Amneal Pharamceuticals, LLCv.Supernus Pharmaceuticals, Inc.

Patent Trial and Appeal Board

Dec 9, 2014

12926932 (P.T.A.B. Dec. 9, 2014)

Trials@uspto.gov Paper 96
Tel: 571-272-7822 Entered: December 9, 2014

UNITED STATES PATENT AND TRADEMARK OFFICE
_______________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
_______________
AMNEAL PHARMACEUTICALS, LLC,
Petitioner,

v.

SUPERNUS PHARMACEUTICALS, INC.,
Patent Owner.
_______________

Case IPR2013-00371
Patent 8,394,405 B2
_______________

Before LORA M. GREEN, SCOTT E. KAMHOLZ, and
GEORGIANNA W. BRADEN, Administrative Patent Judges.

KAMHOLZ, Administrative Patent Judge.

FINAL WRITTEN DECISION
35 U.S.C. § 318(a) and 37 C.F.R. § 42.73(b)

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I. INTRODUCTION
A. Background
Amneal Pharmaceuticals, LLC (“Amneal”) filed a Petition (Paper 1,
“Pet.”) requesting an inter partes review of claims 1–13 and 17–20 of
U.S. Patent No. 8,394,405 B2 (Ex. 1007, “the ’405 patent”). The Board
instituted trial for the challenged claims on the ground, asserted by Amneal,
of obviousness over WO 02/080932 A1 (Ex. 1002, “Ashley ’932”), which
incorporates by reference provisional patent application serial No.
60/281,854 (Ex. 1003, “Ashley ’854”) and U.S. Patent No. 5,348,748
(Ex. 1005, “Sheth”). Decision to Institute (Paper 11, “Dec.”) 14.
After institution of trial, Patent Owner Supernus Pharmaceuticals, Inc.
(“Supernus”) filed a Patent Owner Response in redacted (Paper 41, “Resp.”)
and unredacted (Paper 40) forms. Amneal filed a Reply (Paper 58,
“Reply”). Supernus did not file a Motion to Amend.
Amneal filed a Motion to Exclude certain of Supernus’s evidence
(Paper 72, “Pet. Motion to Exclude”). Supernus filed an Opposition in
redacted (Paper 84) and unredacted (Paper 85) forms, and Amneal filed a
Reply (Paper 88).
Amneal relies upon declarations from Dr. Glenn A. Van Buskirk in
support of its Petition (Ex. 1022) and its Reply (Ex. 1066). Supernus relies
upon a declaration from Dr. Edward M. Rudnic in support of its Response
(Ex. 2016), as well as deposition testimony from Dr. Van Buskirk
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(Exs. 2015, 2193).1 Amneal relies upon deposition testimony from
Dr. Rudnic in its Reply (Ex. 1052). Supernus filed a Motion for
Observations on Cross-Examination of Amneal’s Reply witnesses (Paper 78,
“Obs.”), and Amneal filed a Response to the Observations (Paper 80,
“Obs. Resp.”).
Oral argument was conducted on August 12, 2014. A transcript is
entered as Paper 94 (“Tr.”).
The Board has jurisdiction under 35 U.S.C. § 6(c). This final written
decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
Amneal has not proved that claims 1–13 and 17–20 are unpatentable.
Amneal’s Motion to Exclude Evidence is dismissed as moot.
B. The ’405 Patent
The ’405 patent relates to once-daily, sub-antimicrobial formulations
of doxycycline. Ex. 1007, 2:38–46. Such formulations can be used to
inhibit activity of collagen destruction enzymes, which are associated with
human diseases, such as rosacea, without provoking undesired side effects
attendant to an antibacterial dose. Id. at 3:6–9. A combination of an
immediate-release (“IR”) portion, with 30 mg doxycycline, and a delayed-
release (“DR”) portion, with 10 mg doxycycline, facilitates once-daily
dosing by providing a steady-state blood level of 0.1 to 1.0 µg/ml or 0.3 to
0.8 µg/ml. Id. at 3:61–68, 10:14–20. The composition may be a pellet, a
combination of pellets, a tablet, or a capsule. Id. at 5:50–64. The DR
portion may have an enteric polymer, such as hydroxypropyl

