction for “pharmaceutical solution,” which Patent Owner opposes.
Reply 11; PO Sur-Reply 4, 18–19.
IPR2019-00451
Patent 9,763,876 B2
13
Upon review of the parties’ arguments and the evidence of record, we
determine that no terms of the ’876 patent require express construction for
purposes of this Decision. See Nidec Motor Corp. v. Zhongshan Broad
Ocean Motor Co., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (citing Vivid Techs.,
Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (“[O]nly
those terms need be construed that are in controversy, and only to the extent
necessary to resolve the controversy.”)).
D. Priority Claim of the ’876 patent
The ’876 patent was filed as U.S. Application No. 14/527,613
(“the ’613 application”) on October 29, 2014. Ex. 1001, codes (21), (22).
The ’876 patent is a continuation of U.S. Application No. 13/495,942 (“the
’942 application”) (issued as U.S. Patent No. 8,895,546) (“the ’546 patent”),
filed on June 13, 2012, which is in turn a continuation-in-part (“CIP”) of
U.S. Application No. 12/413,439 (“the ’439 application”), filed on March
27, 2009. Id. at code (63). The ’876 patent also claims priority to
provisional applications 61/040,558 (“the ’558 provisional”), 61/497,017
(“the ’017 provisional”), and 61/570,110 (“the ’110 provisional”), filed on
March 28, 2008; June 14, 2011; and December 13, 2011, respectively. Id. at
code (60).
Petitioner contends that Meezan ’962 qualifies as prior art to the
claims of the ’876 patent under 35 U.S.C. § 102(b) and that Gwozdz and
Cartt ’784 qualify as prior art at least under 35 U.S.C. § 102(e)(1). Pet. 6–8.
Petitioner asserts that Cartt ’784 is prior art based on its May 7, 2008, filing
date and its November 13, 2008, publication date. Id. at 8. Petitioner also
contends that Gwozdz qualifies as prior art based on the March 28, 2008,
filing date of its U.S. Provisional Application No. 61/040,281 (“Gwozdz
IPR2019-00451
Patent 9,763,876 B2
14
provisional”) (Ex. 1046). Id. at 6. Petitioner has shown that the claims of
Gwozdz are supported by the Gwozdz provisional, “at least because
Gwozdz’s claims are literally identical to the claims filed in [the] Gwozdz
provisional.” Id. (citing Ex. 1014, 14–15; Ex. 1046, 19–20); see Ex. 1014,
4–10; Ex. 1046, 9–15. Patent Owner does not contest that Gwozdz is
entitled to this filing date. See PO Resp. 17–23. Therefore, we find that
Petitioner has satisfied its burden to show that Gwozdz is entitled to the
filing date of the Gwozdz provisional. See Dynamic Drinkware, 800 F.3d. at
1381 (holding that “[a] reference patent is only entitled to claim the benefit
of the filing date of its provisional application if the disclosure of the
provisional application provides support for the claims in the reference
patent in compliance with § 112, ¶ 1.”).
Petitioner asserts that the claims of the ’876 patent are not entitled to
the priority date of the ’558 provisional and have an effective filing date of
no earlier than the March 27, 2009 filing date of the ’439 application. Pet.
18–20. Specifically, Petitioner contends that the ’558 provisional does not
provide adequate support for the “alkyl glycoside” limitation recited in the
challenged claims6 because the presence of any alkyl glycoside is not
disclosed, described, or enabled by the ’558 provisional. Id. at 19–20.
Petitioner further contends that the ’558 provisional’s “generic disclosure of
‘surface active agents (especially non-ionic materials)’ . . . does not disclose,
describe, and/or enable alkyl glycosides in general (or dodecyl maltoside in
particular).” Id. at 20 (citing Ex. 1008 ¶ 152; Ex. 1041 ¶ 68).

6 Claim 1 requires “an alkyl glycoside.” Ex. 1001, 63:34. Since all of the
remaining claims of the ’876 patent depend, directly or indirectly, from
Claim 1, they also require the presence of “an alkyl glycoside.”
IPR2019-00451
Patent 9,763,876 B2
15
Patent Owner argues that Gwozdz and Cartt ’784 are not prior art to
the challenged claims of the ’876 patent because the claims are properly
supported by the ’558 provisional, which was filed on March 28, 2008. PO
Resp. 1, 17–18.
Patent Owner argues that the ’558 provisional does disclose alkyl
glycosides as part of the formulation claimed. PO Resp. 10. Specifically,
Patent Owner points to the following disclosure from the ’558 provisional:
In some embodiments, the drug delivery system of the
invention may advantageously comprise an absorption enhancer
. . . . In some embodiments, enhancing agents that are
appropriate include . . . acyl glycerols, fatty acids and salts,
tyloxapol and biological detergents listed in the SIGMA
Catalog, 1988, page 316-321 (which is incorporated herein by
reference).
Id. (quoting Ex. 1008 ¶¶ 150–152 (emphasis added)). Patent Owner
contends that the excerpt from the 1988 SIGMA catalog (“SIGMA catalog”)
referenced in the ’558 provisional includes alkyl glycosides such as n-
Dodecyl β-D-Maltoside, n-Dodecyl β-D-Glucopyranoside, n-Heptyl β-D-
Glucopyranoside, n-Hexyl β-D-Glucopyranoside, n-Nonyl β-D-
Glucopyranoside, n-Octyl β-D-Glucopyranoside, and Octyl β-D-
Thioglucopyranoside, amongst others. Id. at 10–11 (citing Ex. 2006, 319–
320). Patent Owner, with supporting testimony from Dr. Gizurarson, asserts
that “a POSA would have recognized and understood that alkyl glycosides
were disclosed and supported in the ’558 Provisional through this
incorporation by reference.” Id. at 19 (citing Ex. 2012 ¶ 68).
Patent Owner also asserts that:
A POSA would have understood that in the context of
pharmaceutical formulations, biological detergents would have
been limited to detergents appropriate for administering to the
IPR2019-00451
Patent 9,763,876 B2
16
nasal cavity of a human or other animal subject – which, in
such a case, would have been non-ionic detergents.
PO Resp. 11 n.5 (citing Ex. 2012 ¶ 70). According to Patent Owner, “of the
10 non-ionic biological detergents listed on page 316 of the SIGMA catalog,
9 of them are alkyl glycosides.” Id. at 11 (citing Ex. 2012 ¶ 71). Patent
Owner also asserts that, of the non-ionic detergents listed on pages 316–321
of the Sigma catalog, alkyl glycosides “were prominently represented.” Id.
at 19 (citing Ex. 2012 ¶¶ 71–72).
Petitioner, with supporting testimony from Dr. Wermeling, responds
that “a POSA would not have understood that the ‘558 provisional was
providing a written description of alkyl glycosides.” Reply 5 (citing
Ex. 1150 ¶¶ 171–177). According to Petitioner, paragraphs 150–152 of the
’558 provisional generically refer to “absorption enhancers” and define the
term “enhancer” as “any material which acts to increase absorption across
the mucosa and/or increase bioavailability,” and describe 15 classes falling
within this broad “absorption enhancer” class. Id. (citing Ex. 1150 ¶¶ 171,
172). Petitioner also contends that “the recited ‘enhancers’ can include
mucolytic agents, degradative enzyme inhibitors, ‘compounds which
increase permeability of the mucosal cell membranes’ [150], only
identifying lysophospholipids and acyl carnitines as preferred candidates
[151].” Id. at 5–6 (citing Ex. 1150 ¶¶ 171–173). According to Petitioner,
paragraph 152 also identifies six additional “enhancer” classes: (i) chelating
agents, (ii) surface active agents (especially non-ionic materials), (iii) acyl
glycerols, (iv) fatty acids and salts, (v) tyloxapol and (vi) the biological
detergents listed on six pages of the SIGMA catalog. Id. at 6 (citing
Ex. 1150 ¶ 172; Ex. 2006).
IPR2019-00451
Patent 9,763,876 B2
17
Petitioner further asserts that there are approximately 150 different
compounds on the cited SIGMA catalog pages divided among four discrete
sub-classes: (i) anionic, (ii) cationic, (iii) zwitterionic (amphoteric) and
(iv) nonionic (polar). Reply 6 (citing Ex. 2006, 316–321). According to
Petitioner and Dr. Wermeling, “[w]ithin the ‘non-ionic’ biological detergent
sub-class are (i) about a dozen alkyl glycoside species and (ii) over eighty
non-alkyl glycoside species.” Id. (citing Ex. 1150 ¶ 175). Petitioner and
Dr. Wermeling further contend that “[t]he ‘558 provisional provides
absolutely no information regarding alkyl glycosides, apart from generally
listing them among approximately 150 other biological detergents appearing
in the SIGMA catalog.” Id. (citing Ex. 1150 ¶¶ 175–177). Petitioner and
Dr. Wermeling conclude:
In fact, nothing in the ‘558 provisional would reasonably lead a
POSA to any particular sub-class, let alone specific species
(compounds) identified in the SIGMA catalog, nor does the
‘558 provisional suggest that alkyl glycosides might be of
special interest, or be significant to the claims. Rather, the ‘558
Provisional directs the POSA to lysophospholipids and acyl
carnitines; all other enhancers being in a “kitchen sink” listing.
Id. at 6–7 (citing Ex. 1150 ¶ 176).
1. Analysis of Priority
“[T]he hallmark of written description is disclosure,” and “the test [for
satisfaction of the written description requirement] requires an objective
inquiry into the four corners of the specification from the perspective of a
person of ordinary skill in the art.” Ariad Pharms., Inc. v. Eli Lilly & Co.,
598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). The written description
“must ‘clearly allow persons of ordinary skill in the art to recognize that [the
inventor] invented what is claimed,’” and “reasonably” convey to those
IPR2019-00451
Patent 9,763,876 B2
18
skilled in the art “that the inventor had possession of the claimed subject
matter as of the filing date.” Id. (alteration in original, internal citations
omitted). Stated another way, “one skilled in the art, reading the original
disclosure, must immediately discern the limitation at issue in the claims.”
Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1323 (Fed. Cir.
2000). “Whether a claim satisfies the written description requirement is a
question of fact.” Nalpropion Pharms., Inc. v. Actavis Labs. Fl, Inc., 934
F.3d 1344, 1348 (Fed. Cir. 2019) (citing Ariad, 598 F.3d at 1351).
Furthermore, as the Board explained in Polaris Wireless, Inc. v.
TruePosition, Inc., IPR2013-00323, Paper 9 (PTAB Nov. 15, 2013), there is
no presumption of earlier priority where the specifications of the earlier
applications are not the same. See id. at 29; Power Oasis, Inc. v. T-Mobile
USA, Inc., 522 F.3d 1299, 1305 (Fed. Cir. 2008). Patent Owner does not
dispute that the specification of the ’876 patent differs from the specification
of the ’558 provisional.
When faced with a prior art challenge to a claim, the burden of
production—alternatively called the burden of going forward—is on the
Patent Owner to show that the claim is entitled to a filing date prior to the
date of the alleged prior art. See Tech. Licensing Corp. v. Videotek, Inc., 545
F.3d 1316, 1327 (Fed. Cir. 2008). Thus, “Patent Owner must come forward
with evidence and argument . . . showing why the challenged claim is
supported by the written description of the priority application.” Nintendo of
Am. Inc. v. iLife Techs., IPR2015-00106, Paper 12 at 16 (PTAB Apr. 29,
2015). After considering all the cited evidence of record on this priority
issue, we find that the evidence favors Petitioner’s position. As explained
IPR2019-00451
Patent 9,763,876 B2
19
below, we find that the challenged claims are not sufficiently supported by
the written description of the ’558 provisional.
We do not find that the ’558 provisional’s incorporation by reference
to six pages of the SIGMA catalog, which includes about 12 alkyl glycosides
in a list of about 150 biological detergents, is sufficient to provide written
description support for the claims.7 See Ex. 2006; Ex. 1150 ¶ 175.
Furthermore, the listing of biological detergents in the SIGMA catalog is
just a subset of the numerous possible “enhancing agents” that are discussed
in the ’558 provisional. See Ex. 1008 ¶¶ 150–152; Ex. 1150 ¶¶ 171–177.
There is nothing in the disclosure of the ’558 provisional that directs one of
skill in the art to the relatively small number of alkyl glycosides disclosed in
the SIGMA catalog. See Ex. 1150 ¶ 176; Purdue Pharma, 230 F.3d at
1326-27 (“[O]ne cannot disclose a forest in the original application and then
later pick a tree out of the forest and say here is my invention. In order to
satisfy the written description requirement, the blaze marks directing the
skilled artisan to that tree must be in the originally filed disclosure.”);
Fujikawa v. Wattanasin, 93 F.3d 1559, 1571 (Fed. Cir. 1996) (“In the
absence of such blazemarks, simply describing a large genus of compounds

7 In our Decision on Institution, we found that reliance on the SIGMA
catalog as adequate support for the “alkyl glycoside” limitation recited in the
claims was an improper incorporation by reference of essential material
under 37 C.F.R. § 1.57(d) (“Rule 57”). Inst. Dec. 9–10. Patent Owner
challenges the propriety of applying Rule 57 in this context. See, e.g., PO
Resp. 21–23. For purposes of this Decision, we do not need to decide the
Rule 57 issue because, even assuming the material in the SIGMA catalog
was properly incorporated by reference, we find that this disclosure is not
sufficient to provide written description support for the “alkyl glycoside”
limitation in the claims.
IPR2019-00451
Patent 9,763,876 B2
20
is not sufficient to satisfy the written description requirement as to particular
species or subgenuses.”).
Patent Owner asserts that a POSA would have understood that “in the
context of pharmaceutical formulations, biological detergents would have
been limited to detergents appropriate for administering to the nasal cavity,”
which would have been non-ionic detergents. PO Resp. 11 n.5 (citing
Ex. 2012 ¶ 70). However, nothing in the ’558 provisional’s disclosure
restricts the “biological detergents” listed in the SIGMA catalog to non-ionic
detergents and, furthermore, the ’558 provisional lists ionic and non-ionic
enhancing agents so there is no disclosure directing a POSA to use only non-
ionic detergents.8 Reply 7–8 (citing Ex. 1150 ¶ 175, n.5, 6). See Ariad, 598
F.3d 1336 at 1352 (“A description that merely renders the invention obvious
does not satisfy” the written description requirement.); see Lockwood v. Am.
Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (“It is not sufficient for
purposes of the written description requirement of § 112 that the disclosure,
when combined with the knowledge in the art, would lead one to speculate
as to the modifications that the inventor might have envisioned, but failed to
disclose.”).
Patent Owner argues that Petitioner never met its burden to establish a
facially reasonable likelihood of unpatentability because they did not address
the incorporation by reference to the SIGMA catalog in the Petition and,
therefore, this inter partes review should be terminated. See PO Resp. 18–

8 Even if the SIGMA catalog’s disclosure was limited to only the non-ionic
compounds listed therein, according to Dr. Wermeling, this list would still
include over 100 compounds with no guidance in choosing the alkyl
glycosides over other non-ionic compounds. See Ex. 1150 ¶ 176.
IPR2019-00451
Patent 9,763,876 B2
21
21. This argument is unavailing. Petitioner clearly challenged the ’876
patent priority claim in contending that “the presence of any alkyl glycosides
(either generally or particularly) – regardless of amount – was not disclosed,
described, or enabled by [the] ’558 Provisional.” Pet. 20. Furthermore, with
supporting testimony from Dr. Peppas, Petitioner further asserted that the
’558 provisional’s “generic disclosure of ‘surface active agents (especially
non-ionic materials)’ . . . does not disclose, describe, and/or enable alkyl
glycosides…” Id. (citing Ex. 1008 ¶ 152; Ex. 1041 ¶ 68). We do not agree
that Petitioner’s failure to specifically address the ’558 provisional’s
incorporation by reference to the SIGMA catalog results in a failure to
establish a reasonable likelihood of unpatentability. Petitioner’s assertion,
with supporting testimony from Dr. Peppas, that the ’558 provisional failed
to describe or enable alkyl glycosides was sufficient, in our view, to provide
a reasonable likelihood of prevailing with respect to at least one of the
challenged claims.9
As discussed above, although the petitioner has the ultimate burden of
persuasion to prove unpatentability, a patent owner must demonstrate
entitlement to a priority date when the patent owner relies on that priority
date to overcome an anticipation or obviousness argument. See Dynamic
Drinkware, 800 F.3d at 1379–80 (discussing burdens in inter partes review
to show entitlement to provisional filing dates and relying on infringement
cases involving continuation-in-part applications); In re NTP, Inc., 654 F.3d

9 Petitioner’s argument and evidence challenging the priority claim of the
’876 patent in the Petition was, at minimum, sufficient to meet a threshold
burden of proceeding, requiring Patent Owner to produce argument and
evidence to the contrary, which it had an opportunity to do during trial. See
Dynamic Drinkware, 800 F.3d at 1379–80.
IPR2019-00451
Patent 9,763,876 B2
22
1268, 1276 (Fed. Cir. 2011) (“[A] patent’s claims are not entitled to an
earlier priority date because the patentee claims priority. Rather, for a
patent’s claims to be entitled to an earlier priority date, the patentee must
demonstrate that the claims meet the requirements of 35 U.S.C. § 120.”
(citations omitted)); Research Corp. Techs., Inc. v. Microsoft Corp., 627
F.3d 859, 870–71 (Fed. Cir. 2010); Tech. Licensing, 545 F.3d at 1327–29;
Power Oasis, 522 F.3d at 1305–06.
As explained in Dynamic Drinkware, a petitioner has the initial
burden of going forward to show that there is invalidating prior art.
Dynamic Drinkware, 800 F.3d at 1379. As discussed above, Petitioner
satisfied its initial burden of production on the issue of whether Gwozdz is
prior art by establishing that Gwozdz is entitled to the effective filing date of
the Gwozdz provisional. Therefore, Gwozdz is prior art to the ’876 patent
under 35 U.S.C. § 102(e)(1) unless Patent Owner can show that the ’876
patent is entitled to the effective filing date of the ’558 provisional. As
discussed above, Petitioner also presented arguments as to why the “alkyl
glycoside” limitation was not sufficiently described or enabled in the ’558
provisional application. Thus, the burden of production shifts to Patent
Owner, who must show not only the existence of earlier applications, but
also how the written description in the earlier applications supports the
challenged claims. Dynamic Drinkware, 800 F.3d at 1379–80. “[T]o gain
the benefit of the filing date of an earlier application under 35 U.S.C. § 120,
each application in the chain leading back to the earlier application must
comply with the written description requirement of 35 U.S.C. § 112.” Zenon
Envtl., Inc. v. U.S. Filter Corp., 506 F.3d 1370, 1378 (Fed. Cir. 2007)
(quoting Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1571 (Fed. Cir.
IPR2019-00451
Patent 9,763,876 B2
23
1997)); see also In re Hogan, 559 F.2d 595, 609 (CCPA 1977) (“[T]here has
to be a continuous chain of copending applications each of which satisfies
the requirements of § 112 with respect to the subject matter presently
claimed.” (alteration in original) (quoting In re Schneider, 481 F.2d 1350,
1356 (CCPA 1973))).
In view of the above, and after reviewing all of the evidence, we find
that the ’558 provisional does not provide adequate written description
support for the “alkyl glycoside” limitation. Therefore, the claims of the
’876 patent are not entitled to the benefit of priority to the ’558 provisional.
Accordingly, we determine that Gwozdz and Cartt ’784 are § 102(e)(1) prior
art to the claims of the ’876 patent.
E. Obviousness of Claims 1–16 and 24–36 over Gwozdz and Meezan
’962
Petitioner contends that the subject matter of claims 1–16 and 24–36
of the ’876 patent would have been obvious over the combined disclosures
of Gwozdz and Meezan ’962. Pet. 23–86. Patent Owner opposes. PO Resp.
23–38; PO Sur-Reply 12–18. Having considered the totality of the
arguments and evidence, we find that Petitioner has shown by a
preponderance of the evidence that claims 1–16 and 24–36 are unpatentable
as having been obvious over Gwozdz and Meezan ’962.
1. Gwozdz
Gwozdz is directed to the use of tocopherols and/or tocotrienols and
one or more alcohols and/or glycols as pharmaceutically acceptable solvents
for solubilizing hydrophobic or lipophilic therapeutic agents, in order to
provide increased bioavailability. Ex. 1014, 4:29–33, 7:3–8. Such
therapeutic agents include benzodiazepines, including diazepam. Id. at 8:6–
IPR2019-00451
Patent 9,763,876 B2
24
10. Specifically, Gwozdz discloses a “pharmaceutical solution comprising a
therapeutic agent dissolved in one or more natural or synthetic tocopherols
or tocotrienols, or any combination thereof and one or more alcohols or
glycols, or any combinations thereof.” Id. at 4:14–17.
Gwozdz teaches that the combination of a tocopherol and an alcohol
“is much less irritating to the skin and/or mucous membranes than pure
alcohol solutions and generally provides higher loading of a therapeutic
agent than emulsions, liposomes, encapsulations, or cyclodextrins.”
Ex. 1014, 5:2–7. Gwozdz also recognizes that “diluting a tocopherol or
tocotrienol with an alcohol or glycol dramatically reduces the inherent
viscosity of the tocopherol or tocotrienol thereby allowing for generation of
sprayable formulations.” Id. at 6:29–7:2. Gwozdz further discloses methods
of treatment with these pharmaceutical solutions, including via intranasal
administration, and states that such solutions are “particularly useful in
formulations to be administered to mucosal membranes, i.e. the nasal
mucosa.” Id. at 4:24–27, 9:2–8, 9:19–21.
Examples of alcohols for use in the compositions disclosed in Gwozdz
include “ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol,
and any isomers thereof, and any combination thereof.” Ex. 1014, 6:16–19.
Gwozdz discloses that, “[i]n some embodiments, the tocopherol(s) and/or
tocotrienol(s) is in an amount from about 30% to about 99% (w/w) and the
alcohol(s) and/or glycol(s) is in an amount from about 1% to about 70%
(w/w).” Id. at 4:17–21. Gwozdz also discloses that ethanol can constitute
1% to 40% or 10% to 30% of the pharmaceutical solution and that the
tocopherol and ethanol can be used in ratios of approximately 95:5, 90:10,
85:15, 80:20, 75:25, 70:30, 65:35, or 60:40, respectively. Id. at 7:20–28.
IPR2019-00451
Patent 9,763,876 B2
25
2. Meezan ’962
Meezan ’962 discloses using an alkyl glycoside and/or saccharide
alkyl ester to improve the bioavailability of drug molecules. Ex. 1011 ¶ 4.
According to Meezan ’962, the compositions of the invention can be used
with “small molecule organic drug molecules” and can be delivered nasally.
Id. The active drug used in its formulations can include many different
types of active ingredients, including anti-seizure agents. Id. ¶¶ 52, 136.
3. Limitations of Independent Claim 1
Petitioner contends that the combination of Gwozdz and Meezan ’962
discloses or suggests each element of claim 1. Pet. 37–41. Petitioner
presents arguments mapping the language of claim 1 to the disclosures of
each reference. Pet. 37–41, 65–69; Ex. 1041, 225–229. We have reviewed
Petitioner’s arguments and, for the reasons articulated below, find that a
preponderance of the evidence supports Petitioner’s contentions.
a. Claim 1
Claim 1 recites “[a] method of treating a patient with a disorder which
is treatable with a benzodiazepine drug, comprising: administering to one or
more nasal mucosal membranes of a patient a pharmaceutical solution for
nasal administration consisting of a benzodiazepine drug.” Ex. 1001, 63:26–
30. Petitioner presents evidence that Gwozdz teaches methods of treating a
patient with pharmaceutical solutions, which may be administered
intranasally, and can include benzodiazepines. Pet. 37, 65–66 (citing
Ex. 1014, 4:24–26, 8:6–13, 9:19–21).
Claim 1 also recites “one or more natural or synthetic tocopherols or
tocotrienols, or any combinations thereof, in an amount from about 30% to
about 95% (w/w).” Ex. 1001, 63:30–32. Petitioner presents evidence that
IPR2019-00451
Patent 9,763,876 B2
26
Gwozdz teaches the use of tocopherols or tocotrienols in amounts of about
30–99%. Pet. 38–39, 67 (citing Ex. 1014, 4:18–19, 5:12–14, 7:8–10). The
percentage range for tocopherols/tocotrienols disclosed by Gwozdz (about
30–99%) significantly overlaps with the claimed range of about 30–95%.
Furthermore, Petitioner contends that Patent Owner never demonstrated any
criticality with respect to the amount of tocopherols. Id. at 39–40. Patent
Owner has not argued, nor do we find that Patent Owner has established,
that a range of about 30% to about 95% (w/w) of tocopherols/tocotrienols
achieves unexpected results. See E.I. du Pont, 904 F.3d at 1006 (explaining
that prior art ranges that overlap with a claimed range create “a presumption
of obviousness,” which may be rebutted if the patentee comes forward with
evidence showing, inter alia, that the claimed invention achieves unexpected
results).
Claim 1 also recites “ethanol and benzyl alcohol in a combined
amount from about 10% to about 70% (w/w).” Ex. 1001, 63:33–34.
Petitioner and Dr. Peppas present evidence that Gwozdz teaches the use of
ethanol, benzyl alcohol, and combinations thereof10 wherein “[t]he alcohol
(or combinations of alcohols) may be present in amounts of about 1-70%”
and “[e]thanol may be present in amounts of 1-40% or 10-30%.” Pet. 40, 68
(citing Ex. 1014, 4:19–21, 7:10–11, 7:20–24). Therefore, the range of