1 The parties rely on the testimony of other witnesses, but that evidence is
not listed here because it is not cited in this decision.
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methylcellulose phthalate. Id. at 7:24–30. The IR and/or DR portions may
incorporate one or more excipients. Id. at 6:16–42. Examples of excipients
include binders, such as hydroxypropyl methylcellulose (HPMC);
disintegration agents, such as cross-linked polyvinylpyrrolidone; and filling
agents, such as lactose. Id. at 6:20–31.
Claim 1 is illustrative of the claimed subject matter and is reproduced
below.
1. An oral pharmaceutical composition
comprising about 40 mg of total doxycycline,
which at a once-daily dosage will give steady state
blood levels of doxycycline of a minimum of 0.1
µg/ml and a maximum of 1.0 µg/ml, wherein the
composition consists of 70 to 80 percent of the
doxycycline formulated as an immediate release
(IR) formulation and 20 to 30 percent of the
doxycycline formulated as a delayed release (DR)
formulation.

II. DISCUSSION
A. Claim Construction
In an inter partes review, claim terms in an unexpired patent are
interpreted according to their broadest reasonable construction in light of the
specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,766 (Aug. 14,
2012). Claim terms are given their ordinary and customary meaning, as
would be understood by one of ordinary skill in the art in the context of the
entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed.
Cir. 2007).
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The only term requiring construction for purposes of this decision is
“delayed release.” Neither party proposed a construction of this term in its
principal brief. The ’405 patent, too, does not provide an express definition
of this term. Tr. 42:7–9.
In response to a request during oral argument, Tr. 48:7–21, the parties
identified the record evidence they rely on concerning construction of
“delayed release.” Amneal cited paragraphs 19 and 20 of Dr. Van Buskirk’s
Second Declaration (Ex. 1066) and paragraph 106 of Dr. Rudnic’s
Declaration (Ex. 2016). Tr. 70:19–71:20.2 Supernus cited column 7, lines
47–53 and Figures 2 and 3 of related U.S. Patent No. 8,206,740 (Ex. 1001);
paragraph 20 of Dr. Van Buskirk’s Second Declaration; paragraph 173 of
Dr. Rudnic’s Declaration; the definition of “delayed release” on page 7 of
Exhibit 2047; the definition of “delayed release” on page 30 of Exhibit
2058; the definition of “enteric coated” on page 32 of Exhibit 2058; and
passages from the transcript of Dr. Van Buskirk’s second deposition at page
11, line 7, to page 13, line 6 and at page 16, line 14, to page 17, line 2
(Ex. 2193). Tr. 80:11–81:20. Supernus also cited a passage from the
transcript of Dr. Van Buskirk’s first deposition in argument that indirectly
addresses construction of “delayed release.” Resp. 19 (citing Ex. 2015,
170:3–171:2).

2 Citations to the record given during oral argument were made with respect
to the record in case IPR2013-00368, which involves U.S. Patent
No. 8,206,740, of which the ’405 patent is a continuation. See Tr. 14:8–9;
Resp. 3. The citations here are adjusted as needed to refer to the same
material cited during the oral argument.
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Review of the evidence cited by the parties indicates their agreement,
as well as that of their experts, that Exhibit 2058 correctly defines “delayed
release” as “release of a drug at a time other than immediately following oral
administration.” Ex. 2058, 30;3 see Ex. 1066 ¶ 20 (citing Ex. 2058, 30);
Ex. 2016 ¶¶ 176 n.40, 178. The parties disagree, however, as to whether the
broadest reasonable construction of “delayed release” requires further that
there be no substantial release in the stomach.
Supernus argues that the delayed release formulations are described in
the ’405 patent as allowing “no substantial release of doxycycline in the
acidic stomach environment of approximately below pH 4.5.” Resp. 19
(citing Ex. 1007, 7:56–62); see also Obs. ¶ 1 (citing Ex. 2193 , 11:7–13:6,
16:14–17:2) (cross-examination testimony of Dr. Van Buskirk agreeing that
the above-quoted passage forms part of the identical disclosure in the related
’740 patent that Dr. Van Buskirk regards as defining “delayed release.”).
The cited passage of the ’405 patent is reproduced below:
With the enteric coated pellets, there is no
substantial release of doxycycline in the acidic
stomach environment of approximately below pH
4.5. The doxycycline becomes available when the
pH-sensitive layer dissolves at the greater pH of
the small intestine; after a certain delayed time; or
after the unit passes through the stomach. The
preferred delay time is in the range of two to six
hours.
Ex. 1007, 7:56–62.