10 Dr. Peppas testifies that the combination of ethanol and benzyl alcohol
was also used (along with other ingredients) in diazepam formulations such
as the rectal gel Diastat and the injectable solution Valium. See Ex. 1041
¶ 133 (citing Ex. 1042, 2, 10). Dr. Peppas also cites to other prior art
references discussing the preference for using a drug solvent system
containing benzyl alcohol and ethanol. See id. ¶¶ 134, 135 (citing Ex. 1018,
3:52–54, 4:7–23; Ex. 1019, 3:65–4:1, 5:5–7, 5:64–6:51).
IPR2019-00451
Patent 9,763,876 B2
27
combined alcohol in Gwozdz overlaps with the claimed range. Furthermore,
Petitioner contends that Patent Owner never demonstrated any criticality
with respect to the amount of alcohol(s). Id. Patent Owner has not argued,
nor do we find that Patent Owner has established, that a range of ethanol and
benzyl alcohol in a combined amount from about 10% to about 70% (w/w)
achieves unexpected results. See E.I. du Pont, 904 F.3d. at 1006.
Claim 1 also recites “an alkyl glycoside.” Ex. 1001, 63:34. Petitioner
presents evidence that Meezan ’962 discloses the use of alkyl glycosides in
pharmaceutical solutions, including nasal sprays. Pet. 41, 69 (citing
Ex. 1011 ¶¶ 4, 8, 12–13, 63, 70, 73).
We determine that Petitioner has shown, by a preponderance of the
evidence, that the combination of Gwozdz and Meezan ’962 teaches or
suggests each and every limitation of claim 1.
4. Limitations of Dependent claims 2–16 and 24–36
Having decided that the combination of Gwozdz and Meezan ’962
teaches or suggests each and every limitation of claim 1, we turn to claims
2–16 and 24–36 of the ’876 patent, which all depend, directly or indirectly,
from claim 1. As discussed below, we find that Petitioner also shows by a
preponderance of the evidence that Gwozdz and Meezan ’962 account for
the limitations in these claims. See Pet. 41–63; 69–86. We have also
reviewed Dr. Peppas’ testimony and find that a preponderance of the
evidence supports his opinion that the cited references collectively disclose
or suggest each and every limitation of claims 2–16 and 24–36. See Ex.
1041, 229–247.
Patent Owner does not present separate arguments for any of the
dependent claims. See generally PO Resp. 23–38.
IPR2019-00451
Patent 9,763,876 B2
28
a. Claim 2
Claim 2 depends from claim 1 and further requires that “the natural or
synthetic tocopherols or tocotrienols is Vitamin E.” Ex. 1001, 63:35–36.
Petitioner, with supporting testimony from Dr. Peppas, presents evidence
that Gwozdz discloses vitamin E. Pet. 41, 69 (citing Ex. 1014, 6:1–2;
Ex. 1041 ¶ 373).
b. Claims 3–4
Claim 3 depends from claim 1 and further requires that “the
benzodiazepine drug is selected from the group consisting of” twenty-two
different benzodiazepines, including diazepam “or any pharmaceutically-
acceptable salts thereof, and any combinations thereof.” Ex. 1001, 63:37–
44. Claim 4 depends from claim 3 and specifies that the benzodiazepine
drug is diazepam (or salt thereof). Id. at 63:45–47. Petitioner, with
supporting testimony from Dr. Peppas, presents evidence that Gwozdz
discloses the use of benzodiazepines such as diazepam as well as ten other
benzodiazepines that are recited in claim 3. Pet. 42, 69–70 (citing Ex. 1014,
8:9–13; Ex. 1041 ¶ 376).
c. Claims 5–6
Claim 5 depends from claim 1 and further requires that “the solution
contains about 1 to about 20% (w/v) of benzodiazepine.” Ex. 1001, 63:48–
49. Claim 6 depends from claim 5 and requires that the benzodiazepine is
diazepam. Id. at 63:50–51. Petitioner, with supporting testimony from
Dr. Peppas, presents evidence that Gwozdz teaches “that it is possible to
make diazepam solutions of 6.67% (in ethanol); in combinations of
tocopherol and alcohol (ethanol), it is possible to make diazepam solutions
of ‘greater than or equal to 8%’, ‘greater than or equal to 9%’, and
IPR2019-00451
Patent 9,763,876 B2
29
‘approaching the 10% level.’” Pet. 43, 70–71 (citing Ex. 1014, 7:12–19;
Ex. 1041 ¶ 379).
d. Claim 7
Claim 7 depends from claim 1 and requires that the one or more
tocopherols or tocotrienols are selected from a group of nine different
tocopherols or tocotrienols, including α-tocopherol, β-tocopherol, γ-
tocopherol, and δ-tocopherol, or any isomers thereof, any esters thereof, any
analogs or derivatives thereof, or any combinations thereof. Ex. 1001,
63:52–58. Petitioner, with supporting testimony from Dr. Peppas, presents
evidence that Gwozdz teaches use of α-tocopherol, β-, γ-, and δ-tocopherol,
as well as isomers thereof and esters thereof. Pet. 43–44, 71 (citing
Ex. 1014, 6:2–13; Ex. 1041 ¶ 382).
e. Claims 8 and 15
Claim 8 depends from claim 1 and requires that “the solution contains
ethanol from 1 to 25% (w/v) and benzyl alcohol from 1 to 25% (w/v).”
Ex. 1001, 63:59–61. Claim 15 depends from claim 1 and requires that “the
solution comprises ethanol from 10 to 22.5% (w/v) and benzyl alcohol from
7.5 to 12.5% (w/v).” Ex. 1001, 64:15–17.
Petitioner contends that Gwozdz teaches that the alcohols can be
ethanol, benzyl alcohol, and combinations thereof, and that the total
alcoholic content can be about 1–70%, of which ethanol can be 1–40%, or
10–30%. Pet. 44 (citing Ex. 1014, 4:19–21, 6:16–19, 7:10–11, 7:20–24).
Petitioner further asserts that Patent Owner “never demonstrated any
criticality to the amount(s) or types of alcohol(s)” and, therefore, “lacking
criticality, [one of ordinary skill in the art] would easily and routinely
experiment with various amounts of ethanol between 10-30%, combined
IPR2019-00451
Patent 9,763,876 B2
30
with benzyl alcohol making up the remainder of the total of 1-70% alcohol
(i.e., 1-40%).” Id. at 44–45. Petitioner contends that these values overlap
with or encompass the amounts recited in claims 8 and 15, and, therefore,
render the claims obvious. Id. at 45.
In our Institution Decision, we expressed skepticism that Petitioner
had demonstrated the absence of any unexpected results in using a solution
with 1 to 25% (w/v) ethanol and 1 to 25% (w/v) benzyl alcohol or 10 to
22.5% (w/v) ethanol and 7.5 to 12.5% (w/v) benzyl alcohol based on
arguments made during prosecution of a counterpart European application.
See Inst. Dec. 18–19. In response, Petitioner argues, with supporting
testimony from Dr. Wermeling, that the data relied on by the European
Patent Office (“EPO”) does not support unexpected results or criticality
because there were no tests done inside or outside the recited ranges to test
for criticality or unexpected results and the comparison between a solution
and a suspension is improper. Reply 24 (citing Ex. 1150 ¶¶ 178–207). We
find Petitioner’s argument and Dr. Wermeling’s testimony persuasive on this
issue. Patent Owner has not argued in this proceeding, nor do we find that
Patent Owner has established, that a solution with 1 to 25% (w/v) ethanol
and 1 to 25% (w/v) benzyl alcohol or 10 to 22.5% (w/v) ethanol and 7.5 to
12.5% (w/v) benzyl alcohol achieves unexpected results. See E.I. du Pont,
904 F.3d. at 1006.
In view of the foregoing, we find that Petitioner has sufficiently
shown that there is no persuasive evidence of unexpected results or
criticality for the claimed ranges.
IPR2019-00451
Patent 9,763,876 B2
31
f. Claims 9–10
Claim 9 depends from claim 8 and requires that the “benzodiazepine
drug is present in the pharmaceutical solution in a concentration from about
10 mg/mL to about 250 mg/mL.” Ex. 1001, 63:62–64. Claim 10 depends
from claim 9 and requires that the benzodiazepine drug concentration is
“from about 20 mg/mL to about 50 mg/mL.” Id. at 63:65–67. Petitioner,
with supporting testimony from Dr. Peppas, asserts that these ranges are
equivalent to about 1–25% (w/v) and about 2–5% (w/v), respectively. Pet.
46 (citing Ex. 1041 ¶¶ 210, 387–388).
Petitioner presents evidence that Gwozdz teaches “that it is possible to
make diazepam solutions of ‘greater than or equal to 8%’, ‘greater than or
equal to 9%’, and ‘approaching the 10% level’ in tocopherol/alcohol
combinations.” Pet. 46, 73 (citing Ex. 1014, 7:14–19). Petitioner, with
supporting testimony from Dr. Peppas, further contends that one of ordinary
skill in the art “could easily reduce the percentage of dissolved diazepam
simply by including less diazepam in the formulation.” Id. (citing Ex. 1041
¶¶ 390–391).
g. Claims 11–12
Claim 11 depends from claim 1 and requires that “the one or more
natural or synthetic tocopherols . . . is in an amount from about 45% to about
85% (w/w).” Ex. 1001, 64:1–4. Claim 12 depends from claim 11 and
requires that the amount is “from about 60% to about 75% (w/w).” Id. at
64:5–8.
Petitioner presents evidence that “Gwozdz teaches that tocopherols
may be present in amounts of about 30-99%. Alpha-tocopherol may be
present in amounts of 60-99% or 70-90%.” Pet. 47 (citing Ex. 1014, 4:17–
IPR2019-00451
Patent 9,763,876 B2
32
19, 7:8–10, 7:20–25; Ex. 1041 ¶ 395). The tocopherol percentage ranges
disclosed by Gwozdz overlap with the claimed ranges. Furthermore,
Petitioner contends that Patent Owner never demonstrated any criticality to
the amounts of tocopherols. Id. Patent Owner has not argued, nor do we
find that Patent Owner has established, that a tocopherol range of from about
45% to about 85% (w/w) or from about 60% to about 75% (w/w) achieves
unexpected results. See E.I. du Pont, 904 F.3d. at 1006.
h. Claims 13–14
Claim 13 depends from claim 1 and requires that “the ethanol and
benzyl alcohol is in a combined amount from about 15% to about 55%
(w/w).” Ex. 1001, 64:9–11. Claim 14 depends from claim 13 and requires
“a combined amount from about 25% to about 40% (w/w).” Id. at 64:12–14.
Petitioner presents evidence that “Gwozdz teaches that the alcohols can be
ethanol, benzyl alcohol, and combinations thereof” and the “[t]otal alcoholic
content can be about 1-70%.” Pet. 47–48 (citing Ex. 1014, 4:19–21, 6:16–
19, 7:10–11).
The range of combined alcohol in Gwozdz fully encompasses the
claimed ranges. Furthermore, Petitioner contends that Patent Owner never
demonstrated any criticality with respect to the amount of alcohol(s). Pet.
48. Patent Owner does not argue, nor do we find after considering the
evidence of record, that a range of ethanol and benzyl alcohol in a combined
amount from about 15% to about 55% (w/w) or from about 25% to about
40% (w/w) achieves unexpected results. See E.I. du Pont, 904 F.3d. at 1006.
i. Claim 16
Claim 16 depends from claim 1 and requires that “the solution is in a
pharmaceutically-acceptable spray formulation.” Ex. 1001, 64:18–19.
IPR2019-00451
Patent 9,763,876 B2
33
Petitioner, with supporting testimony from Dr. Peppas, presents evidence
that Gwozdz teaches “that the combination of a tocopherol and an alcohol
can result in sprayable formulations.” Pet. 48–49, 75 (citing Ex. 1014, 6:29–
7:2; Ex. 1041 ¶ 401).
j. Claims 24–26
Claim 24 depends from claim 1 and requires that “the solution
contains at least about 0.01% (w/w) of an alkyl glycoside.” Ex. 1001,
64:50–51. Claim 25 depends from claim 24 and requires that “the solution
contains about 0.01% to 1% (w/w) of an alkyl glycoside.” Id. at 64:52–53.
Claim 26 depends from claim 25 and specifies that the alkyl glycoside is
dodecyl maltoside. Id. at 64:54–55. Petitioner presents evidence that
“Meezan ’962 teaches that alkyl glycosides are present in amounts of about
0.1-2%, about 0.01-1%, and most preferably about 0.01-0.125% by weight.”
Pet. 55, 76–77 (citing Ex. 1011 ¶ 70). Petitioner also argues that Meezan
’962 discloses dodecyl maltoside as “a preferred alkyl glycoside.” Id. at 55
(citing Ex. 1011 ¶¶ 56, 58, 61, 92, 155–158, Table 1).
k. Claims 27 and 29
Claim 27 depends from claim 1 and requires that “the solution
consists of diazepam, vitamin E, ethanol, benzyl alcohol and dodecyl
maltoside.” Ex. 1001, 64:56–58. Claim 29 also depends from claim 1 and
requires that “the solution consists of diazepam, alkyl glycoside, vitamin E,
ethanol, and benzyl alcohol.” Ex. 1001, 64:63–65. Petitioner, with
supporting testimony from Dr. Peppas, presents evidence that “Gwozdz
teaches dissolving diazepam in a combination of tocopherols (i.e., vitamin
E) and alcohols, including ethanol and benzyl alcohol.” Pet. 55–56, 77
(citing Ex. 6:16–19, 7:3–19; Ex. 1041 ¶ 422). Petitioner also contends that
IPR2019-00451
Patent 9,763,876 B2
34
Meezan ’962 discloses the use of an alkyl glycoside, e.g., dodecyl maltoside,
in the solution. Id. at 56 (citing Ex. 1011 ¶¶ 56, 58, 61, 92, 155–158,
Table I).
l. Claim 28
Claim 28 depends from claim 1 and requires that “the solution
consists of about 56.47% (w/v) vitamin E, about 10.5% (w/v) benzyl
alcohol, about 10% (w/v) diazepam, about 0.25% (w/v) dodecyl maltoside,
q.s. dehydrated ethanol.” Ex. 1001, 64:59–62. As pointed out by Petitioner,
this claim requires about 22.78% of ethanol. Pet. 56.
Petitioner presents evidence that Gwozdz teaches that tocopherols
may be present in amounts of about 30–99% and alpha-tocopherol may be
present in amounts of 60–99% and contends that Patent Owner never
demonstrated any criticality to the amount of tocopherols. Pet. 57, 78 (citing
Ex. 1014, 4:17–19, 7:8–10, 7:20–22). Petitioner also presents evidence that
Gwozdz teaches “that in combinations of tocopherol and alcohol (ethanol), it
is possible to make diazepam solutions ‘approaching the 10% level.’” Id. at
58, 79 (citing Ex. 1014, 7:12–19). Petitioner also presents evidence that
“Meezan ’962 teaches that 0.25% is a preferred amount of alkyl glycoside,”
“dodecyl maltoside is a specifically preferred alkyl glycoside,” and “0.25%
dodecyl maltoside is also specifically disclosed.” Id. (citing Ex. 1011 ¶¶ 56,
61, 150, 151, 158, 167, Table I, Fig. 1; Ex. 1041 ¶¶ 365–367).
With respect to the percentages of benzyl alcohol and ethanol required
by claim 28, Petitioner argues that Patent Owner never demonstrated any
criticality for the amounts or types of alcohols; therefore, “Gwozdz’s
disclosure of: (i) alcohols, including combinations of ethanol and benzyl
alcohol, and (ii) total alcoholic content of about 1-70%, and ethanol content
IPR2019-00451
Patent 9,763,876 B2
35
of 1-40% or 10-30%, renders obvious the alcohol amounts/combination
recited in Claim 28.” Pet. 57. For the reasons stated supra with regard to
claims 8–10 and 15, Petitioner’s assertion that Patent Owner never showed
any unexpected results with respect to the amount of ethanol and benzyl
alcohol is sufficiently supported by the evidence of record.
m. Claims 30–33
Claim 30 depends from claim 1 and requires that “the solution
consists of diazepam from 5 to 15% (w/v), dodecyl maltoside from about
0.01 to 1% (w/v), vitamin E from 45 to 65% (w/v), ethanol from 10 to 25%
(w/v) and benzyl alcohol from 5 to 15% (w/v).” Ex. 1001, 64:66–65:3.
Claim 31 depends from claim 1 and is similar to claim 30 but does not
include “about” with respect to dodecyl maltoside. Id. at 65:4–8. Claim 32
depends from Claim 1 and requires that “the solution consists of diazepam
from 9 to 11% (w/v), dodecyl maltoside from 0.1 to 0.5% (w/v), vitamin E
from 50 to 60% (w/v), ethanol from 15 to 22.5% (w/v) and benzyl alcohol
from 7.5 to 12.5% (w/v).” Id. at 65:9–13. Claim 33 depends from claim 1
and is similar to claim 32 but limits the amounts to: 10% diazepam, 0.15–
0.3% dodecyl maltoside, 50–60% vitamin E, 17–20% ethanol, and 10–12%
benzyl alcohol. Id. at 65:14–17.
In arguing the obviousness of these claims, Petitioner makes
arguments similar to those made for claim 28. See Pet. 59–61. For the
reasons stated supra with regard to claims 8–10, 15, and 28, Petitioner’s
assertion that Patent Owner never showed any unexpected results is
sufficiently supported by the evidence of record.
IPR2019-00451
Patent 9,763,876 B2
36
n. Claims 34–36
Claim 34 depends from claim 1 and requires “wherein said treatment
achieves bioavailability that is from about 80 to 125% of that achieved with
the same benzodiazepine administered intravenously.” Ex. 1001, 65:18–21.
Claim 35 depends from claim 34 and requires 90 to 110% bioavailability
and claims 36 depends from claim 35 and requires 92.5 to 107.5%
bioavailability. Id. at 65:22–29.
Petitioner contends that Gwozdz teaches that the combination of
tocopherols and alcohol(s) “increased bioavailability of the therapeutic
agent.” Pet. 61 (citing Ex. 1014, 7:3–8). Petitioner further contends that one
of ordinary skill in the art would readily understand how to determine
bioavailability and that it was known in the art that bioavailability levels of
about 100% should be targeted in order to obtain FDA approval. Id. at 61–
62 (citing Ex. 1023; Ex. 1044, 7). According to Petitioner, in order to
achieve such levels of bioavailability, one of ordinary skill in the art, aware
of Gwozdz, “would turn to Meezan ’962, which had successfully improved
the bioavailability of intranasally administered drugs.” Id. at 62.
Petitioner also contends, with supporting testimony from Dr. Peppas,
that one of ordinary skill in the art would have turned to Meezan ’962
because it “increased bioavailabilities of intranasally administered drugs
from 3% up to 98% with alkyl glycosides” and that one of ordinary skill in
the art “would be motivated to routinely experiment with a combination of
Gwozdz’s and Meezan ’962’s teachings to arrive at a desired bioavailability
approaching 100%.” Pet. 63 (citing Ex. 1041 ¶¶ 424–425, 428–430, 434).
Petitioner asserts that “[s]uch routine experimentation would be well within
IPR2019-00451
Patent 9,763,876 B2
37
the skill” of one of ordinary skill in the art. Id. (citing Ex. 1041 ¶¶ 424–425,
428–430, 434).
In our Decision on Institution, we expressed skepticism that Petitioner
sufficiently showed that a POSA would have reasonably expected to achieve
the bioavailabilities recited in claims 34–36. See Inst. Dec. 27–31. In
response, Petitioner and Dr. Wermeling assert that:
at least with respect to diazepam (which has oral bioavailability
of about 100%) – and due to the fact that there is always an oral
absorption phase during intranasal administration – a POSA
would have expected to achieve bioavailabilities approaching
100% (which falls within the ranges recited in Claims 34-36).
Reply 26–27 (citing Ex. 1150 ¶¶ 188–190).
Other than the general arguments regarding motivation to combine
and reasonable expectation of success discussed infra, Patent Owner does
not make any specific arguments regarding these claims.
In view of the foregoing, we find that Petitioner has sufficiently
shown that one of ordinary skill in the art would have reasonably expected
success in achieving the bioavailabilities recited in claims 34–36 of the ’876
patent based on the disclosures of Gwozdz and Meezan ’962.
In view of the above and the evidence of record, we determine that
Petitioner has shown, by a preponderance of the evidence, that the
combination of Gwozdz and Meezan ’962 teaches or suggests each and
every limitation of claims 2–16 and 24–36.
5. Motivation to combine/reasonable expectation of success
Even “[i]f all elements of the claims are found in a combination of
prior art references,” “the factfinder should further consider whether a
person of ordinary skill in the art would [have been] motivated to combine
those references, and whether in making that combination, a person of
IPR2019-00451
Patent 9,763,876 B2
38
ordinary skill would have [had] a reasonable expectation of success.” Merck
& Cie v. Gnosis S.P.A., 808 F.3d 829, 833 (Fed. Cir. 2015). The
“motivation to combine” and “reasonable expectation of success” factors are
subsidiary requirements for obviousness subsumed within the Graham
factors. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007).
We address motivation to combine and reasonable expectation of success in
turn below.
a) Motivation to combine
Petitioner, with supporting testimony from Dr. Peppas, asserts that a
person of ordinary skill in the art would have had reason to combine the
teachings of Gwozdz and Meezan ’962. Pet. 33–34 (citing Ex. 1041 ¶¶ 193–
194, 225–226, 257–260, 364, 424). Petitioner contends that “Gwozdz
relates to solving generally-recognized problems associated with, inter alia,
intranasal administration of low-solubility drugs” and was “directed to using
solvents to increase the dissolved drug percentage.” Id. at 33 (citing
Ex. 1014, 4:29–33, 9:22–28; Ex. 1041 ¶¶ 193–194). According to
Petitioner, one of ordinary skill in the art, “seeking to optimize and improve
upon Gwozdz would be motivated to modify Gwozdz with the teachings of
another reference that solved the same general problems.” Id. Petitioner
contends that a POSA “would be motivated to look to Meezan ’962”
because it is “similarly directed to solving generally-recognized problems
associated with, e.g., intranasal administration of drugs” and it recognized
the utility of including solvents. Id. (citing Ex. 1011 ¶¶ 2–3, 74, 146;
Ex. 1041 ¶¶ 225–226).
According to Petitioner, Meezan ’962 solves the intranasal drug
administration problems differently than Gwozdz in that “Meezan ’962
IPR2019-00451
Patent 9,763,876 B2
39
recognized that alkyl glycosides ‘stabilize[] the biological activity and
increase[] the bioavailability of the drug’” and, therefore, “solved the known
problems by increasing the drug amount available to the body, instead of
increasing the % of drug that was dissolved and administered.” Pet. 33–34
(citing Ex. 1011 ¶ 5; Ex. 1041 ¶ 226). Petitioner concludes that “a POSITA
would seek to combine the teachings of the references in an effort to
successfully increase the bioavailable amount of drug.” Id. at 34 (citing
Ex. 1041 ¶¶ 257–260, 364, 424).
Patent Owner asserts that Petitioner has failed to demonstrate a
motivation to combine the disclosure of Gwozdz with Meezan ’962. See PO
Resp. 27–29, 35–38. Patent Owner and Dr. Gizurarson assert that a POSA
would not look to both (1) increase drug solubility and (2) use penetration
enhancers to increase the permeability of the nasal mucosa in order to
increase the permeation problems associated with intranasal administration.
Id. at 27–28 (citing Ex. 1041 ¶¶ 121–168; Ex. 2012 ¶ 79). Patent Owner
contends that “a POSA would not recognize the solutions as necessarily
compatible and instead would look to pursue one or the other.” Id. (citing
Ex. 2012 ¶ 79).
On this point, we credit the testimony of Dr. Peppas discussed supra
and are not persuaded that a person of ordinary skill in the art would have
been deterred from looking to both increase drug solubility and use
penetration enhancers as ways to overcome problems associated with
intranasal administration of low-solubility drugs. Dr. Gizurarson provides
no reason or evidence as to why these two solutions would be mutually
exclusive. Furthermore, as pointed out by Petitioner, a patent application on
which Dr. Gizurarson is named as an inventor, discusses the use of alkoxy-
IPR2019-00451
Patent 9,763,876 B2
40
polethylene glycol as a solubilizer for poorly soluble therapeutic agents and
also discloses adding additional compounds such as ethanol and benzyl
alcohol to enhance solubility as well as adding surfactants, i.e., enhancing
agents. Reply 13–14 (citing Ex. 1070 ¶¶ 17, 60–62). Patent Owner asserts
that Dr. Gizurarson testified that the components disclosed in the patent
application “were chosen based on the targeted mucosal route.” PO Sur-
Reply 15. We are not persuaded by this argument because the patent
application lists intranasal administration as a type of mucosal
administration and Dr. Gizurarson testified that the disclosure does not
exclude intranasal administration in its discussion of using solubilizers such
as alcohols with enhancing agents. See Ex. 1070 ¶¶ 4, 60–62; Ex. 1149,
115:1–117:19.
Patent Owner also contends that Gwozdz provides no motivation to
modify its disclosed formulations. PO Resp. 28. Specifically, Patent Owner
asserts that Gwozdz dealt with the issue of bioavailability of
benzodiazepines for intranasal administration by focusing on solubility and
“left no room for modification in its precipitation sensitive formulations.”
Id. (citing Pet. 28; Ex. 1041 ¶ 194). In support of its arguments, Patent
Owner cites to the following disclosure from Gwozdz:
. . . the solubility of Diazepam at room temperature is less than
or equal to 6.67% in 190 proof ethanol. However, combining
tocopherol and ethanol has been found to provide solubility of
the Diazepam approaching the 10% level. By way of
illustration, at 70% tocopherol:30% ethanol (200 proof),
Diazepam is soluble to greater than or equal to 8% and at 95%
tocopherol:5% ethanol (200 proof), Diazepam is soluble at
greater than or equal to 9%.
Id. at 29 (citing Ex. 1014, 7).
Based on this disclosure, Patent Owner asserts:
IPR2019-00451
Patent 9,763,876 B2
41
A POSA, knowing that Gwozdz’s solubility level for diazepam
is close to the same amount as the clinical dose needed for
therapeutic effect (10 mg), and combined with the above
statement, would understand that increasing the amount of
tocopherol and decreasing the amount of ethanol increases the
solubility and approaches diazepam’s saturation concentration.
PO Resp. at 29 (citing Ex. 2012 ¶ 83). According to Patent Owner, this
brings the formulation of Gwozdz close to risk of precipitation in the humid
nasal cavity and “a POSA would learn from the teachings of Gwozdz that
adding less tocopherol reduces the solubility of diazepam.” Id. (citing
Ex. 2012 ¶¶ 65, 82–83).
Patent Owner contends that “a POSA would have no motivation – and
instead would be turned away from – adjusting the formulation any further
(let alone adding any additional excipient such as benzyl alcohol or an alkyl
glycoside to the mix).” PO Resp. 29–30 (citing Ex. 2012 ¶¶ 80–85).
According to Patent Owner:
A POSA would understand that doing so would potentially take
away from the amount of either or both of the tocopherol and
ethanol and, in turn, decrease the solubility of diazepam – i.e.,
he would not sacrifice drug solubility by removing or reducing
a co-solvent necessary for maximizing solubility of the
benzodiazepine drug.
Id.
On this point, we credit the testimony of Dr. Peppas and
Dr. Wermeling that a person of ordinary skill in the art would have been
motivated to use tocopherol along with a combination of alcohols such as
ethanol and benzyl alcohol, as disclosed in Gwozdz. See Ex. 1041 ¶¶ 103
n.9, 131–136, 192–203, 363; Ex. 1150 ¶¶ 129–156. We are not persuaded
that a POSA would have been deterred based on a single specific example in
Gwozdz cited by Patent Owner. In fact, the example discussed by Patent
IPR2019-00451
Patent 9,763,876 B2
42
Owner is described as a “non-limiting example” and Gwozdz also discloses
the use of tocopherol with combinations of different alcohols including
ethanol and benzyl alcohol. See Ex. 1014, 4, 6, 7; Ex. 1150 ¶¶ 129–142.
Furthermore, as Dr. Wermeling testified, a “POSA would have recognized
that the addition of benzyl alcohol to a tocopherol+ethanol co-solvent
system – as suggested by Gwozdz – would result in a ternary co-solvent
system with different solubility characteristics” and a POSA “would adjust
the amounts of the three solvents to maximize solubility of the drug.” Ex.
1150 ¶ 139.
Dr. Wermeling concludes:
Indeed, a POSA would have been very motivated to routinely
experiment with a ternary system, which would inherently
require that at least one of the two co-solvents in the binary
system be reduced in order to make room for the third co-
solvent (i.e., to create the ternary system). Combining and
adjusting three solvents to maximize solubility of any water-
insoluble drug (such as diazepam) is a simple, well-known, and
routine technique that a POSA could (and would) easily do
when directed (as by Gwozdz) to use three solvents (especially
when the three solvents are specifically identified, as by
Gwozdz).
Ex. 1150 ¶ 141.
Even assuming, arguendo, that the example cited by Patent Owner
was considered a preferred embodiment, disclosed examples and preferred
embodiments do not constitute a teaching away from a broader disclosure or
non-preferred embodiments. In re Susi, 440 F.2d 442, 446 n.3 (CCPA
1971). Furthermore, a reference may be relied upon for all that it would
have reasonably suggested to one having ordinary skill the art, including
nonpreferred embodiments. Merck & Co. v. Biocraft Labs., 874 F.2d 804
(Fed. Cir.), cert. denied, 493 U.S. 975 (1989).
IPR2019-00451
Patent 9,763,876 B2
43
We also find that Petitioner, along with the testimony of Dr. Peppas
and Dr. Wermeling, has persuasively shown that a person of ordinary skill in
the art would have been motivated to combine tocopherol with ethanol and
benzyl alcohol. As discussed supra, Dr. Peppas testifies that the
combination of ethanol and benzyl alcohol was also used (along with other
ingredients) in diazepam formulations such as the rectal gel Diastat and the
injectable solution Valium. See Ex. 1041 ¶ 133 (citing Ex. 1042, 2, 10).
Dr. Peppas also cites to other prior art references discussing the preference
for using a drug solvent system containing benzyl alcohol and ethanol. See
Id. ¶¶ 134, 135 (citing Ex. 1018, 3:52–54, 4:7–23; Ex. 1019, 3:65–4:1, 5:5–
7, 5:64–6:51). Similarly, Dr. Wermeling testifies that a “POSA would know
that there are historic and commercial examples that combined benzyl
alcohol with ethanol and diazepam, along with other solvents” such as
Diastat and Valium and “benzyl alcohol and ethanol were known to be
readily miscible.” Ex. 1150 ¶ 146 (citing Ex. 1031, 10; Ex. 1042, 2, 10;
Ex. 1076, 11).
Furthermore, with regard to Patent Owner’s argument that a POSA
would not have used another excipient due to fear of precipitation, the
disclosure of Gwozdz is not limited to administration in one nostril and
administration in more than one nostril would allow for a lower
concentration of drug in solution being administered in each nostril, which
would avoid the potential for diazepam to precipitate out of the solution.
See Reply 14–15 (citing Ex. 1150 ¶¶ 130–132; Ex. 1149, 38:9–18).
Patent Owner argues that Petitioner overlooks the label for Nayzilam,
a commercialized intranasal diazepam formulation, which requires to dose
one nostril, wait at least 10 minutes, and then dose the other nostril if the
IPR2019-00451
Patent 9,763,876 B2
44
patient has not responded. PO Sur-Reply, 17 (citing Ex. 1072, 1). We are
not persuaded by this argument. The fact that a nasal diazepam product,
approved in 2019, includes such dosing instructions does not indicate that
one of ordinary skill in the art in 2009 would have been deterred from
providing administration in both nostrils. See Ex. 2018. In fact, as
discussed infra, Cartt ’784 discloses (in 2008) that intranasal solutions of
benzodiazepines can be administered in one nostril, in both nostrils
sequentially, or in one nostril, then the second nostril, and then the first
nostril again (and, optionally, in the second nostril again). See Ex. 1015
¶¶ 31, 33, 35, 39, 42, 45; Ex. 1150 ¶¶ 144–145. Dr. Wermeling and
Dr. Gizurarson agree that a POSA would reduce the diazepam concentration
and apply a lower concentration to both nostrils in order to avoid
precipitating, while still achieving the desired therapeutic effect. See
Ex. 1149, 38:9–18; Ex. 1150 ¶¶ 143, 144.
Patent Owner also asserts that Petitioner shows no motivation to
combine the formulations of Gwozdz with the formulations of Meezan ’962.
See PO Resp. 35–38. Specifically, Patent Owner contends that Petitioner
“provides no motivation for a POSA to increase bioavailability of Gwozdz’s
intranasal formulation with addition of a penetration enhancer.” Id. at 35–
36. According to Patent Owner, Gwozdz “distinguishes itself from prior art
solutions containing surfactants or micellar formulations and exemplifies a
maximized tocopherol formulation necessary for achieving increased
solubility.” Id. at 36 (citing Ex. 2012 ¶ 82). Therefore, Patent Owner
asserts that there would have been no motivation for a POSA to modify
Gwozdz by adding a surfactant such as an alkyl glycoside. Id.
IPR2019-00451
Patent 9,763,876 B2
45
Patent Owner further contends that one of skill in the art would not
have been motivated to combine the formulations of Gwozdz and Meezan
’962 because Meezan ’962 was concerned with “increasing absorption and
decreasing adverse effects of water-soluble therapeutic drugs” and
“increasing stability of its peptide and protein formulations by addition of
surfactants” such as alkyl glycosides. PO Resp. 36 (citing Ex. 2012 ¶ 96;
Ex. 1011 ¶ 4). Patent Owner also asserts that Meezan ’962 does not disclose
benzodiazepines (directly or indirectly) and concludes that “a POSA would
not find Meezan ’962 relevant to poorly water-soluble therapeutic agents
such as benzodiazepines.” Id. at 26, 37 (citing Ex. 2012 ¶ 97).
Further, according to Patent Owner, Meezan ’962 “disclosed the use
of surfactants in an aqueous setting” and a “POSA would need more
information (outside of either Gwozdz or Meezan’962 disclosure) in order to
determine how the alkyl glycosides of Meezan’962 would function
including, e.g., ‘[s]olubility of the glycoside in other solvents, [] other
carriers . . . [p]robably a number of other parameters; pH, pH sensitivity,
concentrations’ etc.” PO Resp. 37 (citing Ex. 2012 ¶ 98; Ex. 1011 ¶¶ 146–
172; Ex. 2011, 141:8–11, 141:14–18). Patent Owner asserts that Petitioner
fails to discuss how alkyl glycosides function in a non-aqueous environment
and Meezan ’962 “discloses alkyl glycosides as a stabilizer only in aqueous
formulations.” PO Sur-Reply 15 (citing Ex. 2011, 140:20–23).
According to Patent Owner, “[b]ecause independent claim 1 of the
’876 patent excludes water from its benzodiazepine solution – through its
‘consisting of’ language – it does not provide a vehicle for which a
surfactant such as alkyl glycoside could work to stabilize or act as a
traditional penetration enhancer in a solution.” PO Resp. 38 (citing
IPR2019-00451
Patent 9,763,876 B2
46
Ex. 2011, 138:12–139:23). Patent Owner concludes that, for these reasons,
“a POSA would have been discouraged from selecting the alkyl glycoside as
disclosed and used in Meezan’962 to add to the non-aqueous formulations of
Gwozdz.” Id.
As discussed supra, we are not persuaded that a POSA would have
been deterred from modifying the one specific example in Gwozdz cited by
Patent Owner. We, furthermore, credit the testimony of Dr. Peppas and
Dr. Wermeling that a POSA would have been motivated to look at multiple
ways of increasing intranasal delivery of drugs. For example, Dr.
Wermeling testifies that “a POSA would understand the benefits from using
a penetration enhancer, even in situations of already-high bioavailability, as
penetration enhancers would (among other things) be useful in adjusting the
rate and amount of drug absorbed purely intranasally.” Ex. 1150 ¶ 146 n.4.
Also, while Meezan ’962 does not specifically reference benzodiazepines, it
does refer to small organic molecules and anti-seizure agents, which
encompass benzodiazepines. See Ex. 1011 ¶¶ 3, 4, 130; Ex. 1041 ¶ 222;
Ex. 1150 ¶ 150.
Furthermore, contrary to the arguments of Patent Owner, Meezan
’962 is not limited to water soluble therapeutic drugs and discloses using
alkyl glycosides in aqueous or non-aqueous systems:
Additionally, the therapeutic compositions of the invention can
consist of a pharmaceutically acceptable carrier. A
‘pharmaceutically acceptable carrier’ is an aqueous or non-
aqueous agent, for example alcoholic or oleaginous, or a
mixture thereof, and can contain a surfactant,…a solvent,…
Pharmaceutically acceptable carriers are well known in the art
and include, for example,…oils such as olive oil or injectable
organic esters…A pharmaceutically acceptable carrier can also
be selected from substances such as…benzyl alcohol,….
IPR2019-00451
Patent 9,763,876 B2
47
Ex. 1011 ¶ 74 (emphasis added). Given this disclosure, we credit the
testimony of Dr. Wermeling that “a POSA would be motivated to increase
the solubility of diazepam given its lower potency as compared to other
benzodiazepines and in recognition of limited water solubility.” Ex. 1150
¶ 152.11
Thus, Petitioner demonstrates, by a preponderance of the evidence,
that a person of ordinary skill in the art would have had reason to add alkyl
glycoside as a penetration enhancer, as disclosed in Meezan ’962, with a
formulation of benzodiazepine, tocopherol, ethanol, and benzyl alcohol, as
disclosed in Gwozdz.
b) Reasonable Expectation of Success
We next consider whether Petitioner has shown by a preponderance of
the evidence that the skilled artisan would have had a reasonable expectation
of success in achieving the method claimed in the ’876 patent. “The
reasonable expectation of success requirement refers to the likelihood of
success in combining references to meet the limitations of the claimed
invention.” Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d
1359, 1367 (Fed. Cir. 2016).
Petitioner’s declarant, Dr. Peppas, testifies that Patent Owner never
demonstrated any criticality for the amount of ingredients in the claims;
therefore, a POSA would have easily been able to experiment with different
amounts and types of tocopherols, alcohols, benzodiazepines, and alkyl