3 Exhibit 2058 is a “Guidance for Industry” document issued by the Food
and Drug Administration in 1997 that concerns scale-up and post-approval
changes for modified release solid oral dosage forms. Ex. 2058, 1.
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Amneal argues that “delayed release” should be construed broadly
enough to include drug release after only a time lag and without respect to
whether release occurs in the stomach. Obs. Resp. ¶ 1; Tr. 11:5–11. In
particular, Amneal argues that the term “delayed release” encompasses
release that begins in the stomach. Id. at 11:7. Amneal cites paragraph 20
of Dr. Van Buskirk’s Second Declaration in support of this argument, as
well as paragraph 106 of Dr. Rudnic’s Declaration. Tr. 70:19–71:20 (citing
Ex. 1066 ¶¶ 19–20, Ex. 2016 ¶ 106). In paragraph 20 of his Second
Declaration, Dr. Van Buskirk cites the definition in Exhibit 2058 with favor.
Ex. 1066 ¶ 20. In paragraph 106 of his Declaration, Dr. Rudnic states that
Ashley ’854 defines a “delayed release agent” as one which “prevents the
active ingredient . . . from being made available to the host until some time
after initial administration.” Ex. 2016 ¶ 106 (citing Ex. 1003, 11:4–6).
Upon consideration of the parties’ arguments and cited evidence, we
agree with Amneal that the broadest reasonable construction of “delayed
release,” in light of the specification of the ’405 patent, is not limited to
formulations requiring that there be no substantial release in the stomach.
The portion of the ’405 patent specification upon which Supernus relies to
support its narrower construction addresses properties of “enteric coated
pellets,” not a delayed-release component. Ex. 1007, 7:56. The ’405 patent
discloses formats other than enteric coated pellets, such as an “uncoated
matrix tablet,” as being delayed-release components. Id. at 5:38–40
(“delayed-release portion can be . . . uncoated matrix tablet.”).
Consequently, properties of enteric coated pellets do not address the full
scope of “delayed release” as that term is used in the ’405 patent. We will
not read the limitations of an embodiment, even a preferred embodiment,
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into the construction of a claim term that is plainly used elsewhere in the
specification more broadly. In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir.
2004).
As Supernus concedes, Tr. 42:7–9, the ’405 patent does not provide
an express definition of “delayed release.” We turn, therefore, to other
evidence of how the term is understood and used by persons of ordinary skill
in the art. We find, upon consideration of this evidence, that the term
“delayed release” is used, more-or-less uniformly, to refer to formats that
allow for release of a drug only after some delay following oral
administration. See, e.g., Ex. 2058, 30 (quoted supra); Ex. 2047, 7 (defining
“delayed release” as “release of a drug (or drugs) at a time other than
promptly after administration”);4 Ex. 2016 ¶ 106 (citing definition of
“delayed release” in Ashley ’854, quoted supra, with approval). Those
definitions are consistent with one another, both parties and their experts cite
them with favor, and we discern nothing in the use of the term “delayed
release” in the ’405 patent specification that is inconsistent with those
definitions or more limiting than them. For these reasons, we determine that
the broadest reasonable construction of “delayed release,” consistent with
the ’405 patent, is “release of a drug at a time other than immediately
following oral administration.” See Ex. 2058, 30; Ex. 2047, 7; Ex. 1003,
11:4–6.