11 Dr. Gizurarson also testified that he was unaware of any documents to
support the position that alkyl glycosides could not be used in non-aqueous
solutions and that he was unaware of any documents to support the position
that alkyl glycosides could not be used with benzodiazepines. See Ex. 1149,
85:2–3, 94:9–18; Ex. 1150 ¶¶ 162–165.
IPR2019-00451
Patent 9,763,876 B2
48
glycosides with an expectation of success. Ex. 1041 ¶¶ 363, 368. He also
testifies that “[b]ased on Meezan’962’s teachings, the POSITA would add an
alkyl glycoside to Gwozdz’s teachings with an expectation of successfully
increasing the bioavailability.” Id. ¶ 364.
Patent Owner asserts that Petitioner’s theory of obviousness lacks a
showing of a reasonable expectation of success in modifying Gwozdz to
include ethanol, benzyl alcohol, tocopherol or tocotrienol, and alkyl
glycosides. PO Resp. 30. First, Patent Owner asserts that Petitioner has not
shown a reasonable expectation of success in adding a penetration enhancer
such as alkyl glycoside to the Gwozdz formulation. Id. at 31. According to
Patent Owner, alkyl glycosides are known nonionic surfactants and “[t]he
Handbook of Pharmaceutical Excipients (“Handbook”) (Ex. 1031) teaches
that non-ionic surfactants interact to the detriment of the disclosed solvents.”
Id. For example, the Handbook states that “[e]thanol is inactivated in the
presence of nonionic surfactants and is ineffective against bacterial spores.”
Id. (citing Ex. 1031, 4). The Handbook also states that “antimicrobial
activity is reduced in the presence of nonionic surfactants…” Id. (citing
Ex. 1031, 10). Patent Owner concludes that:
A POSA would recognize that especially when dealing with
multidose intranasal use, the inactivation of microbial activity
of ethanol and/or benzyl alcohol could have consequences in
the successful approval of an intranasal formulation. EX2012,
¶¶ 88–89. A POSA by 2008 would have been aware of such
interactions and, thus, less likely to look to a nonionic
surfactant to combine with a formulation that already included
ethanol and benzyl alcohol. Id.
Id.
We do not find this argument persuasive. First, Dr. Wermeling and
Dr. Gizurarson testify that ethanol is not known to be used as an
IPR2019-00451
Patent 9,763,876 B2
49
antibacterial agent in benzodiazepine formulations. See Ex. 1149, 78:15–21;
Ex. 1150 ¶ 154. Furthermore, according to Dr. Wermeling, the
benzodiazepine formulation in the final package has to be aseptic so there
are no bacteria to kill. Ex. 1150 ¶ 155. Therefore, we credit
Dr. Wermeling’s testimony and agree with Petitioner that “whether or not
the antimicrobial properties are inactivated is irrelevant and a POSA would
not be led away from considering nonionic surfactants.” Reply 17 (citing
Ex. 1150 ¶ 155). Even if such antimicrobial properties were important, we
credit the testimony of Dr. Wermeling that “a POSA would not expect that
the very small amounts of nonionic surfactants being used would be
sufficient to inactivate the antimicrobial properties of high concentrations of
ethanol and/or benzyl alcohol being used here.” Ex. 1150 ¶ 156.
Patent Owner also contends that Petitioner has not shown a reasonable
expectation of success in adding additional solvents such as benzyl alcohol
to the Gwozdz formulation. PO Resp. 33. According to Patent Owner, the
Handbook entry for benzyl alcohol provides the following regarding the
combination of benzyl alcohol with fats:
Benzyl alcohol is incompatible with oxidizing agents and
strong acids. It can also accelerate the autoxidation of fats.
Id. (citing Ex. 1031, 10). Based on this disclosure, Patent Owner asserts:
A POSA relying on the Handbook would have at least been
cautioned not to combine benzyl alcohol with tocopherols or
tocotrienols. EX2012, ¶¶ 86–87. A POSA would recognize that
doing so would negate the anti-oxidation properties of
tocopherols and, as a result, degrade the compound such that
undesirable by-products could be introduced into the
formulation. Id.
Id.
IPR2019-00451
Patent 9,763,876 B2
50
In addition, according to Patent Owner, a POSA as of 2008 would
also have been aware that solvents such as benzyl alcohol were known
irritants to the nasal cavity. PO Resp. 33–34 (citing Ex. 1041 ¶ 103(b);
Ex. 2012 ¶ 90). Therefore, Patent Owner asserts that “a POSA would
understand that because of the presence of benzyl alcohol, which is used as a
preservative in pharmaceutical formulations, injectable compositions
containing benzyl alcohol could not be used in intranasal formulations.” Id.
at 34.
We do not find this argument persuasive and credit the testimony of
Dr. Wermeling that a POSA would not be concerned about potential auto-
oxidation of fats by the benzyl alcohol because oxygen is absent in these
single-use emergency rescue products. See Ex. 1150 ¶ 134 n.2. We also
find persuasive the testimony of Dr. Wermeling that the Handbook, relied on
by Patent Owner, does not provide any conditions necessary for such
autoxidation to occur, nor does it indicate that tocopherols would autoxidize
in the presence of benzyl alcohol. See id. We also find persuasive
Dr. Wermeling’s testimony that, “in cases of acute life-threatening
indications such as epileptic seizures, a relatively high local irritation to the
mucosa is acceptable.” Id. ¶ 211.
Upon review of the record as a whole, we find that one of ordinary
skill in the art would have had a reasonable likelihood of success in
combining the disclosures of Gwozdz and Meezan ’962 to achieve the
claimed invention. In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985) (“Only a
reasonable expectation of success, not absolute predictability, is necessary
for a conclusion of obviousness.”).
IPR2019-00451
Patent 9,763,876 B2
51
Therefore, we determine that Petitioner has demonstrated by a
preponderance of the evidence that each limitation of claims 1–16 and 24–36
are taught or suggested by the combination of Gwozdz and Meezan ’962 and
further that the skilled artisan would have had reason to make the suggested
combination with a reasonable expectation of success.
6. Objective indicia of non-obvious
In determining whether a claim is obvious in light of the prior art, we
also consider any relevant evidence of secondary considerations of non-
obviousness. See Graham, 383 U.S. at 17. Notwithstanding what the
teachings of the prior art would have suggested to one of ordinary skill in the
art at the time of the invention, the totality of the evidence submitted,
including objective evidence of non-obviousness, may lead to a conclusion
that the challenged claims would not have been obvious to one of ordinary
skill. In re Piasecki, 745 F.2d 1468, 1471–72 (Fed. Cir. 1984). Patent
Owner presents evidence of failure of others and long-felt need. See PO
Resp. 40–44.
Patent Owner argues that, as of 2008 and 2009, “there was a well-
known need in the market for immediate treatment of epileptic seizures –
with intranasal administration of benzodiazepines – and more specifically,
diazepam – proving to be a promising solution.” PO Resp. 41 (citing
Ex. 2012 ¶¶ 111–112). According to Patent Owner, “while the ability to
administer therapeutic drugs intranasally was first realized as early as 1980
(EX2008, 1240), intranasal formulation of benzodiazepines has been
hampered by technical challenges posed by benzodiazepines.” Id. at 41–42.
Patent Owner further asserts that the fact that the industry had failed
to develop the benzodiazepine formulation of the ’876 patent is evident from
IPR2019-00451
Patent 9,763,876 B2
52
the fact that, before Patent Owner’s invention, no company had ever
commercialized an intranasal benzodiazepine formulation and only one
company has ever done so (i.e., Nayzilam, a midazolam formulation), which
was released in 2019. PO Resp. 43 (citing Ex. 2012 ¶ 75; Ex. 2018). Patent
Owner also asserts that, “to address this unmet need,” it submitted a New
Drug Application (“NDA”) with the Food and Drug Administration
(“FDA”) for Valtoco, which it refers to as “diazepam nasal spray that is
representative of the ’876 patent claims.” Id. (citing Ex. 2024). According
to Patent Owner, “the fact that Neurelis, with the Valtoco® formulation, met
this long-felt but unmet need – especially in light of the failure of others –
confirms the non-obviousness of the ’876 patent.” Id. at 44 (citing Ex. 2012
¶ 113).
Objective evidence of nonobviousness is relevant only if there is a
nexus between this evidence and the claimed invention. Fox Factory, Inc. v.
SRAM, LLC, 944 F.3d 1366, 1373 (Fed. Cir. 2019). A presumption of nexus
applies if the asserted objective evidence “is tied to a specific product and
that product ‘embodies the claimed features, and is coextensive with them.’”
Id. (quoting Polaris Indus., Inc. v. Artic Cat, Inc., 882 F.3d 1056, 1072 (Fed.
Cir. 2018)). To the extent that a presumption of nexus does not apply,
Patent Owner may still prove nexus “by showing that the evidence of
secondary considerations is the ‘direct result of the unique characteristics of
the claimed invention.’” Id. (quoting In re Huang, 100 F.3d 135, 140 (Fed.
Cir. 1996).
At the outset, we give Patent Owner’s arguments about failure of
others and long-felt need very little weight in our obviousness analysis.
Patent Owner relies on Valtoco as meeting the alleged long-felt need, yet
IPR2019-00451
Patent 9,763,876 B2
53
Patent Owner does not allege (or even mention) any “nexus” with respect to
that formulation in its briefing. See PO Resp. 40–44; PO Sur-Reply 19–26.
Although Patent Owner asserts that Valtoco “is representative of the ’876
patent claims”12 and “met [the] long-felt but unmet need,” it provides no
description of the Valtoco formulation as compared to the claims of the ’876
patent. As pointed out by Petitioner, “Dr. Gizurarson testified he did not
know Valtoco’s formulation. Absent that information, [Patent Owner] did
not establish the required nexus connecting the ‘876 patent claims to
Valtoco.” Reply 28; Ex. 1149, 18–19.
When asked about nexus at the Oral Hearing, Patent Owner appeared
to change their position and Patent Owner’s counsel stated that they “don’t
argue a nexus between VALTOCO…and the claims” and that “[i]t is the
formulation of the claim and the disclosure of the patent that meets the
needs, not the product itself.” Tr. 50:20–26. Patent Owner’s counsel also
cited to Paragraph 113 of the Gizurarson Declaration (Tr. 51:7–12);
however, that paragraph also does not specifically tie the limitations of the
’876 patent claims to the presented evidence of failure of others or long-felt
need. Rather, the secondary consideration evidence presented is broadly
directed to an intranasal benzodiazepine formulation rather than to the
specific formulation recited in the claims of the ’876 patent. See Ex. 2012
¶ 113.
Moreover, even if nexus had been shown, the objective evidence of
nonobviousness identified by Patent Owner provides only limited support
for nonobviousness of the challenged claims. For example, Petitioner has

12 This assertion comes up only once in a brief, unsupported parenthetical.
IPR2019-00451
Patent 9,763,876 B2
54
presented persuasive evidence that benzodiazepines were delivered
intranasally prior to 2009, which undercuts Patent Owner’s arguments of
failure of others and long-felt need. See Ex. 1150 ¶¶ 82–87 (citing Exs.
1121, 1136–1144).
For these reasons, we are not persuaded by Patent Owner’s arguments
that failure of others and long-felt need weigh toward the non-obviousness
of the claimed subject matter.
7. Conclusions as to obviousness of claims 1–16 and 24–36 over Gwozdz
and Meezan ’962
In sum, we find that the combination of Gwozdz and Meezan ’962
teaches or suggests each and every element of claim 1–16 and 24–36. We
find that an ordinarily skilled artisan would have been motivated to combine
Gwozdz with Meezan ’962, and would have had a reasonable expectation of
success in achieving the claimed invention. On this record, we also find that
the evidence of secondary considerations of non-obviousness is weak, at
best. As discussed above, we find that Patent Owner has not established the
requisite nexus between the challenged claims and any of the asserted
secondary considerations. We are therefore unable to accord them any
substantial weight. Fox Factory, 944 F.3d at 1373.
Thus, after carefully considering the arguments and evidence, we
determine that Petitioner has shown by a preponderance of evidence that
claims 1–16 and 24–36 of the ’876 patent would have been obvious over
Gwozdz and Meezan ’962.
F. Asserted Obviousness of Claims 17–23 over Gwozdz, Meezan ’962,
and Cartt ’784
Petitioner contends that the subject matter of claims 17–23 of the ’876
patent would have been obvious over the combined disclosures of Gwozdz,
IPR2019-00451
Patent 9,763,876 B2
55
Meezan ’962, and Cartt ’784. Pet. 49–54, 87–92. Patent Owner opposes.
PO Resp. 23–39; PO Sur-Reply 12–19. Having considered the totality of the
arguments and evidence, we find that Petitioner has shown by a
preponderance of the evidence that claims 17–23 are unpatentable as having
been obvious over Gwozdz, Meezan ’962, and Cartt ’784.
1. Cartt ’784
Cartt ’784 discloses “nasal formulations for administering
benzodiazepine drugs, such as diazepam, lorazepam or midazolam, to a
patient in need of therapeutic treatment with a benzodiazepine drug.”
Ex. 1015 ¶ 28. Cartt ’784 is directed to intranasal particulate formulations
but discloses that the formulations can be liquid nasal sprays and that the
drug may be in solution. Id. ¶¶ 9, 138–139, 141. Cartt ’784 also discloses a
list of solvents including ethanol and benzyl alcohol, as well as nonionic
surfactants including dodecyl maltoside. Id. ¶¶ 47, 48, 130, 182. Cartt ’784
also provides different dosing amounts, volumes, and regimens for the
benzodiazepine formulations. Id. ¶¶ 7, 31, 33–36, 39, 42, 45, 47, 55–56, 64,
71–72, 79–80, 87–88, 95–96, 104–105, 112–113, 144.
2. Limitations of Claims 17–23
a. Claims 17–18
Claim 17 depends from claim 16, which depends from claim 1, and
requires the pharmaceutically-acceptable spray formulation of claim 16
“wherein the benzodiazepine is administered in a therapeutically effective
amount from about 1 mg to about 20 mg.” Ex. 1001, 64:19–23. Claim 18
depends from claim 17 and requires that “said pharmaceutical solution is in
a pharmaceutically-acceptable spray formulation having volume from about
10 µL to about 200 µL.” Id. at 64:24–26. Petitioner presents evidence that
IPR2019-00451
Patent 9,763,876 B2
56
Cartt ’784 discloses that diazepam may be present in amounts of about 1 to
about 20 mg per dose, and discloses “diazepam volumes include 25-250 µl,
preferably 50-150 µl, and especially about 100 µl.” Pet. 49, 87–88 (citing
Ex. 1015 ¶¶ 63–64).
b. Claims 19–22
Claim 19 depends from claim 18 and requires that the method
“comprises spraying at least a portion of the therapeutically effective amount
of the benzodiazepine into at least one nostril.” Ex. 1001, 64:27–30.
Claim 20 also depends from claim 18 and requires spraying the
“benzodiazepine into each nostril.” Id. at 64:31–34. Claim 21 depends from
Claim 20 and recites the optional step of “spraying a third quantity of the
pharmaceutical solution into the first nostril.” Id. at 64:35–41. Claim 22
depends from Claim 21 and recites the optional step of “administering at
least a fourth quantity of the pharmaceutical solution to the second nostril.”
Id. at 64:42–45. Petitioner, with supporting testimony from Dr. Peppas,
presents evidence that Cartt ’784 discloses the dosing regimen elements of
claims 19–22. See Pet. 51–52, 88–91 (citing Ex. 1015 ¶¶ 31, 33, 35, 39, 42,
45; Ex. 1041 ¶ 451).
c. Claim 23
Claim 23 depends from claim 21 and requires “wherein the nasal
administration of the pharmaceutical solution begins at any time before or
after onset of symptoms of a disorder which is treatable with the
pharmaceutical solution.” Ex. 1001, 64:46–49. Petitioner, with supporting
testimony from Dr. Peppas, presents evidence that Cartt ’784 discloses the
use of benzodiazepines for treating symptoms before and/or after they start.
Pet. 52–54, 91–92 (citing Ex. 1015 ¶¶ 3, 60, 61, 68, 69; Ex. 1041 ¶ 455).
IPR2019-00451
Patent 9,763,876 B2
57
We determine that Petitioner has shown, by a preponderance of the
evidence, that the combination of Gwozdz, Meezan ’962, and Cartt ’784
teaches or suggests each and every limitation of claims 17–23.
3. Motivation to combine/reasonable expectation of success
Petitioner argues that, since neither Gwozdz nor Meezan ’962 provide
specific dosing regimens for benzodiazepines/diazepam, one of ordinary
skill in the art would look to the similar reference of Cartt ’784, titled “Nasal
Administration of Benzodiazepines,” for these teachings. Pet. 34.
Petitioner, with supporting testimony from Dr. Peppas, further argues that
one of ordinary skill in the art “would not be deterred from incorporating the
teachings of Cartt ’784, even though it is not specifically directed to
solutions (instead disclosing intranasal particulate formulations)” and
“would easily adapt” these teachings “to the Gwozdz/Meezan ’962
combination.” Id. at 34–35 (citing Ex. 1041 ¶¶ 257–260).
Patent Owner argues that Petitioner fails to demonstrate a motivation
to combine the formulation of Cartt ’784 to the Gwozdz and/or Meezan ’962
formulations. PO Resp. 38–40. First, Patent Owner asserts that “Gwozdz
distinguished its non-aqueous lipophilic and hydrophobic formulations from
Cartt ’784 by stating, ‘[a]dvantageously, the resulting pharmaceutical
solution is not an emulsion or vesicle, and can be used directly in the
production of pharmaceutical compositions.’” Id. at 39 (citing Ex. 1014, 4–
5; Ex. 2012 ¶ 107). Patent Owner further asserts that Cartt ’784 applies to
particulate formulations of benzodiazepines so “a POSA would not find
particulate formulations of benzodiazepines as easily translatable to
solutions of benzodiazepines, especially as it relates to dosing regimens.”
Id. (citing Ex. 2011, 145:13–17).
IPR2019-00451
Patent 9,763,876 B2
58
We find that Petitioner has persuasively shown that a person of
ordinary skill in the art would have been motivated to combine the
disclosures of Gwozdz and Meezan ’962 with Cartt ’784. Cartt ’784
recognized the:
need for benzodiazepine formulations that are capable of
providing to the nasal mucosa sufficient quantity of
benzodiazepine in a small enough volume to provide
therapeutically effective blood plasma concentration of
benzodiazepine within a short period after administration of the
formulation to the nasal mucosa.
Ex. 1015 ¶ 8. Cartt ’784 also:
provides methods of administering a benzodiazepine to a
patient, comprising nasally administering an effective amount
of the benzodiazepine to the patient, wherein the effective
amount of the composition is effective to treat seizure, protect
against seizure, reduce or ameliorate the intensity of seizure,
reduce or ameliorate the frequency of seizure, and/or prevent
occurrence or re-occurrence of seizure.
Id. ¶ 28.
Although Cartt ’784 discusses benzodiazepines in particulate form, it
states that the dosage form may be “a nasal spray or nasal drop, although
presently preferred embodiments are nasal sprays…[which] may be liquid or
solid nasal sprays” and acknowledges that “[i]t is also possible for the drug
to be fully soluble in the liquid.” Ex. 1015 ¶¶ 138–139. Cartt ’784 also
states that the dosage form may be in the form of liquid droplets which “may
be formed from solutions…” Id. ¶ 139. The solution may be a combination
of the drug in a “non-aqueous medium.” Id. Dr. Peppas testified that
tocopherol would be such a non-aqueous medium. See Ex. 1041 ¶ 248.
Cartt ’784 also “classifies both ethanol and benzyl alcohol as useful
solvents.” Id. ¶ 249 (citing Ex. 1015 ¶ 182). Cartt ’784 further discloses the
IPR2019-00451
Patent 9,763,876 B2
59
use of absorption enhancers, including alkyl glycosides. See Ex. 1015
¶¶ 128–129; Ex. 1041 ¶¶ 250–252.
Based on these disclosures, we credit the testimony of Dr. Peppas that
the teachings of Gwozdz, Meezan ’962, and Cartt ’784 are “naturally
combinable” because they “all recognized that there are benefits to
administering active agents intranasally” and “sought to provide solutions to
these difficult problems” with “different potential solutions.” See Ex. 1041
¶¶ 257–258. We also credit the testimony of Dr. Wermeling that a “POSA
would have looked to Cartt’784 for its disclosure of dosing regimens
(including dosing amounts and volume amounts) for benzodiazepines
(including diazepam)” and would have combined this disclosure with
Gwozdz’s disclosure of “intranasal benzodiazepine (diazepam) in ternary
solvent systems, and further with Meezan’962’s disclosure of alkyl
glycosides (penetration enhancers).” Ex. 1150 ¶ 170.
On this record, and upon review of Petitioner’s arguments and
supporting evidence, we determine that Petitioner sufficiently explains why
one of ordinary skill in the art would have looked to Cartt ’784’s disclosure
when seeking dosing regimens for the compositions disclosed in Gwozdz
and Meezan ’962, and would have had a reasonable expectation of success
in achieving the claimed invention. Petitioner also sufficiently explains how
the combined disclosures of Gwozdz, Meezan ’962, and Cartt ’784 would
have taught or suggested the subject matter of claims 17–23. As discussed
supra, we also find that the evidence of secondary considerations of non-
obviousness is weak, at best.
Thus, after carefully considering the arguments and evidence, we
determine that Petitioner has shown by a preponderance of evidence that
IPR2019-00451
Patent 9,763,876 B2
60
claims 17–23 of the ’876 patent would have been obvious over Gwozdz,
Meezan ’962, and Cartt ’784.
III. PATENT OWNER’S IDENTIFICATION OF ALLEGEDLY
IMPROPER REPLY ARGUMENTS AND EVIDENCE
Patent Owner previously requested permission to file a Motion to
Strike portions of Petitioner’s Reply and the Declaration of Dr. Daniel P.
Wermeling, Pharm.D. (Ex. 1150). We denied this request, but authorized
the parties to file a joint chart identifying the Reply arguments and evidence
Patent Owner believes are improper and providing Petitioner’s response to
Patent Owner’s arguments. Paper 26 (“Objec.”). We address the issues the
parties identify below.
A. Claim Construction
Patent Owner contends that Petitioner provided new claim
constructions for the terms “ethanol,” “consisting of,” and “solution.”
Objec. 1–2. As discussed supra, upon review of the parties’ arguments and
the evidence of record, we determine that no terms of the ’876 patent require
express construction for purposes of this Decision. Therefore, Patent
Owner’s arguments regarding Petitioner’s new claim construction arguments
are moot.
B. Person of Ordinary Skill in the Art
The Petition provides a definition of one of ordinary skill in the art
and supports that definition with testimony from Dr. Peppas. Pet. 4;
Ex. 1041 ¶ 74. Patent Owner disagrees with this definition in its Response,
providing testimony of Dr. Gizurarson to support its arguments. PO Resp.
15–17; Ex. 2012 ¶¶ 27–33. Dr. Wermeling responds to the definition of a
POSA provided by Patent Owner and testifies that it is necessary to add
IPR2019-00451
Patent 9,763,876 B2
61
transmembrane experience to the definition provided by Dr. Gizurarson.
Ex. 1150 ¶¶ 20–22.
Patent Owner objects to page 12 of the Reply and paragraphs 20–22
of Dr. Wermeling’s Declaration as allegedly offering new opinions on the
level of skill in the art that are not in the Petition. Objec. 2.
Neither Petitioner’s Reply nor Dr. Wermeling’s Declaration testimony
seek to change the proposed definition of one of ordinary skill in the art set
forth in the Petition. Dr. Wermeling, instead, addresses the specific
arguments made in Patent Owner’s Response and Dr. Gizurarson’s
Declaration and asserts that the POSA would also need transmembrane
experience. Petitioner and Dr. Wermeling’s assertion that transmembrane
experience is needed is also consistent with Petitioner and Dr. Peppas’s
assertion that a POSITA would have experience with transmucosal
pharmaceutical formulation development and/or delivery. See Pet. 4–5; Ex.
1041 ¶ 74. As such, we find that Dr. Wermeling’s testimony related to the
level of ordinary skill in the art constitutes proper rebuttal.
C. General Rebuttal Arguments and Evidence
Patent Owner also objects to multiple portions of the Reply and
Dr. Wermeling’s testimony as advancing new theories and relying on new
evidence. Objec. 2–7. Upon review of Patent Owner’s objections and
Petitioner’s responses to those objections, we are persuaded that the
identified portions of the Reply and Dr. Wermeling’s testimony represent
proper rebuttal arguments intended to respond to arguments raised by Patent
IPR2019-00451
Patent 9,763,876 B2
62
Owner, opinions Dr. Gizurarson presented in his declaration, and/or
statements made in the Decision on Institution.13
Patent Owner is correct that some exhibits Dr. Wermeling discusses
are not addressed in the Petition. As our reviewing court has instructed,
however, “the introduction of new evidence in the course of the trial is to be
expected in inter partes review trial proceedings and, as long as the
opposing party is given notice of the evidence and an opportunity to respond
to it, the introduction of such evidence is perfectly permissible under the
[Administrative Procedure Act].” Genzyme Therapeutic Prod. Ltd. P’ship v.
Biomarin Pharm. Inc., 825 F. 3d 1360, 1366 (Fed. Cir. 2016). Here, Patent
Owner deposed Dr. Wermeling after receiving his reply Declaration, had an
opportunity to respond to his arguments and supporting evidence in a Sur-
Reply, and has filed a Motion to Exclude his testimony on relevance and
prejudice grounds. See Yeda Research v. Mylan Pharms, Inc., 906 F.3d
1031, 1040 (Fed. Cir. 2018). Thus, we find that the portions of the Reply
and Dr. Wermeling’s testimony and supporting documentary evidence cited
by Patent Owner are not improper. See Apple Inc. v. Andrea Elecs. Corp.,
949 F.3d 697, 706-07 (Fed. Cir. 2020).
IV. MOTIONS TO EXCLUDE
Both parties moved to exclude evidence in this proceeding.