4 Exhibit 2047 is a report, of which Dr. Van Buskirk was a co-author,
entitled “Workshop II Report: Scaleup of Oral Extended Release Dosage
Forms” and published in the Journal of Pharmaceutical Science and
Technology in 1994. Ex. 2047, 2–3.
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B. Obviousness of claims 1, 2, 5–15, and 19–22 over Ashley ’932 and
Sheth
Amneal contends that claims 1–13 and 17–20 are unpatentable for
obviousness over Ashley ’932, as it incorporates Ashley ’854, and Sheth.
Pet. 20–29; Ex. 1022 ¶¶ 164–344.
1. Overview of Ashley ’932
Ashley ’932 discloses administering a tetracycline compound, e.g.,
doxycycline or minocycline, in sub-antibacterial doses to treat acne,
including acne rosacea. Ex. 1002, 5:17–20, 7:3, 7:24–25. Doxycycline is
administered in a sub-antibacterial total daily dose of about 30 to 60
milligrams, to give steady-state blood levels of about 0.1–0.8 µg/ml,
preferably 0.4–0.7 µg/ml. Id. at 9:17–20, 10:25–11:2. The composition
may take, e.g., tablet, capsule, or pill form, id. at 14:14–17, and may include
excipients, such as lactose. Id. at 14:30–31. Ashley ’932 discloses that
doxycycline may be administered by sustained release, such as 40 mg by
sustained release over a 24-hour period, and cites Ashley ’854 for further
description of the sustained release formulation. Id. at 15:23–16:2. Ashley
’932 incorporates by reference Ashley ’854 in its entirety. Id. at 15:30.5
Ashley ’854 discloses administering controlled-release compositions
of doxycycline to achieve a sub-antibacterial serum level of 0.4 to 0.8 µg/ml.
Ex. 1003, 5:15–22. The composition includes a controlled-release agent,