13 “[T]he Board will permit the petitioner, in its reply brief, to address issues
discussed in the institution decision.” Patent Trial and Appeal Board
Consolidated Trial Practice Guide (Nov. 2019) (“Consolidated Trial Practice
Guide”), available at
https://www.uspto.gov/TrialPracticeGuideConsolidated, at 73.
IPR2019-00451
Patent 9,763,876 B2
63
A. Petitioner’s Motion to Exclude
Petitioner moved to exclude Exhibits 2001–2010 and 2013–2024
generally for relevancy under Fed. R. Evid. 402, confusion, waste, and
prejudice under Fed. R. Evid. 403, hearsay under Fed. R. Evid. 802, and lack
of authentication under Fed. R. Evid. 901. Pet. MTE. Petitioner also moved
to exclude portions of Ex. 2012 (Declaration of Dr. Gizurarson) for
relevancy under Fed. R. Evid. 402, confusion, waste, and prejudice under
Fed. R. Evid. 403, improper lay testimony under Fed. R. Evid. 701,
unqualified expert testimony under Fed. R. Evid. 702, hearsay under Fed. R.
Evid. 802, and improper summary without underlying documents under Fed.
R. Evid. 1006. Id. at 6–7. Our conclusions in this Final Written Decision do
not rely upon any of the evidence in Exhibits 2001–2005, 2007–2010, and
2013–2024 that Petitioner seeks to exclude. Accordingly, Petitioner’s
Motion to Exclude these exhibits is dismissed as moot.
1. Exhibit 2006
With regard to Exhibit 2006, the 1988 SIGMA catalog, Petitioner
argues that the exhibit is offered to prove the truth of the matter asserted
without meeting any hearsay exception and that Patent Owner failed to
provide evidence sufficient to establish that the exhibit is what it is
purported to be. Pet. MTE, 4.
First, we do not rely on Ex. 2006 for the matter asserted but rather for
what it described to an ordinary artisan. Therefore, it is not hearsay under
Fed. R. Evid. 801(c). Furthermore, Patent Owner provided library affidavits
(Ex. 2025, Ex. 2026) authenticating Ex. 2006. Therefore, Ex. 2006 is
properly authenticated. Thus, we deny the Motion to Exclude Exhibit 2006.
IPR2019-00451
Patent 9,763,876 B2
64
2. Exhibit 2012
With regard to Exhibit 2012, the Declaration of Dr. Sveinbjörn
Gizurarson, Ph.D., Petitioner argues that we should exclude paragraphs 2, 5,
7, and 67 for relevancy under Fed. R. Evid. 402, and confusion, waste, and
prejudice under Fed. R. Evid. 403. Pet MTE, 6. Petitioner also argues that
we should exclude paragraphs 2, 3, 5, 28–33, 36, 44, 48, and 50–51 because
they “include assertions for which evidence has not been introduced
sufficient to show that the witness has personal knowledge of the matters
asserted.” Id. Petitioner further asserts that we should exclude paragraphs
16–25, 26, 28, 31–36, 38–39, 41–43, 48, 50–52, 54–56, 58, 60–61, 67–70,
75, 77–80, 82–87, 89–95, 97, 99–109, and 111–116 under Fed. R. Evid. 701
and 702 because of improper lay testimony and unqualified expert
testimony. Id. at 6–7. Petitioner further asserts that we should exclude
paragraphs 28-33, 44–46, 48, 50–52, 54, 56–61, 63–67, 71–72, 74, 77–78,
83–84, 89, 92, and 111–113 under Fed. R. Evid. 802 as “the exhibit is
offered to prove the truth of the matter asserted without meeting any hearsay
exception.” Id. at 7. Lastly, Petitioner asserts that we should exclude
paragraphs 28–29, 36, 48, 50–51, 56, 58, 59–60, 79, 85, 87, 89, 95, 100–
102, 104–105, 109, and 114–116 under Fed. R. Evid. 1006 because they
“constitute improper summary with underlying documents not made
available.” Id.
Our conclusions in this Final Written Decision do not rely upon any of
the evidence in paragraphs 2, 3, 5, 7, 16–26, 33–36, 38–39, 41–46, 48, 50–
52, 54–61, 63–72, 74, 75, 77–80, 82–87, 89–95, 97, 99–109, and 111–116 of
Exhibit 2012. Accordingly, Patent Owner’s Motion to Exclude these
IPR2019-00451
Patent 9,763,876 B2
65
paragraphs under Fed. R. Evid. 402, 403, 701, 702, 802, and 1006 is
dismissed as moot.
With respect to paragraphs 28–32 of the Gizurarson Declaration, in
which Dr. Gizurarson provides his opinion regarding the definition of a
person of ordinary skill in the art, we find that Dr. Gizurarson has provided
sufficient background qualifications to opine on this issue. With regard to
Petitioner’s hearsay argument, we find that Dr. Gizurarson’s opinions in
these paragraphs are based on his experience in the field, which has been
sufficiently shown. Therefore, these opinions are not predicated on hearsay.
Similarly, because the opinions in these paragraphs are based on Dr.
Gizurarson’s prior experience, they do not constitute an improper summary
without underlying documents under Fed. R. Evid. 1006. Accordingly,
Petitioner’s Motion to Exclude paragraphs 28–32 of Exhibit 2012 under Fed.
R. Evid. 402, 403, 701, 702, 802, and 1006 is denied.
B. Patent Owner’s Motion to Exclude
Patent Owner moved to exclude Exhibits 1009, 1013, 1017, 1021,
1022, 1033, 1036, 1038, 1048, 1050, 1065, 1069, 1080, 1081, 1122, portions
of Exhibit 1149, and the entirety of, or portions of, Exhibit 1150, generally
for relevancy under Fed. R. Evid. 402, confusion, waste, and prejudice under
Fed. R. Evid. 403, hearsay under Fed. R. Evid. 802, and lack of
authentication under Fed. R. Evid. 901. PO MTE. Patent Owner also
moved to exclude paragraphs 29–63, 167–168, 171–191, 264–362, and
Appendix A (pp. 197–224) of Exhibit 1041 (Declaration of Dr. Peppas) for
relevancy under Fed. R. Evid. 402, confusion, waste, and prejudice under
Fed. R. Evid. 403, and outside the scope of expertise and conclusory and
unreliable statements under Fed. R. Evid. 602 and 701–702. Id. at 2–4. Our
IPR2019-00451
Patent 9,763,876 B2
66
conclusions in this Final Written Decision do not rely upon any of the
evidence in Exhibits 1009, 1013, 1017, 1021, 1022, 1033, 1036, 1038, 1048,
1050, 1065, 1069, 1080, 1081, 1122, and 1149 that Patent Owner seeks to
exclude. We also do not rely upon any of the evidence at paragraphs 29–63,
167–168, 171–191, 264–362, and Appendix A (pp. 197–224) of Exhibit
1041 (Declaration of Dr. Peppas). Accordingly, Patent Owner’s Motion to
Exclude is dismissed as moot with respect to these Exhibits (or portions
thereof).
1. Exhibit 1150
With regard to Exhibit 1150, the Declaration of Daniel P. Wermeling,
Pharm.D., Patent Owner argues that we should exclude this exhibit or
portions thereof, because “it sets forth arguments that were not presented in
the Petition, cannot be relevant to it, and consequently serves only to
confuse and create unfair prejudice through belated surprise” under Fed. R.
Evid. 402–403. PO MTE, 9–11.
As discussed above, we determine that no terms of the ’876 patent
require express construction for purposes of this Decision. Therefore, Patent
Owner’s argument that we should exclude paragraphs 23–30 of the
Wermeling Declaration because they relate to new claim construction
arguments is dismissed as moot. Also, as discussed above, we find that the
other cited portions of Dr. Wermeling’s testimony properly respond to
Patent Owner’s arguments, the testimony of Dr. Gizurarson, and the
Decision on Institution. See Genzyme, 825 F. 3d at 1366; Consolidated Trial
Practice Guide, 73. Accordingly, Patent Owner’s Motion to Exclude Exhibit
1150 or portions thereof under Fed. R. Evid. 402–403 is denied.
IPR2019-00451
Patent 9,763,876 B2
67
Patent Owner also asserts that we should exclude paragraphs 59–89
and 90–126 of Exhibit 1150 under Fed. R. Evid. 602 because “Dr.
Wermeling testifies outside the scope of his expertise in analyzing
regulatory approval and commercialization of drug products.” PO MTE, 11.
Our conclusions in this Final Written Decision do not rely upon any of the
evidence in paragraphs 59–81 or 88–126 of Exhibit 1150. Accordingly,
Patent Owner’s Motion to Exclude these paragraphs under Fed. R. Evid. 602
is dismissed as moot. With respect to paragraphs 82–87, we do not find that
these paragraphs discuss regulatory approval or commercialization of drug
products. Rather, these paragraphs discuss prior art references that describe
intranasal delivery of benzodiazepines for the treatment of seizures prior to
2009, upon which we find Dr. Wermeling qualified to opine. Accordingly,
Patent Owner’s Motion to Exclude paragraphs 82–87 under Fed. R. Evid.
602 is denied.
Patent Owner further asserts that paragraphs 23–30, 59–89, 95–100,
114–118, and 171–177 of Exhibit 1150 should be excluded under Fed. R.
Evid. 701–702 because Dr. Wermeling’s opinions therein “are conclusory
and unreliable as Dr. Wermeling does not disclose the underlying facts or
any basis in support of his opinions.” PO MTE, 11–12. Our conclusions in
this Final Written Decision do not rely upon any of the evidence in
paragraphs 23–30, 59–81, 88–89, 95–100, or 114–118 of Exhibit 1150.
Accordingly, Patent Owner’s Motion to Exclude these paragraphs under
Fed. R. Evid. 701–702 is dismissed as moot.
With respect to paragraphs 82–87, as discussed above, we find that
these paragraphs discuss prior art references that discuss intranasal delivery
of benzodiazepines for the treatment of seizures prior to 2009. We find that
IPR2019-00451
Patent 9,763,876 B2
68
these paragraphs are properly supported by citations to the prior art
references being discussed. Furthermore, paragraphs 171–177 discuss
Dr. Wermeling’s opinions with regard to the ’558 provisional application
and its incorporation by reference to the Sigma Catalog and how such
disclosure would be understood by a person of ordinary skill in the art. We
find these opinions to be properly supported. Therefore, Patent Owner’s
Motion to Exclude paragraphs 82–87 and 171–177 under Fed. R. Evid. 701–
702 is denied.
Patent Owner further contends that we should exclude paragraphs
191–194 and 102–104 of Exhibit 1150 under Fed. R. Evid. 805 and 1006,
respectively. PO MTE, 13. Our conclusions in this Final Written Decision
do not rely upon any of the evidence in paragraphs 191–194 or 102–104 of
Exhibit 1150. Accordingly, Patent Owner’s Motion to Exclude these
paragraphs under Fed. R. Evid. 805 and 1006 is dismissed as moot.
V. CONCLUSION14
Petitioner establishes by a preponderance of the evidence that claim
1–36 of the ’876 patent are unpatentable as follows.

14 Should Patent Owner wish to pursue amendment of the challenged claims
in a reissue or reexamination proceeding subsequent to the issuance of this
decision, we draw Patent Owner’s attention to the April 2019 Notice
Regarding Options for Amendments by Patent Owner Through Reissue or
Reexamination During a Pending AIA Trial Proceeding. See 84 Fed. Reg.
16,654 (Apr. 22, 2019). If Patent Owner chooses to file a reissue application
or a request for reexamination of the challenged patent, we remind Patent
Owner of its continuing obligation to notify the Board of any such related
matters in updated mandatory notices. See 37 C.F.R. § 42.8(a)(3), (b)(2).
IPR2019-00451
Patent 9,763,876 B2
69

VI. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that claims 1–36 of the ’876 patent have been proven to
be unpatentable; and
FURTHER ORDERED that because this is a Final Written Decision,
parties to the proceeding seeking judicial review of the Decision must
comply with the notice and service requirements of 37 C.F.R. § 90.2.
FURTHER ORDERED that Petitioner’s Motion to Exclude is
dismissed as moot with respect to Exhibits 2001–2005, 2007–2010, 2013–
2024, and portions of Exhibit 2012, and denied with respect to Exhibit 2006
and paragraphs 28–32 of Exhibit 2012; and
FURTHER ORDERED that Patent Owner’s Motions to Exclude is
dismissed as moot with respect to Exhibits 1009, 1013, 1017, 1021, 1022,
1033, 1036, 1038, 1048, 1050, 1065, 1069, 1080, 1081, 1122, and portions
of Exhibits 1041, 1149, and 1150, and denied with respect to Exhibit 1150
and portions thereof.

Claims

35
U.S.C. §
Reference(s)/Basis Claims
Shown
Unpatentable
Claims
Not Shown
Unpatentable
1–16,
24–36
103(a) Gwozdz, Meezan
’962
1–16, 24–36
17–23 103(a) Gwozdz, Meezan
’962, Cartt ’784
17–23
Overall
Outcome
1–36
IPR2019-00451
Patent 9,763,876 B2
70
For PETITIONER:

Daniel Scola
Michael Chakansky
James Harrington
Matthew Solow
HOFFMAN & BARON, LLP
dscola@hbiplaw.com
mchakansky@hbiplaw.com
jfhdocket@hbiplaw.com
msolow@hbiplaw.com

For PATENT OWNER:

Jeffrey Guise
Richard Torczon
Lorelei Westin
Lee Johnson
Nathaniel Leachman
WILSON, SONSINI, GOODRICH & ROSATI
jguise@wsgr.com
rtorczon@wsgr.com
lwestin@wsgr.com
ljohnson@wsgr.com
nleachman@wsgr.com