5 Ashley ’932 does not identify Ashley ’854 by serial number. Rather, it
identifies Ashley ’854 by title, filing date, and assignee. Ex. 1002, 15:28–
29. The parties dispute whether the incorporation-by-reference was
effective. Resp. 52–53; Reply 12–13. For purposes of this decision, we
assume, without deciding, that the incorporation was effective.
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which is an instantaneous-release agent, a sustained-release agent, a delayed-
release agent, or combinations of these. Id. at 5:24–26. A delayed-release
agent is defined as one that “prevents the active ingredient . . . from being
made available to the host until some time after initial administration.” Id. at
11:4–6.
2. Overview of Sheth
Sheth discloses a once-daily formulation of minocycline that provides
an antibacterial total daily dose. Ex. 1005, 6:27–32. The formulation
includes an initial loading component of quick-release pellets and a
secondary loading component of slow-release pellets. Id. at 3:48–52. The
quick-release pellets in the initial loading component optionally may be
coated with a polymer that does not interfere with immediate release of drug
from the initial loading component. Id. at 10:2–7. Hydroxypropyl
methylcellulose (HPMC), when adapted to dissolve completely in the typical
stomach pH of below 3.9, is a suitable coating for the initial loading
component. Id. at 3:16, 10:13, 10:21–22, 10:43–45.
The pellets of the secondary loading component are coated with a
mixture of at least two polymers, one that is pH-sensitive and one that is not
pH-sensitive. Id. at 4:67–5:5. The pH-insensitive polymer may be HPMC.
Id. at 14:12–14, 15:34–37. The pH-insensitive polymer dissolves rapidly in
water. Id. at 5:1–2, 12:58–59. Upon oral administration of the dose form,
the pH-insensitive polymer erodes and provides a slow release of
minocycline in the stomach, id. at 7:17, 10:59–60, 15:48–50, of preferably 5
to 20 or 20 to 50 percent of the minocycline it carries. Id. at 8:53–62.
Dissolution of the pH-sensitive polymer on the secondary loading portion is
inhibited but not precluded in the low pH of the stomach. Id. at 10:65–67.
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The pH-sensitive coating dissolves rapidly once the pellet passes to the
duodenum, where the pH is typically in the range of 4.0 to 7.5, thereby
causing rapid release of the rest of the minocycline in the secondary loading
portion. Id. at 10:60–65. The secondary loading portion thus provides
partly a release of minocycline in the stomach and partly a delayed release of
minocycline in the duodenum. Id. at 7:15–21, 7:33–35.
Sheth discloses that the ratio of initial loading component to coated
secondary loading component may vary from 51:49 to 80:20, with a
preferred range of 55:45 to 70:30. Id. at 6:10–13, 6:15–20, 18:24–26.
3. Analysis
Amneal argues that Ashley ’932 discloses all limitations of claim 1,
except for the requirement that 70 to 80 percent of the doxycycline be
formulated as an immediate release (IR) formulation and 20 to 30 percent of
the doxycycline be formulated as a delayed release (DR) formulation.
Pet. 20-24. Amneal argues that Sheth discloses formulations of minocycline
having a range of IR:DR ratios that encompasses 70:30 to 80:20. Id. 24-25;
Ex. 1022 ¶¶ 176-179. Although Amneal acknowledges that Sheth concerns
antibacterial-strength minocycline formulations, Amneal argues that one of
ordinary skill, developing sub-antibacterial doxycycline formulations, would
have looked to Sheth’s teachings, because the two drugs are members of the
tetracycline family, and have comparable structure, function, and utility, and
because minocycline was recognized as suitable for sub-antibacterial dosing.
Pet. 25 (citing Ex. 1022 ¶ 180). Amneal argues that it would have been
obvious to employ an IR:DR ratio range of 70:30 to 80:20 in Ashley ’932’s
formulation in light of Sheth’s disclosure. Pet. 25-27.
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Supernus argues, among other things, that Sheth does not disclose any
IR:DR formulations because Sheth fails to disclose a “delayed release”
format. Resp. 17–19. Supernus argues that the release provided by Sheth’s
secondary loading portion is more of a “modified sustained release” that
begins slowly but promptly in the stomach, followed by rapid release in the
intestine. Id. at 18–19 (citing Ex. 2016 ¶¶ 169–74). Dr. Rudnic opined, at
least partly on the basis of the disclosure in Sheth that the pH-insensitive
polymer dissolves rapidly in water, that drug release would begin from the
secondary loading portion “promptly” after oral administration. Ex. 2016 ¶
172 (citing, inter alia, Ex. 1005, 5:1–2). Supernus argues that Sheth’s
secondary loading portion thus does not fall within the scope of “delayed
release,” because part of the release occurs in the stomach promptly after
administration. Resp. 19.
Amneal argues, in reply, that even Dr. Rudnic agrees that there would
be a “lag” in the initial release of drug from the secondary loading portion.
Reply 7. Amneal cites the following exchange from the transcript of
Dr. Rudnic’s deposition:
Q. Would you agree with me that as a result of
the water soluble polymer there would be a delay
in the release of the drug?
. . .
A. Again, you’re over simplifying the question.
I think there would be some lag between when the
polymer hydrated and the drug diffused through,
but you wouldn’t consider that a delay. It’s not
designed to delay.
Id. (citing Ex. 1052, 247:20–248:5).
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We credit Dr. Rudnic’s declaration testimony that inclusion of a
water-soluble polymer in the coating of Sheth’s secondary loading portion
results in release of drug promptly after administration. See Ex. 2016 ¶ 172.
Amneal does not cite credible evidence to refute Dr. Rudnic’s testimony.
Although Dr. Rudnic conceded that there must be some lag while the
polymer hydrates, we further credit his testimony that this lag, essentially the
time required to wet the material, would not be considered a “delay.” See
Ex. 1052, 248:3–5. We agree with Dr. Rudnic that dissolution, however
rapid, necessarily requires some finite amount of time to allow interaction of
the solvent and the solute. See Ex. 1005, 5:1–2. Amneal does not explain
why we should not credit all of Dr. Rudnic’s testimony on this point.
Because we credit Dr. Rudnic’s testimony, we agree with Supernus
that Sheth’s secondary loading portion is not a “delayed release” portion. A
“delayed release” format, when that term is construed to mean “release of a
drug at a time other than immediately following oral administration,”
specifically excludes formats that result in release of drug starting
immediately after oral administration. To conclude otherwise would read
the phrase “delayed release” out of the claim. See In re Wilson, 424 F.2d
1382, 1385 (CCPA 1970) (all limitations of a claim must be considered
when considering patentability over prior art). Amneal has not explained
how there is any appreciable delay in the onset of drug release from the
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secondary loading portion once water in the patient’s saliva or gastric fluid
has begun to solubilize the pH-insensitive polymer in the coating.6
For this reason, we determine that Amneal has failed to show that
Sheth discloses a “delayed release” portion.
Amneal’s argument that Sheth discloses the claimed IR:DR ratio (or
makes the claimed ratio reachable through routine experimentation) thus
becomes untenable. Dr. Van Buskirk’s evidence concerning ratios in Sheth
is premised on an assumption that Sheth’s secondary loading portion is a
delayed release portion. See, e.g., Ex. 1022 ¶ 59 (“Additionally, the
secondary loading coated pellets (the DR component) described in the ’748
patent . . .”). That assumption is unwarranted, for the reasons given above.
Consequently, Sheth’s disclosure of ratios involving the secondary loading
portion does not constitute disclosure of ratios involving a delayed release
portion. Put another way, Amneal has failed to persuade us that the prior art
it cites for disclosure of IR:DR ratios actually discloses such ratios. Without
evidence that the claimed IR:DR ratio was known or could have been
reached through routine experimentation, Amneal’s challenge fails.
For the reasons discussed above, we conclude that Amneal has not
proved the unpatentability of claims 1–13 and 17–20 by a preponderance of
the evidence.

6 Amneal’s argument that Sheth uses the words “delayed release” to describe
the secondary loading portion, Reply 7 (citing Ex. 1005, 7:34–36), is
unpersuasive for similar reasons. Sheth uses those words to describe the
effect of the polymer in the coating blend that favors release in the intestine.
It does not account for the effects of the other coating polymer, which favors
release immediately after oral administration. See Ex. 1005, 7:14–41;
Resp. 17–18.
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III. MOTION TO EXCLUDE EVIDENCE
Amneal moves to exclude Supernus Exhibits 2028, 2029, 2032–2034,
2039, 2049, 2050, 2147, 2149–2154, and 2156. Pet. Motion to Exclude 1.
We dismiss Amneal’s motion as moot, because we do not rely on any
of the objected-to evidence in our final decision.
IV. CONCLUSION
Amneal has not proved, by a preponderance of the evidence, that
claims 1–13 and 17–20 of the ’405 patent are unpatentable for obviousness
over Ashley ’932 and Sheth.
V. ORDER
For the reasons given, it is
ORDERED that claims 1–13 and 17–20 of U.S. Patent No. 8,394,405
B2 are not determined to be unpatentable;
FURTHER ORDERED that Amneal’s Motion to Exclude Evidence is
dismissed as moot; and
FURTHER ORDERED that because this is a final 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.

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FOR PETITIONER:

Eldora L. Ellison
Ralph Powers
Jonathan Tuminaro
David Holman
H. Keeto Sabharwal
Paul Ainsworth
STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
eellison-PTAB@skgf.com
tpowers-PTAB@skgf.com
jtuminar-PTAB@skgf.com
dholman-PTAB@skgf.com
keetos-PTAB@skgf.com
painsworth@skgf.com

FOR PATENT OWNER:

Stephen B. Maebius
Sunit Talapatra
Andrew S. Baluch
FOLEY & LARDNER LLP
smaebius@foley.com
stalapatra@foley.com
WASH-Abaluch-PTAB@foley.com

Gregory Morris
Gerald Flattmann
Evan Diamond
PAUL HASTINGS LLP
gregorymorris@paulhastings.com
geraldflattmann@paulhastings.com
evandiamond@paulhastings.com